Wind-up of spinal cord neurones and pain sensation: much ado about something?

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1 Progress in Neurobiology 61 (2000) 169±203 Wind-up of spinal cord neurones and pain sensation: much ado about something? Juan F. Herrero*, Jennifer M.A. Laird, Jose A. Lopez-Garcia Departamento de FisiologõÂa, Edi cio de Medicina, Campus Universitario, Universidad de AlcalaÂ, Alcala de Henares, Madrid, Spain Received 6 August 1999 Abstract Wind-up is a frequency-dependent increase in the excitability of spinal cord neurones, evoked by electrical stimulation of a erent C- bres. Although it has been studied over the past thirty years, there are still uncertainties about its physiological meaning. Glutamate (NMDA) and tachykinin NK1 receptors are required to generate wind-up and therefore a positive modulation between these two receptor types has been suggested by some authors. However, most drugs capable of reducing the excitability of spinal cord neurones, including opioids and NSAIDs, can also reduce or even abolish wind-up. Thus, other theories involving synaptic e cacy, potassium channels, calcium channels, etc. have also been proposed for the generation of this phenomenon. Whatever the mechanisms involved in its generation, wind-up has been interpreted as a system for the ampli cation in the spinal cord of the nociceptive message that arrives from peripheral nociceptors connected to C- bres. This probably re ects the physiological system activated in the spinal cord after an intense or persistent barrage of a erent nociceptive impulses. On the other hand, wind-up, central sensitisation and hyperalgesia are not the same phenomena, although they may share common properties. Wind-up can be an important tool to study the processing of nociceptive information in the spinal cord, and the central e ects of drugs that modulate the nociceptive system. This paper reviews the physiological and pharmacological data on wind-up of spinal cord neurones, and the perceptual correlates of wind-up in human subjects, in the context of its possible relation to the triggering of hyperalgesic states, and also the multiple factors which contribute to the generation of wind-up. # 2000 Elsevier Science Ltd. All rights reserved. Contents 1. Introduction Recording techniques and characteristics of wind-up in di erent types of neurones and preparations Recording of wind-up in in-vivo preparations Intracellular recordings in vivo Wind-up of eld potentials Wind-up of spinal re exes Abbreviations: 5HT, Serotonin; ACPD,1RS, 3RS-cis1-aminocyclopentyl-1,3-dicarboxilate; AMPA, a-amino-3-hydroxy-5-methylisoxazole-4- propionic acid; AP5, 2-amino-5-phosphonopentanoate; BU-224, 2-(4,5-dihydroimidazol-2yl)-quinoline hydrochloride; CNS, Central nervous system; COX, Cyclooxygenase; CPP, (2)-2-carboxypiperazine-4-yl-propyl-1-phosphonic acid; DAG, Diacylglicerol; DCPP, 3((R)-2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid; DAG, Diacylglicerol; DNIC, Di use noxious inhibitory control; DRG, Dorsal root ganglia; DR-VRR, Dorsal root-ventral root re exes; EPSP, Excitatory postsynaptic potential; EMG, Electromyogram; GABA, Gamma-amino-butyric acid; IP3, inositol 1,4,5-triphosphate; IPSP, Inhibitory postsynaptic potential; ITH, Intrathecal; MCPG, (+)-a-methyl-4-carboxyphenylglycine; MGluR, Metabotropic glutamate receptor; NGF, Nerve growth factor; NMDA, N-methyl-D-aspartate; NSAIDs, Non-steroidal anti in ammatory drugs; PKC, Protein kinase C; SMU, Single motor unit; SP, Substance P; STT, Spinothalamic tract; TRH, Thyrotropic-releasing hormone; WDR, Wide dynamic range. * Corresponding author. Tel.: ; fax: address: (J.F. Herrero) /00/ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S (99)

2 170 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± Recording of wind-up in in-vitro preparations Parameters of electrical stimulation that generate wind-up Frequency dependence of wind-up generation Relationship between the properties of nociceptive a erent C- bres and the frequency dependence of wind-up Mechanisms involved in the generation of wind-up Introduction Neuronal networks that underlie wind-up Di erent types of dorsal horn neurone show di erent degrees of wind-up Time course of wind-up Wind-up and descending control Wind-up evoked by visceral a erents Pre-synaptic mechanisms Post-synaptic receptors and signal ampli cation during wind-up NMDA receptors Tachykinin receptors Contribution of membrane conductances to the generation of wind-up Plateau potentials and wind-up: role of calcium channels Are plateau-potentials involved in mammalian wind-up? Biophysical diversity among mammalian spinal cord neurones: neuronal excitability and potassium conductances Clustering of biophysical and pharmacological characteristics in wind-up neurones Summary and conclusions Pharmacology of wind-up Introduction Metabotropic glutamate receptors (MGluR) Non-steroidal anti-in ammatory drugs (NSAIDs) Opioids and nociceptin Local anaesthetics Alpha-2 adrenergic and imidazoline I2 receptors Serotonin Thyrotropin-releasing hormone (TRH) Galanin Wind-up in hyperalgesic states Wind-up and in ammation Wind-up and neuropathic pain Wind-up mediated by activation of large myelinated primary a erents (Ab- bres) Perceptual correlates of wind-up in human subjects Introduction E ect of experimentally-induced hyperalgesia E ect of morphine E ect of NMDA receptor antagonists The meaning of wind-up Wind-up as an ampli cation mechanism Wind-up as an electrophysiological correlate of central sensitisation Wind-up and secondary hyperalgesia General conclusions Acknowledgements References

3 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± Introduction Wind-up is a progressive, frequency-dependent facilitation of the responses of a neurone observed on the application of repetitive (usually electrical) stimuli of constant intensity (see Figs. 1±3). The phenomenon of wind-up was rst described by Lorne Mendell (Mendell and Wall, 1965; Mendell, 1996) as a frequency-dependent facilitation of spinal cord neuronal responses mediated by a erent C- bres. Mendell suggested that this phenomenon may be due to a reverberatory activity evoked by a erent C- bres in interneurones of the spinal cord lasting for 2±3 s. ``If in this period of time another stimulus arrives to the cord, it sums with the ongoing activity to produce a more intense discharge in the interneurones than the one before it'' (Mendell, 1996). More than thirty years Fig. 1. Wind-up of a class 2 (multireceptive) dorsal horn neurone recorded in the deep dorsal horn in an anaesthetised rat. The responses to 16 electrical stimuli delivered transcutaneously at a frequency of 1 Hz are shown. The upper panel (A) shows the data plotted as a "dot-raster" in which each dot represents a single action potential at a position corresponding to the latency after application of the stimulus (indicated by `S') on the x-axis, and stimulus number on the y-axis. Action potentials occurring within the rst 50 ms are likely due to activity in a erent A- bres (indicated by `A-volley'), and those occurring between 100 and 500 ms, due to activity in a erent C- bres (indicated as `C-volley'). The lower panel (B) shows the same data plotted as total number of action potentials in the A- bre and the C- bre evoked components of the response. Note the progressive increase in the long latency, C- bre evoked component, with repetitive stimulation, compared to the constant short-latency, A- bre evoked component. Unpublished data from our laboratory. after the rst description of this phenomenon, the mechanisms underlying the generation of wind-up are not fully established, and there is little consensus as to the role of wind-up in spinal cord physiology/pathophysiology, despite the hundreds of papers that have been published on this subject. In the past ten years or so, wind-up has been studied more intensively for two reasons. First, the discovery by two di erent groups (Davies and Lodge, 1987; Dickenson and Sullivan, 1987) that the blockade of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors inhibited the generation of windup. Second, the observation that there were prolonged increases in the excitability of dorsal horn neurones subsequent to the application of a wind-up evoking stimulus (Cervero et al., 1984; Cook et al., 1987). This led to the proposal (Cook et al., 1987; Dickenson, 1990) that there was a causal relationship between wind-up and the hyperexcitability of spinal cord nociceptive neurones observed after peripheral damage known as `central sensitisation' (Woolf, 1983b). These two factors were further linked by the observation that NMDA receptor antagonists inhibited both wind-up and central sensitisation in a nociceptive re ex preparation (Woolf and Thompson, 1991). These authors suggested that NMDA receptor-sensitive wind-up was a necessary prelude to the induction of central sensitisation. Thereafter, various authors have proposed that wind-up initiates and maintains central sensitisation, and that it could be used as an experimental model to study what happens in spinal cord neurones in situations of central sensitisation leading to hyperalgesia (Baranauskas and Nistri, 1998; McMahon et al., 1993; Price, 1996; Urban et al., 1994b). However, we now know that the excitatory amino acids are not the only family of neuromediators in the spinal cord involved in the generation of wind-up. Tachykinin receptor antagonists, opioids or even nonsteroidal anti in ammatory drugs (NSAIDs) with a central action also depress wind-up. On the other hand, the direct relationship between wind-up and hyperalgesia has been questioned in the past few years (Magerl et al., 1998; Woolf, 1996). It has become clear that hyperalgesia and central sensitisation can occur in the absence of wind-up (De Felipe et al., 1998; Laird et al., 1995; Woolf, 1996), and that wind-up and central sensitisation are separate phenomena, although they may share common mechanisms (Magerl et al., 1998; Li et al., 1999). It is therefore still unclear how wind-up is generated and whether or not wind-up has a physiological meaning. In the present review, we have tried to address these questions by examining the main lines of thought in the interpretation of wind-up, the charac-

4 172 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169±203 Fig. 2. Original illustration of the wind-up recorded in a single motor unit in an a-chloralose anaesthetised rat. Sixteen stimuli were applied in the most sensitive area of the cutaneous receptive eld of the unit. The number of spikes recorded after each of the stimuli increase progressively until reaching a saturation point at stimulus number 12. Note the gap between the early and late responses, presumably A- and C- bre mediated responses. teristics of wind-up in the di erent experimental preparations used, the involvement of di erent families of neuromediators in the generation and maintenance of wind-up, the new phenomenon of Ab- bre evoked wind-up, etc. in an attempt to present in a systematic way the current data on wind-up and to give our view as to what wind-up might represent in physiological terms. 2. Recording techniques and characteristics of wind-up in di erent types of neurones and preparations 2.1. Recording of wind-up in in-vivo preparations The rst description of wind-up was in a decerebrate-spinal preparation in vivo, recording from axons presumed to originate from spinocervical tract cells in the dorsolateral column of the cat spinal cord (Mendell and Wall, 1965; Mendell, 1996). In these studies it was established that wind-up required the activation of unmyelinated a erent bres (C- bres), with a minimum stimulation frequency of 0.3±0.5 Hz. These authors also determined that wind-up occurred in the spinal cord, rather than in the periphery. Subsequently, these features of wind-up were con- rmed in extracellular recordings from single dorsal horn neurones (Wagman and Price, 1969), and from identi ed spinothalamic tract (STT) cells (Chung et al., 1979) in anaesthetised primates. The characteristics of the spinal neurones that exhibit wind-up (Fig. 1) were rst studied systematically by Schouenborg and SjoÈ lund (1983) in the anaesthetised rat. Dorsal horn interneurones are usually classi ed according to their input properties. Schouenborg and SjoÈ lund (1983) used the classi cation of Iggo (1974) and Mene trey et al. (1977), in which neurones are classi ed on the basis on their response to mechanical stimulation of the skin. In this scheme, class 1 neurones are excited by non-noxious stimuli only, class 2 by both innocuous and noxious stimulation and class 3 by noxious stimuli only. Thus classes 1, 2 and 3 are roughly equivalent to low-threshold, multireceptive or wide dynamic range (WDR), and high threshold or nociceptor-speci c groups, respectively (see Cervero, 1985 for further discussion of the classi cation of dorsal horn neurones). Schouenborg and SjoÈ lund (1983) examined dorsal horn neurones with a C- bre input, and found that class 2 neurones showed the most pronounced wind-up (Fig. 1). Class 3 neurones did not show marked windup, as was also found for the small group of class 1 neurones with a C- bre input. Almost all of the studies of wind-up in dorsal horn neurones in vivo have concentrated on class 2 cells (wide-dynamic range) located in the deeper laminae. In their experiments, Schouenborg and SjoÈ lund (1983) also established that up to 16 stimuli were required to reach maximal discharge, but that with more than 16 stimuli, the windup process ceased, and a steady state was maintained,

5 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± important in determining whether or not they can generate wind-up Intracellular recordings in vivo There are relatively few studies of wind-up in vivo that have used intracellular recordings of spinal neurones, due to the greater technical di culties involved in obtaining su ciently stable recording conditions than those experienced in vitro. These di culties lead to a sampling problem, since larger neurones will almost inevitably be `selected' over small neurones. However, in the case of wind-up, this is less of a disadvantage, since the neurones that show most prominent wind-up are class 2 cells in the deeper laminae of the dorsal horn and these cells tend to be amongst the larger neurones in the dorsal horn. The rst intracellular study of wind-up in spinal dorsal horn cells described a slow, progressive depolarisation occurring during action potential wind-up (Price et al., 1971). More quantitative studies of wind-up in lamina V cells in the decerebrate-spinal rat (Woolf and King, 1987) and in identi ed spinothalamic tract cells in the monkey (Zhang et al., 1991) have reported a variety of e ects in di erent groups of neurones of repetitive electrical stimulation on action potential windup and membrane potential. These results are discussed in more detail in Section 4. Fig. 3. Original recordings of wind-up in the immature rat hemisected spinal cord preparation in vitro. The top trace (A) shows a ventral root record obtained with a tight suction electrode in response to a train of high intensity stimuli delivered to the dorsal root at 1 Hz. The electrical signal was ampli ed through a DC system to allow the study of slow components. (B) and (C): Intracellular recordings from two di erent motoneurones, showing responses to trains of stimuli as in (A). Note in (B) the action potential wind-up and the prolonged afterdischarge. In contrast the neurone in (C) showed only a cumulative depolarisation and no spike discharge. or a gradual decline in the number of spikes was observed. The after e ects of a period of electrical stimulation evoking wind-up were also observed to last for only 1±5 min. Wind-up of dorsal horn neurones recorded in vivo is thus observed in various species of experimental animal (cat, primate, rat), and in di erent types of preparations, including both decerebrate-spinal and anaesthetised animals. However, all of the studies quoted above used stimulation of a cutaneous or somatic mixed nerve to evoke wind-up. Viscerosomatic neurones in the thoracic spinal cord of the cat have been shown to exhibit wind-up to stimulation of a somatic a erent nerve, but not to stimulation of a visceral nerve (Alarcon and Cervero, 1990). Thus, the peripheral target of the a erent C- bres seems to be Wind-up of eld potentials The stimulation of a erent C- bres evokes a eld potential that can be recorded within the dorsal horn grey matter, with maximal intensity in lamina II and lamina V of the dorsal horn (Schouenborg, 1984; Liu and SandkuÈ hler, 1997). Schouenborg (1984) described wind-up of the C- bre eld potential located in the super cial dorsal horn, with similar frequency requirements to the wind-up in dorsal horn neurones, although in contrast to dorsal horn neurones, potentiation of the C- bre eld potential continues for up to 100 stimuli at 1 Hz. However, Liu and SandkuÈ hler (1997) failed to evoke wind-up of the C- bre eld potential in the super cial dorsal horn, perhaps due to di erences in the anaesthetic regime, although they did observe long term potentiation of the C- bre eld potential lasting several hours after the application of the wind-up stimulus. The C- bre potential located in the deep dorsal horn does not show wind-up (Schouenborg, 1984), which may be explained by the fact that the deeply located potential is polysynaptic, and is therefore less synchronous, and also that C- bre input to deep laminae is more heterogeneous and may evoke inhibitions in some neurones Wind-up of spinal re exes The recording of nociceptive withdrawal re exes has been used extensively in the study of the processing of

6 174 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169±203 nociceptive information in the spinal cord. One reason is that, compared to recordings from the spinal cord, this type of technique requires less preparative surgery and can be considered as more `physiological'. Windup is easily recorded in this type of preparation, from either the axons of motoneurones travelling in peripheral nerves (e.g. Schouenborg and SjoÈ lund, 1983; Woolf and Wall, 1986), or from the muscle itself as an electromyogram (e.g. Gozariu et al., 1997; Herrero and Headley, 1996; Solano and Herrero, 1997a). In some studies the activity of a group of motoneurones, or the activity of a whole muscle is recorded (e.g. Gozariu et al., 1997). In other studies the activity of a single motoneurone is recorded either by progressive splitting of the peripheral nerve, or by isolating single motor units within the muscle (e.g. Solano and Herrero, 1997a). Fig. 2 shows an example of wind-up in a single motor unit. The characteristics of wind-up in motoneurones of the spinal cord are similar to those observed in windup of dorsal horn neurones. However, it has some special properties as a consequence of a greater integration and of more intense modulation from supraspinal structures. Also, the activity recorded in nociceptive re exes is the result of the processing of a complete nociceptive pathway as a result of which the response is more homogeneous, since it re ects integration made at the spinal cord level after receiving a nociceptive input. Wind-up of spinal re exes was rst described in experiments in the cat (Price, 1972), and demonstrated to have similar frequency requirements as wind-up of dorsal horn neurones. Schouenborg and SjoÈ lund (1983) examined the wind-up of hindlimb re exes in the intact, anaesthetised rat, compared to the wind-up in di erent classes of dorsal horn neurone. In this study, electrical stimulation of the sural nerve evoked a re ex discharge in the common peroneal nerve whose magnitude was potentiated at frequencies higher than 0.3 Hz. The potentiation observed in the re ex responses after repetitive stimulation had similar characteristics to the wind-up observed in class 2 neurones recorded in the deep dorsal horn. Potentiation was seen only in the late response of the re ex (presumably mediated by the activation of C- bres) but not in the early response when stimulated at low intensity (mediated by A- bres). Schouenborg and SjoÈ lund (1983) also noted that re ex wind-up peaked after 8±10 stimuli at 1 Hz, earlier than the peak at 16 stimuli observed in dorsal horn neurones. This has been con rmed in other studies in intact preparations (e.g. Gozariu et al., 1997; Solano and Herrero, 1998). In contrast, studies in decerebrate spinal animals have observed that under these conditions, the wind-up of re exes shows a monotonic increase up to and beyond 16 stimuli (Woolf and Wall, 1986; Cook et al., 1986; Gozariu et al., 1997). Thus, the characteristics of wind-up in re exes are very dependent on the presence of anaesthesia, and on the integrity of the spinal cord. For further discussion of this point, see Section 4: descending control of wind-up. The pattern of wind-up observed in spinal cord nociceptive re exes can be di erent in di erent muscles, even in the same preparation. For example, Solano and Herrero (1997b) recording in intact, anaesthetised rats, observed a slow progressive wind-up in peroneus longus throughout the application of a train of 16 stimulus pulses at 1 Hz. In contrast, in extensor digitorum longus, the response was biphasic, with an initial phase in which wind-up was observed and a second phase in which there was a clear wind-down. The di erences noted in the e ectiveness of visceral and somatic C- bre stimulation in producing wind-up in dorsal horn neurones (Alarcon and Cervero, 1990), have also been con rmed in spinal re exes. In decerebrate and spinalised rabbits, wind-up was observed in somato-somatic re exes, evoked by the stimulation of skin and muscle a erents and recorded from the L1 spinal nerve, but not in viscero-somatic re exes, evoked by stimulating visceral a erents in the splanchnic nerve (Laird et al., 1995, see Section 4) Recording of wind-up in in-vitro preparations Recently in vitro techniques have been used to study the mechanisms and the modulation of wind-up. In vitro preparations have advantages and disadvantages with respect to in vivo techniques and the type of preparation used depends on the objective of the investigation. In vitro preparations o er a good experimental control of the external milieu and the administration of drugs at known concentrations. In these preparations the mechanical stability is good and allows for the use of intracellular and whole-cell recordings. The in vitro spinal cord slice preparation can be obtained from adult animals, usually rats, but transverse slices have to be prepared carefully to keep at least a few bres from a dorsal root. Some groups use longitudinal slices to make the dorsal roots more readily available, especially when targeting the super- cial layers of the dorsal horn with intracellular electrodes (e.g. Jeftinija and Urban, 1994). More often, a hemisected spinal cord preparation is used since it preserves dorsal and ventral roots and some of the ascending and descending pathways (Thompson et al., 1994; Thompson et al., 1995; Lopez-Garcia and Laird, 1998). Unfortunately, immature animals (generally under two weeks of age) have to be used for this preparation since they are more resistant to hypoxia. Fig. 3 shows examples of di erent recordings of wind-up in an isolated spinal cord from immature rats.

7 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± Intracellular techniques have been used successfully to record the responses of dorsal horn (Jeftinija and Urban, 1994) and ventral horn neurones including motoneurones (Thompson et al., 1990; Thompson et al., 1993b; Baranauskas et al., 1995; Baranauskas and Nistri, 1996) to the application of repetitive low frequency (0.5±2 Hz) and high intensity (C- bre strength) electrical stimulation of a dorsal root. With this kind of recording, spike counts can be obtained readily and hence the traditional action potential wind-up can be accurately measured. In addition, intracellular recordings reveal that a population of spinal neurones display a `subthreshold wind-up' which takes the form of a progressive cumulative depolarisation with no signi cant increase in spike counts. Subthreshold excitatory postsynaptic potential (EPSPs) are devoid of signalling value at the network level but it is conceivable that under appropriate conditions of excitability, cumulative depolarisation could be transformed into action potential wind-up. Cumulative depolarisations are usually quanti ed in terms of the amplitude at the end of a train of stimulus or of the rise rate in the amplitude between the rst and last responses to stimuli within the train. More recently, a simpler approach has been employed to study motoneuronal wind-up using extracellular recordings of whole ventral roots often with suction electrodes coupled to DC ampli ers (Thompson et al., 1994; Thompson et al., 1995; Lopez- Garcia and Laird, 1998; Hedo et al., 1999). In theory the ventral root response to electrical stimulation of the dorsal root should re ect the number of action potentials produced by the motoneuronal population averaged over time. In other words, synchronous ring in the population of motoneurones that send their axons through the recorded root will produce high amplitude peaks in these recordings, whereas asynchronous ring will generate a long duration and low amplitude wave. In practical terms the suction electrodes may pick up the subthreshold depolarisation of motoneurones and the separation between action potential wind-up and subthreshold wind-up may not be possible. Methods for the quanti cation of this cumulative depolarisation include measurements of the integrated area under the curve and the rate of rise of the depolarisation. 3. Parameters of electrical stimulation that generate wind-up 3.1. Frequency dependence of wind-up generation Wind-up is a frequency-dependent phenomenon that is triggered at a critical frequency of activation of a erent C- bres (Mendell, 1996). Below the critical frequency of 0.2±0.3 Hz wind-up is not observed, and above frequencies of 20 Hz the usual observation is a habituation of the response or wind-down (Schouenborg, 1984). The greatest wind-up is seen at frequencies around 1±2 Hz. This indicates that windup only occurs in narrow range of frequencies of stimulation, though the variation of other parameters may also a ect the induction of this phenomenon. In fact, the frequencies of stimulation used are not very di erent when comparing di erent studies in dorsal horn neurones, although the duration of the stimulus pulse and the intensity of stimulation used are variable: for example, 0.5 Hz, 2 ms pulse, three times threshold for C- bres (Stanfa et al., 1992; Stanfa et al., 1996), 0.5 Hz, 0.5 ms pulse at C- bre strength (Woolf, 1983a), 1 Hz, 1 ms pulse, two times threshold for C- bres (Traub, 1997), etc. In nociceptive re exes recorded in vivo in normal anaesthetised animals, wind-up is observed with a stimulation frequency between 0.5 and 3 Hz, (Schouenborg and SjoÈ lund, 1983; Gozariu et al., 1997). In a spinal cord preparation in vitro, wind-up of the dorsal root-ventral root re ex is observed at a frequency of 1±5 Hz (Thompson et al., 1994). However, the generation of wind-up is not only a frequency-dependent phenomenon, it also depends on the other parameters of stimulation being adequate to produce su cient activation of a erent C- bres. The generation of wind-up in nociceptive re exes recorded as single motor units depends on the frequency of stimulation but also on the duration of the pulses (Herrero and Cervero, 1996a; see Section 4). In these experiments, the generation of wind-up was observed at low frequencies of stimulation of 0.2 or 0.5 Hz if the duration of the pulses was 2 ms (Herrero and Cervero, 1996a), but not when using a lower pulse duration of 0.2 or 0.5 ms. The generation of wind-up in spinal cord nociceptive re exes is therefore not only dependent on the frequency of stimulation but also on the duration of the pulses used. Wind-up is therefore triggered by temporal summation of C- bre impulses and also by spatial summation of impulses arriving in the larger population of C- bres recruited by wider pulses (Herrero and Cervero, 1996a). Furthermore, an important parameter for the generation of wind-up is the previous level of excitability of spinal cord neurones. Accordingly, wind-up is generated at lower frequencies or pulse widths in situations of spinal cord hyperexcitability (see Section 6) Relationship between the properties of nociceptive a erent C- bres and the frequency dependence of windup As described in the previous section, wind-up is not observed at frequencies below about 0.2±0.3 Hz, is

8 176 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169±203 maximal around 1±2 Hz, and declines up to 20 Hz (Schouenborg, 1984). With increasing frequencies of stimulation, a erent C- bres show a progressive slowing in conduction velocity, resulting in conduction blockade with su ciently high frequencies. It has recently been shown that this slowing in conduction velocity is particularly marked in nociceptive C- bres, compared to those connected to other types of receptors, for example, cold receptors (Raymond et al., 1990; Gee et al., 1996; Serra et al., 1999). In rats, failure of impulse conduction has been observed in nociceptive C- bre a erents at frequencies around 10 Hz in the sciatic nerve (Raymond et al., 1990), and above 20 Hz in the saphenous nerve (Gee et al., 1996). These results explain why maximal wind-up occurs at around 1±2 Hz, since at higher frequencies, the number of impulses reaching the spinal cord will be lower. Recent work in human nerves shows that nociceptive C- bre a erents, especially those connected to mechanically insensitive (or `silent') nociceptors, are unable to follow frequencies above 1±2 Hz (Schmidt et al., 1992; Serra et al., 1999), suggesting that the frequencydependence of wind-up should be even more pronounced in humans. 4. Mechanisms involved in the generation of wind-up 4.1. Introduction A large number of studies have investigated the mechanisms which make possible or limit the generation of wind-up. Multiple factors may contribute to wind-up and di erent groups have focussed their studies in one direction or another. We have identi ed four major elds of interest: network factors, presynaptic mechanisms, post-synaptic receptors and post-synaptic membrane properties Neuronal networks that underlie wind-up Di erent types of dorsal horn neurone show di erent degrees of wind-up An investigation by Schouenborg and SjoÈ lund (1983) revealed that class 2 neurones recorded in the deep dorsal horn showed the most pronounced windup to stimulation of cutaneous a erent C- bres, of the order of 200%, whereas class 2 neurones recorded in the super cial dorsal horn also showed some wind-up, but to a lesser degree (44%). Class 3 neurones (mostly super cial, although 2/16 were recorded in the deep dorsal horn) did not show marked wind-up, as was also found for the small group of class 1 neurones with a C- bre input (Schouenborg and SjoÈ lund, 1983). Thus, the individual neurones most likely to show a pronounced wind-up are located in the deep dorsal horn, whereas class 2 and 3 neurones in super cial laminae show little or no wind-up (Schouenborg and SjoÈ lund, 1983). In contrast, the C- bre eld potential located in the super cial dorsal horn shows wind-up, whereas that located in the deep dorsal horn does not (Schouenborg, 1984). The lack of wind-up of the C- bre eld potential in the deep dorsal horn may be explained by the fact that this potential is polysynaptic, and is therefore less synchronous, and also that C- bre input to deep laminae is more heterogeneous and may evoke inhibitions in some neurones. The C- bre eld potential in the super cial dorsal horn is maximal in lamina II, and extends rostrocaudally in a position corresponding to the central cells of the substantia gelatinosa (Schouenborg, 1984). Central cells are unlikely to be typical class 2 or 3 neurones, but rather small neurones with on-going activity and which are inhibited by a erent input (`inverse' neurones; Molony et al., 1981, for review see Cervero and Iggo, 1980). Typical class 2 and 3 neurones recorded in the super cial dorsal horn are usually located not in lamina II, but rather in lamina I. This may account for the mismatch in the behaviour of individual neurones and for the unusual properties of the C- bre eld potential. Furthermore, in a preparation in vitro, where small neurones are more likely to be recorded successfully, Jeftinija and Urban (1994) found that 17% of super cial dorsal horn neurones produced action potential wind-up. However, Yoshimura (1996) has failed to nd wind-up in neurones in lamina II in experiments using whole cell patch technique in spinal cord slices in vitro. Further, according to his observations, very few lamina II neurones receive monosynaptic C- bre inputs. Thus, it is also possible that the C- bre eld potential in lamina II is generated largely by synapses of a erent C- bres on dendrites of neurones whose cell bodies are located outside lamina II Time course of wind-up The C- bre eld potential in the super cial dorsal horn shows wind-up which continues to increase during 70±100 stimuli at 1 Hz (Schouenborg, 1984), whereas the wind-up responses of dorsal horn neurones and nociceptive re exes do not increase after 16 or 8 stimuli, respectively (Schouenborg and SjoÈ lund, 1983). The reason for these di erences is not clear, since the experimental conditions were very similar in these two studies (halothane anaesthetised, paralysed rats with intact spinal cords), and the results in single neurones and in spinal re exes have been con rmed in numerous studies. One possibility is that an inhibitory mechanism counteracts the increase in responses after the rst few stimuli in dorsal horn neurones and spinal re exes and that this mechanism does not a ect the processes underlying the generation and wind-up of the C- bre

9 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± eld potential in the super cial dorsal horn. A candidate for such an inhibitory mechanism has recently been described by Le Bars and colleagues (Gozariu et al., 1997), and has been shown to be supraspinally mediated (see Section 4.2.3). There is considerable evidence that neurones in the super cial dorsal horn receive less descending control from supraspinal structures than neurones more deeply located in the spinal cord (e.g. Cervero et al., 1976; Cervero et al., 1979; Laird and Cervero, 1990), which may explain why the C- bre eld potential in the super cial dorsal horn is not a ected by this inhibition. Another possible source of inhibition could be a superimposed post-tetanic depression of neuronal ring, as has been described by Woolf (1983a). The dorsal horn neurones which show the most pronounced wind-up (class 2 neurones located in the deep dorsal horn) and spinal re exes are unlikely to receive a mono-synaptic C- bre input, whereas the C- bre eld potential located in the super cial dorsal horn is likely primarily due to the synapses between a erent C- bres and the second order neurones (Schouenborg, 1984). This suggests that there are greater possibilities for inhibitory control of the wind-up of deep dorsal horn neurones than of the C- bre eld potential located in the super cial dorsal horn Wind-up and descending control The phenomenon of wind-up, like many other properties of spinal cord neurones, is modulated by supraspinal structures. Reversible spinalisation induces a signi cant enhancement of dorsal horn neurone excitability and of wind-up, whereas electrical stimulation of the dorsal columns reduces wind-up (Hillman and Wall, 1969). Gozariu and colleagues (1997) have studied these phenomena in detail in the C- breevoked re exes recorded as electromyogram (EMG) from the biceps femoris muscle in intact, anaesthetised animals. In these experiments, a typical biphasic curve was observed with a progressive increase of responses during the rst seven stimuli followed by a short plateau and a decrease of responses. However, after a transection at the level of the obex or in decerebratespinalised preparations (without anaesthesia), the C- bre re ex increased continuously from one stimulus to the next during the whole period of stimulation, and the response curve became monophasic (Gozariu et al., 1997). It seems therefore that the habituation observed in intact animals in these experiments was a consequence of either supraspinal descending in uences and/or an e ect of anaesthesia. Transection of the spinal cord may also have the opposite e ect on wind-up. In experiments in which single motor units were recorded in anaesthetised rats, wind-up facilitation and a novel A- bre mediated wind-up evoked in arthritic animals were only observed in intact, but not spinalised preparations (Herrero and Cervero, 1996b; see Fig. 4). Therefore, under these conditions, the enhancement of the re ex wind-up observed during hyperalgesia, required an intact spinal cord (Herrero and Cervero, 1996b; but see also Section 6.3), and might be explained as the consequence of a direct descending excitatory in uence on spinal cord neurones (Cervero and Wolstencroft, 1984). Wind-up can also be modulated supraspinally by other nociceptive messages. When wind-up was induced in deep dorsal horn class 2 neurones, it was signi cantly reduced by applying a remote noxious mechanical stimulation to the nose of the rat (Schouenborg and Dickenson, 1985), showing that wind-up is also a ected by di use noxious inhibitory controls (DNIC, Le Bars et al., 1979a; Le Bars et al., 1979b). Interestingly, the time-course of the wind-up, or shape of the stimulus-response curve, did not change much, but the C- bre discharge was decreased by a constant number of spikes in each of the stimuli. This e ect was independent of the level of neuronal activity (Schouenborg and Dickenson, 1985). A similar situation was observed in the wind-up of withdrawal re exes, when recording activity in the common peroneal nerve evoked by sural nerve stimulation (Schouenborg and Dickenson, 1985) Wind-up evoked by visceral a erents Viscero-somatic neurones in the spinal cord have been shown to exhibit wind-up to their somatic a erent inputs, but not to their visceral inputs (Alarcon and Cervero, 1990). Furthermore, motoneurones inner- Fig. 4. C- bre mediated wind-up in single motor unit recordings in the presence of in ammation. The experiments were performed in rats with monoarthritis induced by the intraarticular injection of carrageenan into the knee. The skin of the paw was stimulated electrically at 1 Hz, 2 ms wide pulses, at an intensity su cient to recruit a long latency response, in intact and spinalised animals. The wind-up and ring rate was much higher in intact animals than that in the group of spinalised animals (modi ed from Herrero and Cervero, 1996b).

10 178 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169±203 vating the muscles of the trunk (recorded from the L1 or L2 spinal nerves) do not show wind-up to stimulation of the splanchnic nerve (which carries a erents from the upper abdominal viscera), whereas they show a pronounced wind-up to stimulation of somatic a erents running in the T13 or L1 nerve (Laird et al., 1995, Fig. 5). These data indicate that these are fundamental di erences in the post-synaptic e ects of C- bre stimulation depending on whether the bres innervate somatic or visceral structures Pre-synaptic mechanisms Schouenborg (1984) has proposed that wind-up is due to an increase in synaptic e cacy via a phenomenon similar to that of post-tetanic potentiation. Posttetanic potentiation describes the increase in the magnitude of a post-synaptic response, for example, muscle contraction, immediately after a train of conditioning stimuli, compared to the magnitude of the response prior to conditioning. Systems that show post-tetanic potentiation can also show a facilitation of the responses during the train of conditioning stimuli. Posttetanic potentiation declines exponentially over time, and the time constant of this decline increases when the number of conditioning stimuli is increased (Magleby and Zengel, 1975), as has been shown for the wind-up of the C- bre eld potential in the rat spinal cord (Schouenborg, 1984). Post-tetanic potentiation has been studied, in detail, in the neuromuscular junction (e.g. Magleby and Zengel, 1975), but is Fig. 5. Comparison of wind-up of a nociceptive spinal re ex evoked by stimulation of somatic or visceral primary a erent bres in a decerebrate-spinal rabbit preparation. The data shown was taken from an individual experiment. The re ex was evoked by electrical stimulation at an intensity supramaximal for C- bres in a somatic nerve, the L2 spinal nerve, and a visceral nerve, the splanchnic nerve. The response was recorded from the L1 spinal nerve. The data is depicted as number of spikes in the long latency (C- bre evoked) component of the response evoked by the application of a train of 16 stimuli at 1 Hz to the somatic (open circles) and then 5 min later to the visceral nerve (closed circles). Data taken from Laird et al. (1995). also observed at central synapses (Hughes, 1958), for example those between Ia a erents and motoneurones in the spinal cord (Hirst et al., 1981). It is due to a build-up of intracellular free calcium within the terminal endings with repeated depolarisations, resulting in an increase in the number of transmitter vesicles (quanta) released by subsequent incoming action potentials (Erulkar and Rahamimo, 1978). The similarities between the mechanisms of wind-up and those of post-tetanic potentiation suggest that these mechanisms are pre- synaptic and act to increase the release of transmitter from primary a erents. It is well established that wind-up is induced only by primary a erent C- bres under normal circumstances (see Section 6). C- bres are known to release small molecule transmitters, such as glutamate, and also a variety of peptide neurotransmitters such as substance P (SP). The small molecule transmitters are concentrated in small clear vesicles, whereas neuropeptides are stored in large, dense core vesicles (Fried et al., 1989). Increases in vesicle release induced by potentiation mechanisms may, in theory, a ect preferentially one type of vesicle or the other, particularly since there is evidence that the release mechanisms for the two types of vesicles in the spinal cord are di erent (Suzuki et al., 1998).Therefore, if wind-up is due to an increase in transmitter release, this increase could be either of small molecule transmitters, of neuropeptides, or of both, since the two types of transmitter are stored and released separately. In several systems, there is evidence that co-existing peptides and small molecule transmitters require di erent frequencies for their optimal release, with higher frequencies being required for peptides. This data would appear to be at odds with the idea that facilitation of the release of neuropeptides from C- bres could underlie wind-up, which is maximal at relatively low frequencies (see Section 3). However, high frequencies do not seem to be required for the maximal release of peptides from primary a erent C- bres. In the periphery, antidromic vasodilatation is maximal at frequencies similar to those that produce wind-up, (i.e. 1±4 Hz; Lynn et al., 1992). At the central terminals, the release of SP, which is a strong candidate for involvement in wind-up (see Section 5), has been shown to be maximal at the same low frequencies (Duggan et al., 1995). Detailed study of the e ect of interstimulus interval on the release of SP in the dorsal horn of the spinal cord (Duggan et al., 1995) shows that conditioning stimuli potentiate its release. Furthermore, the facilitation observed with trains of 3 stimuli at di erent frequencies lasts more than 1.5 s, but less than 6 s (Duggan et al., 1995), which corresponds to the frequency dependence of wind-up (6 s interstimulus interval is equivalent to 0.17 Hz, whereas 1.5 s is equivalent to 0.6 Hz). Therefore, it seems possible that a pre-synaptic mechanism invol-

11 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± ving the facilitation of SP release via a post-tetanic potentiation-like mechanism could contribute to wind-up (see Fig. 6). Much less is known about the characteristics of the release of small molecule transmitters such as glutamate from primary a erent C- bres, but in principle a similar mechanism could also apply Post-synaptic receptors and signal ampli cation during wind-up NMDA receptors The rst pharmacological inhibition of wind-up was achieved with NMDA receptor antagonists such as ketamine or 2-amino- 5-phosphonopentanoate, d-ap5, (Davies and Lodge, 1987; Dickenson and Sullivan, 1987), thus suggesting that the NMDA receptor was intimately involved in the mechanisms of wind-up. In these experiments, most of the class 2 or wide dynamic range neurones tested (located in deep dorsal horn) showed wind-up when stimulated at low frequencies, using C- bre intensity electrical stimuli. Ketamine or d-ap5 and the non-selective excitatory amino acid receptor antagonist, kynureic acid, reduced signi cantly or abolished wind-up. An example of the e ect of ketamine on wind-up is shown in Fig. 7. NMDA receptors have also been implicated in wind-up of the hamstring exor motoneurones during stimulation of the sural nerve at C- bre strength. In this case, the systemic administration of a competitive 3 ((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (D-CPP) and a non-competitive NMDA receptor antagonist (dizocipline) prevented the induction of wind-up after repetitive stimulation (Woolf and Thompson, 1991). Although there is little doubt about the involvement of NMDA receptors in wind-up in normal animals, they do not seem to be important under other circumstances, such as after peripheral nerve section. In this case, the NMDA receptor antagonist dizocipline failed to induce any modi cation of wind-up or post-stimulation facilitation in animals with a chronic section of the sciatic nerve (Xu et al., 1995). The original model to explain the contribution of NMDA receptors to wind-up depends on the blockade of the NMDA receptor channel by extracellular mag- Fig. 6. Possible molecular mechanisms for the generation of wind-up. The diagram summarises the mechanisms that may elicit wind up. It represents a standard spinal neurone receiving monosynaptic input from mechanoreceptors and polysynaptic input from nociceptors as may occur in many deep dorsal and ventral horn neurones. Mechanisms are numbered from 1 to 7. Build-up of Ca 2+ in the presynaptic terminal (1) leads to increased neurotransmitter release of, (2) amino acids and substance P. Activation of AMPA receptors in the postsynaptic membrane causes fast membrane depolarisation which contributes to lifting the Mg 2+ block of NMDA receptors (3). Activation of NMDA receptors and NK1 receptors generates a long-lasting cumulative depolarisation (4). Cytosolic Ca 2+ concentration increases due to Ca 2+ entry through the NMDA ionophore, and to a lesser extent through some AMPA receptor channels and through voltage-sensitive Ca 2+ channels activated by depolarisation. Elevated Ca 2+ concentration (5) and (6) the activation of NK1 receptors via second messenger systems enhances the performance of NMDA receptors. (7) Finally, activation of NK1 receptors, cumulative depolarisations, elevated cytosolic Ca 2+ and other factors regulate the behaviour of membrane channels that facilitate the production of action potentials and lead to wind-up.

12 180 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169±203 Fig. 7. E ect of the NMDA receptor antagonist, ketamine, on windup of a nociceptive spinal re ex in decerebrate-spinal rabbits (n = 7). The wind-up was evoked by electrically stimulating the L2 spinal nerve at an intensity supramaximal for C- bres at a frequency of 1 Hz. The re ex response was recorded from the L1 spinal nerve. The number of spikes in the long latency (C- bre evoked) component of the response was counted. The results are shown as the mean of the percentage of the maximal individual response evoked by a single stimulus in each individual experiment (2sem). Ketamine was administered i.v. in sequential doses at 15 min intervals. Data taken from Laird et al. (1995). nesium ions at resting membrane potential (Nowak et al., 1984; Dickenson, 1990; Dickenson et al., 1997). The basic interpretation is that input in a erent C- bres is su ciently intense to depolarise the cell membrane via the activation of a-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) receptors and thus relieve the Mg 2+ block, thereby allowing the NMDA receptor to be co-activated by glutamate release. This model, based on extracellular observations, assumes that the activation of the NMDA receptor produces a cumulative depolarisation that underlies wind-up. It should be noted that cumulative depolarisations are very often observed without wind-up (see below) and that action potential wind-up can occur without a noticeable cumulative depolarisation as appears to be the case of spinothalamic tract neurones recorded from macaque monkeys (Zhang et al., 1991), some lamina V neurones of the rat (Woolf and King, 1987) and turtle spinal neurones (see Section 4.5.1). In addition, a mathematical model based on the removal of the Mg 2+ block fails to reproduce the same time course of cumulative depolarisation that often takes place during wind-up (Britton et al., 1996) although this could be due to the assumptions made in this model about the circuitry driving dorsal horn neurones. Thompson et al. (1990) using intracellular recordings in the hemisected cord in vitro found that a proportion of rat ventral horn neurones close to 50% responded with long-lasting EPSPs to single dorsal root electrical stimuli at C- bre strength. This long lasting depolarisation was partially blocked by d-ap5 indicating the involvement of NMDA receptors but not excluding the intervention of other transmitters. An interesting nding reported in this paper is that a majority of neurones displaying long lasting responses to single stimulus showed a cumulative depolarisation to repetitive stimulation although not all of them show action potential wind up. The authors focused their attention on explaining the mechanisms underlying the cumulative depolarisation but did not address the reasons why some neurones translated their depolarisations into spiking activity and other did not. During repetitive stimulation each stimulus would nd the cell at a more depolarised membrane potential and this, the authors hypothesise, may contribute to the removal of the Mg 2+ block from the NMDA receptors. The progressive release of the Mg 2+ block would act as an ampli- er mechanism boosting summation of EPSPs and hence multiplying subsequent a erent input. In this context Chen and Huang (1992) have proposed a secondary ampli cation mechanism dependent upon Ca 2+ entry via the NMDA ionophore or other Ca 2+ channels during depolarisation (see Fig. 6). An increase in intracellular Ca 2+ would activate protein kinase C (PKC) and this, in turn, would increase further the e cacy of NMDA receptors by increasing the probability of channel opening and by reducing the voltage-dependency of the Mg 2+ block of the receptor. A similar picture emerges from the work of Jeftinija and Urban (1994) who carried out using rat super cial dorsal horn neurones studied in in vitro slices of the lumbar spinal cord. They found no di erences in membrane potential and input resistance between the neurones that developed action potential wind-up (17% of the total) and those that did not. These authors found that some neurones that developed wind up showed a compound excitatory postsynaptic potential±inhibitory postsynaptic potential (EPSP±IPSP) complex in response to single stimuli and that the inhibitory potential diminished during repetitive stimulation concluding that in some cases the facilitation of excitatory transmission could have been the result of disinhibition. However, they also observed a small proportion of neurones that developed cumulative hyperpolarisation to repetitive stimuli. These authors demonstrated, in addition, that the wind up produced in super cial dorsal horn neurones by repetitive stimulation of the fth lumbar dorsal root did not potentiate responses to stimulation of the adjacent fourth lumbar dorsal root. This favours the involvement of a homosynaptic mechanism and suggests that wind up in the super cial layers of the dorsal horn could be governed by a presyn-

13 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± aptic mechanism, whereas in deeper neurones other mechanisms may be involved (Thompson et al., 1993b). Blockade of wind up by NMDA receptor antagonists is only partial, both in vitro (Thompson et al., 1990; Jeftinija and Urban, 1994), and in vivo (Davies and Lodge, 1987; Dickenson and Sullivan, 1987), and in fact NMDA receptor antagonists also reduce the amplitude and duration of responses to single stimuli. D-AP5 reduces the long latency components of EPSPs recorded from dorsal horn neurones (King et al., 1992), single motoneurones (Baranauskas et al., 1995) and motoneuronal populations (Thompson et al., 1994) to electrical stimulation of dorsal roots so that in the cumulative response to a train of stimulus each elementary response is reduced but a certain degree of accumulation remains (Baranauskas and Nistri, 1996). On the basis of this partial blockade it was suggested that perhaps other modulators such as peptides contributed to the long latency responses to single stimulus and to the accumulation observed during wind up (Thompson et al., 1990) Tachykinin receptors Substance P, a member of the tachykinin family of peptide neurotransmitters, has been proposed for some time to be involved in wind-up (Urban and Randic, 1984; Akagi et al., 1985; Kellstein et al., 1990), on the grounds that wind-up is due to summation of slow potentials (Price et al., 1971), and that SP is known to produce such slow potentials in vitro. Furthermore, tachykinin receptor antagonists inhibit the slow potentials evoked by dorsal root stimulation (e.g. Urban and Randic, 1984). The NK1 receptor is a member of the family of tachykinin receptors, for which the highest a nity endogenous ligand is substance P. The advent of NK1 receptor-speci c non-peptide antagonists (Snider et al., 1991; Garret et al., 1991) allowed easier testing of this hypothesis. Wiesenfeld± Hallin and colleagues (Xu et al., 1992) showed that the rst non-peptide NK1 receptor antagonist to be described, CP-96,345 (Snider et al., 1991), reduced the wind-up of spinal re exes in a rat preparation in vivo, although only the saturated component of the response was reduced (stimuli 15±20). However, another of the rst generation of NK1 receptor antagonist, RP (Garret et al., 1991) reduced wind-up in rat dorsal horn neurones after intrathecal (ITH) administration (Chapman and Dickenson, 1993), and in rat single motor units after systemic administration (Laird et al., 1993), but these e ects were not enantioselective, that is, similar e ects were also produced by the inactive enantiomer of RP 67580, which has very low a nity for the NK1 receptor, and thus the results could not be ascribed to blockade of the NK1 receptor. Similarly, in isolated spinal cord preparations taken from normal rats and maintained in vitro, neither CP-96,345 nor RP were e ective in reducing the temporal summation of the ventral root potential (Thompson et al., 1993a), nor the rate of rise of intracellularly recorded potentials (Baranauskas and Nistri, 1995). These rst generation non-peptide NK1 receptor antagonists were, however, e ective in in vitro preparations taken from animals with in ammatory hyperalgesia (Thompson et al., 1994; Thompson et al., 1995), and in normal animals in co-operation with NMDA receptor antagonists both in vitro (Thompson et al., 1993a) and in vivo (Xu et al., 1992). This observation led to the hypothesis that this was an interaction between NMDA and NK1 receptors (Urban et al., 1994a; Urban et al., 1994b) especially during hyperalgesic states. According to the model proposed, the activation of a G-protein coupled to the NK receptor would induce the production of diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) that, in turn, would activate PKC. PKC would produce a phosphorylation of the NMDA receptor that sets Mg 2+ free from the receptor channel (Chen and Huang, 1992) allowing the movements of ions through it, especially Ca 2+. The entrance of Ca 2+ in the cell would enhance further the activation of PKC. The observation that SP enhances the responses of motoneuronal pools and dorsal horn neurones to NMDA (Rusin et al., 1993; Urban et al., 1994a; Urban et al., 1994b) and that SP modulates the responses of spinothalamic neurones to glutamate (Willcockson et al., 1984; Dougherty et al., 1992) in non-in amed animals suggest that some form of interaction between NK1 and NMDA receptors may be applicable in normal animals as well. However, it is likely that the negative ndings with the rst generation of non-peptide antagonists (CP- 96,345 and RP 67580) were due to the high a nity for L-type Ca 2+ channels exhibited by these compounds, which obscured the e ects of NK1 receptor blockade (Schmidt et al., 1992; Rupniak et al., 1993). Experiments with more recently developed NK1 receptor antagonists, which have much lower a nities for ion channels, have shown enantioselective inhibition of wind-up in normal animals in vivo (Boyce et al., 1993; Budai and Larson, 1996), and a reduction in the rate of rise of cumulative depolarisations observed in intracellular recordings from spinal motoneurones in vitro on repetitive a erent stimulation (Baranauskas et al., 1995). The latter authors estimate that 33% of the rate of rise of membrane potential underlying wind-up is due to NK1 receptor activation and hypothesise that SP, the preferred endogenous ligand for NK1 receptors, could be released from interneurones of the polysynaptic spinal relay contributing to the increase in the rate of rise of motoneuronal wind up. Recent data also suggests that NK1 receptors may modulate L-

14 182 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169±203 type calcium channels and thus the plateau potentials observed in intracellular recordings of dorsal horn neurones, which have been proposed to underlie windup (Russo et al., 1997, see Section 4.5). Thus the available evidence from experiments using antagonists suggests that NK1 receptors do play a role in wind-up, even in normal animals, and that this e ect can be seen without the need to `unmask' the response by blocking NMDA receptors. Furthermore, convincing evidence for an important role of NK1 receptors in wind-up comes from studies in genetically manipulated mice in which the NK1 receptor gene has been disrupted (NK1 knockout mice; De Felipe et al., 1998, Fig. 8). In these experiments, hindpaw withdrawal re ex responses to trains of electrical stimuli at various intensities were compared in anaesthetised mice. NK1 knockout mice did not show wind-up of the re ex response, whereas the wild-type control mice showed marked wind-up under the same conditions (Fig. 8, De Felipe et al., 1998). Therefore, the available evidence shows that activity at NK1 receptors is necessary for the expression of wind-up. Two other peptides, neurokinin A and neurokinin B, form the tachykinin family of peptides along with SP. These two peptides are the preferential endogenous ligands for the NK2 and NK3 receptors, respectively. In contrast to the important role of NK1 receptors in wind-up, NK2 receptors are apparently not involved in wind-up either in normal animals or after in ammation. Studies of spinal cord re exes both in vivo (Xu et al., 1991), and in vitro (Thompson et al., 1993a; Thompson et al., 1994) show that application of the selective NK2 receptor antagonist, MEN directly to the spinal cord failed to a ect wind-up. Other re ex parameters were dose-dependently reduced by MEN in these experiments, showing that the Fig. 8. Wind-up of withdrawal re exes (EMG) recorded from a hindlimb muscle in anaesthetised mice. The left panel (A) shows the wind-up observed in normal (wild- type) mice when using two times (solid symbols) or four times (open symbols) the threshold intensity for the recruitment of a long latency response. The right panel (B) shows the same experimental protocol applied to NK1 receptor knockout mice (modi ed from De Felipe et al., 1998). lack of e ect was not due to poor penetration of the compound into the spinal cord. As far as we are aware, there have been no studies as yet on the possible role of NK3 receptors in windup, undoubtedly because selective NK3 receptor antagonists have only recently become available Contribution of membrane conductances to the generation of wind-up Plateau potentials and wind-up: role of calcium channels A model of particular relevance that illustrates the important role that a single conductance may play in the expression of wind-up emerges from the work of Hounsgaard's group in Denmark. This model has been entirely developed on the basis of work in the dorsal horn of turtles using in vitro techniques and intracellular recordings (Russo and Hounsgaard, 1994; Russo and Hounsgaard, 1996). A proportion of turtle deep dorsal horn neurones show classical action potential wind-up in response to low frequency (down to 0.1± 0.3 Hz) high intensity dorsal root stimulation as occurs in mammals (see Fig. 9). These authors have observed that under their experimental conditions some neurones generate plateau potentials to long duration depolarising current pulses that, in turn, cause an increase in ring frequency as the depolarising pulse progresses in time as well as after discharges that outlast the duration of the pulse. Plateau potentials and increased ring also develop when these neurones are intracellularly stimulated with short duration repetitive depolarising pulses. Thus wind-up like responses can be obtained without stimulating a erent pathways, relying exclusively on the properties of the membrane. Plateau potentials are blocked by the L-type Ca 2+ channel blocker nifedipine (Fig. 9), and by the substitution of extracellular Ca 2+ with Co 2+ or Mn 2+. They are facilitated by the L- type Ca 2+ channel opener BayK indicating that an L- type Ca 2+ conductance is responsible for generating this potential. The L-type calcium channels have been found in a variety of tissues. In chroma n cells the facilitatory mechanism by which repetitive depolarising pulses enhance the amount of current carried by these channels seems to involve both an increase in opening times and the probability of opening (Hoshi and Smith, 1987). Hounsgaard's group has produced convincing evidence showing the interrelation between the generation of plateau potentials and wind-up in the turtle dorsal horn. Nifedipine, which blocks L-type calcium channels, depresses wind-up whereas, BayK8644, which facilitates these channels, increases wind-up. What makes this model even more interesting is the fact that some of the major transmitters with an established role in spinal processing of sensory input such

15 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± Fig. 9. E ect of nifedipine on the generation of wind-up. Intracellular recordings in A and B were obtained from the same dorsal horn neurone in a slice preparation of the turtle spinal cord. A shows the response to a train of stimuli delivered to the dorsal root (a) and the responses to brief depolarising current pulses (b). Note the action potential wind-up induced by both kinds of stimuli. In B the same stimulation sequence is presented during superfusion with nifedipine (50 mm) which prevents action potential wind-up. (modi ed from Russo and Hounsgaard, 1994). as gamma-amino-butyric acid (GABA), glycine, glutamate and substance P can modulate directly and indirectly the L- type Ca 2+ current (Russo et al., 1997; Russo et al., 1998). Baclofen, an agonist of the metabotropic GABA B receptor that reduces wind-up, also reduces plateau potentials and the underlying L-type current via a direct action on the postsynaptic neurone. This direct action is further ampli ed by hyperpolarisation of the postsynaptic neurone increasing the threshold for plateau potential generation. On the other hand, 1RS, 3RS-cis-1-aminocyclopentyl-1,3- dicarboxilate (ACPD), an agonist of metabotropic glutamate receptors, and SP, via the NK1 receptor, have opposite actions to that of baclofen, that is, both promote wind-up and facilitate the passage of calcium through L-type channels and both depolarise the membrane lowering the threshold for plateau potential generation. In addition, it has been shown that this type of plateau potentials are modulated by serotonergic, cholinergic and glutamatergic receptors activated by transmitters released from descending pathways (Delgado-Lezama et al., 1997) providing a possible mechanism by which descending control may modulate wind-up via actions on speci c conductances Are plateau-potentials involved in mammalian wind-up? Despite the great appeal of this model, the structure of the turtle dorsal horn is simpler than that of mammals and, in addition, the involvement of L-type Ca 2+ currents and plateau-potentials in the generation of wind-up in the mammalian spinal cord has not been investigated in depth. Hence, a rm answer to this question is not possible. The L-type Ca 2+ channels seem to be present in the rat spinal cord. High threshold Ca 2+ currents sensitive to dihydropyridines with a slow inactivation time course similar to those described in turtles, have been described in the rat dorsal horn (Huang, 1989; Murase and Randic, 1983; Ryu and Randic, 1990) and in a proportion of neurones this current was enhanced by substance P and neurokinin A (Murase et al., 1986; Murase et al., 1989). Furthermore, in cervical lamina V neurones of the rat, plateau potentials have been reported which are sensitive to nifedipine and closely resemble the properties of those described in the turtle (Moriset and Nagy, 1996). Also a small percentage (10%) of lumbar dorsal horn neurones have been found to increase gradually their spike frequency during long lasting (3 s) depolarising pulses (Jiang et al., 1995). All this experimental evidence makes the plateau-potential model a viable possibility in the rat dorsal horn but unfortunately none of the studies mentioned have established a clear relation between plateau-potentials and wind-up as has been done in turtles. For the purpose of this review, we have tested the e ects of nifedipine on the wind-up observed in the neonatal rat hemisected cord in vitro (n = 4). We used extracellular recordings from ventral roots with suction electrodes coupled to a DC ampli er (for a more complete description of methods see Lopez- Garcia and Laird, 1998). Responses to a train of 20 C- bre intensity electrical stimulus delivered to the corresponding dorsal root were obtained before and after 10 min of superfusion with nifedipine 10±50 mm, the concentrations used by Russo and Hounsgaard (1996) in order to block plateau potentials and wind-up in turtle spinal cord neurones. There was no obvious di erence between the traces obtained in control conditions and those obtained in the presence of nifedipine (Fig. 10). L-type Ca 2+ channels appear to be

16 184 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169±203 fully functional only after 20 days of postnatal development which would explain the lack of e ect of nifedipine in our test, yet the very presence of wind-up in new-born animals, detected by several laboratories, suggests that wind-up does not require the involvement of these channels. No information is available as to whether adult and immature animals may use di erent mechanisms to generate wind-up. Altogether the results of this test are discouraging but they do not provide a de nitive answer to the question asked. Although one would not expect motor and sensory wind-up to be mediated by completely independent mechanisms, there is the possibility that plateau-potentials have a more speci c role in the dorsal horn. Nevertheless, other indirect observations indicate that the situation in the mammalian dorsal horn may be more complex with regard to the role of Ca 2+ channels. For example, nifedipine (as well as omegaconotoxin, an N-type Ca 2+ channel blocker) has been found to depress the responses of dorsal horn neurones to innocuous as well as noxious pressure applied to the knee joint of normal and in amed animals in vivo (Neugebauer et al., 1996). In another study in vivo, nifedipine has been found to be devoid of e ect on responses to formalin injection, whereas N- and P-type channel blockers were found to have antinociceptive actions (Diaz and Dickenson, 1997). Undoubtedly, the turtle model makes a clear contribution to the study of the cellular basis of wind-up by bringing into focus the membrane properties of the neurones involved but more detailed research will be necessary to elucidate the role of L-type Ca 2+ channels and plateau-potentials in the generation of windup in mammals Biophysical diversity among mammalian spinal cord neurones: neuronal excitability and potassium conductances Unfortunately, most of the work performed so far with intracellular recordings in the mammalian spinal cord addresses either the biophysical properties of neurones or their ability to wind-up but do not attempt to relate one to the other. Apart from the low and high threshold calcium currents mentioned above, (see Llinas, 1988) other currents have been described in mammalian spinal neurones for example, A-like potassium, calcium-activated potassium, chloride conductances and rectifying conductances (Yoshimura and Jessell, 1989) but the direct contribution of these conductances to windup have not yet been investigated. Some intracellular studies have focused on the ring properties of dorsal horn neurones (Thomson et al., 1989; King et al., 1988; Lopez-Garcia and King, 1994; Jiang et al., 1995). The studies performed using in vitro preparations clearly detect di erent patterns of ring in response to depolarising current pulses. Some neurones can sustain tonic ring for as long as the depolarising pulses last (typically 200±500 ms). Others show di erent degrees of ring adaptation exhibiting a rather phasic ring pattern to depolarising current pulses. The synaptic responses of these neuronal types to a erent input have been shown to be di erent. Thompson and collaborators (1989) working in a slice preparation of the adult rat spinal cord demonstrated that A- bre strength electrical stimulation elicits the generation of action potentials only in tonic neurones. Lopez-Garcia and King (1994), using the hemisected cord-hindlimb preparation from young rats, found a correlation between the physiological a erent input and the biophysical pro le of the neurone such that class 2 (wide-dynamic range) neurones frequently showed tonic ring patterns to direct depolarising currents whereas speci c neurones (class 1 and 3, low threshold or nociceptive-speci c), often showed phasic patterns. Since it is known that class 2 neurones tend to show the most pronounced wind-up (see Section 4), this would suggest that neurones with a tonic ring pattern are likely to be those which show wind-up. Although the underlying currents governing these distinct ring patterns have not been studied in detail it has been suggested that spike adaptation could be Fig. 10. Lack of e ect of nifedipine on the generation of wind-up. This gure shows the apparent lack of e ect of nifedipine (50 mm) on the cumulative depolarisation recorded from the hemisected spinal cord of a rat pup. Note how the slope of the depolarisation remains constant during nifedipine superfusion. Unpublished data from our laboratory.

17 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± regulated by potassium conductances (such as the outward rectifying or a calcium-activated potassium conductance) in analogy with other neurones involved in the transmission of sensory signals (Forsythe and Barnes-Davis, 1993). These conductances and others actively limit the generation of action potentials thus limiting the neuronal response to a erent input. The possibility exists that physiological or experimental stimuli that block these limiting currents can enhance the neuronal response to a erent input, thus facilitating the appearance of wind-up. Several studies suggest a role for K + as a modulating and signalling agent (Nicholson, 1980) by switching K + and Ca 2+ conductances and altering the membrane potential. Sykova (1986) proposed that as a consequence of repetitive activation of peripheral nerves, K + concentrations in the extracellular space increase signi cantly. This factor could contribute to modify transmission in a number of ways a ecting a erent terminals and dorsal horn neurones: rstly, primary a erent depolarisation may lead to the occurrence of dorsal root potentials which centrally transmitted would cause neurotransmitter release and excitation and secondly, depolarisation of spinal neurones would bring them closer to their thresholds for activation, facilitating the ring of action potentials Clustering of biophysical and pharmacological characteristics in wind-up neurones Dorsal horn neurones are known to possess di erential sensitivity to many of the spinal neurotransmitters and neuromodulators believed to be involved in the generation of wind-up. Excitatory amino acids and tachykinins do not produce the same e ects in all spinal neurones and the cause for this di erential sensitivity is apparently not related to laminar distribution (Schnider and Perl, 1985; Yoshimura and Jessell, 1990; NaÈ sstroè m et al., 1994). It has been shown recently that neurones with a tonic ring pattern are more sensitive to NK1 and NK3 receptor agonists than any other type of neurone (King et al., 1997). Additionally, tonic neurones are more responsive to NMDA than phasic neurones whereas the sensitivity to AMPA is similar in both groups (Lopez-Garcia, 1997). The contribution of these studies is to draw attention to the possibility that conditions favouring the development of wind-up at the cellular level such as the capability to sustain tonic ring and the sensitivity to NMDA and to NK1 receptor agonists may cluster together in some dorsal horn cells, many of which are likely to behave functionally as class 2 (wide-dynamic range) neurones. In addition to cellular and pharmacological traits favouring the generation of wind-up, these neurones are likely to have larger dendritic trees and more numerous synaptic connections Summary and conclusions Fig. 6 summarises some of the possible mechanisms involved in the generation of wind-up discussed in the present section. It seems evident that certain network factors are determinant in some aspects of wind-up. Class 2 neurones located in the deep dorsal horn are likely to generate wind-up of greater magnitude than super cial class 2 neurones but class 1 or class 3 neurones do not show wind-up. In addition, descending control modulates the generation of wind-up in normal and in in amed animals. Of particular interest is the observation that visceral C- bre mediated inputs do not produce wind-up in the same neurones where somatic input induces wind-up. All together, these observations suggest that the position of a neurone within a network is important and that the build up of excitation that takes place during repetitive stimulation may be di cult to explain solely on the basis of cellular mechanisms. Presynaptic mechanisms such as increased neurotransmitter release or co-release of amino acids and peptides from somatic C- bre a erents appear to be of great importance in the super cial dorsal horn. Here, wind-up occurs in few neurones and it is of small amplitude. Furthermore, in the super cial dorsal horn wind-up appears to be homosynaptic. In the deep dorsal and ventral horns wind-up can be heterosynaptic, a higher proportion of cells show wind-up and it reaches higher levels of excitation than that of neurones located in super cial layers. In these deeper layers, in addition to presynaptic mechanisms, other post-synaptic mechanisms appear to have a greater relevance. Such mechanisms could involve the facilitation of NMDA receptors made possible by the cumulative depolarisation or by the release of peptides from interneuronal pools (see Baranauskas and Nistri, 1998). A question as yet unresolved is why cumulative depolarisations are not su cient to generate action potential wind-up. In fact many reports indicate that although cumulative depolarisations are often observed, only a proportion of neurones generate action potential wind-up. On the other hand some mammalian and amphibian dorsal horn neurones can generate action potential wind-up without building up a cumulative depolarisation. This suggests that some speci c conductances are required in order to translate repetitive a erent input and cumulative depolarisation into action potential wind-up. This eld of research may provide the answers to understand fully the generation of wind-up. Finally, it appears that network, cellular and pharmacological features shape the responses of single neurones to repetitive stimulation and that favourable

18 186 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169±203 conditions may cluster together in some neurones enabling them to generate action potential wind-up. 5. Pharmacology of wind-up 5.1. Introduction The e ect of antagonists on the NMDA subtype of ionotropic glutamate receptor, and of the tachykinin receptors (in particular the NK1 receptor) on wind-up have been discussed in the previous section dealing with the mechanisms of generation of wind-up. In this section, the e ects on wind-up of other families of neuromediators and classes of pharmacological agents which have been less fully investigated, is examined. However, when considering the question of which neuromediators may be directly involved in the generation of wind-up, it is important to bear in mind that any agent able to reduce spinal neuronal responses to a erent input, especially C- bre a erent input, is also likely to reduce or even abolish the generation of wind-up Metabotropic glutamate receptors (MGluR) Metabotropic glutamate receptors have been implicated in the generation of wind-up using extracellular recordings of motoneuronal pools in the in vitro hemisected cord (Boxall et al., 1996). (+)-a-methyl-4-carboxyphenylglycine (MCPG), a mglur antagonist, superfused over the cord at concentrations that had no e ect on responses to NMDA produced signi cant reductions of the cumulative responses to repetitive dorsal root stimulation. As in the case of NMDA receptor antagonists, it seems that MCPG reduces the longer latency components of the single elementary responses (Thompson et al., 1992). Furthermore, Russo et al. (1997) have observed that activation of mglur receptors also facilitates plateau properties, via an enhancement of L-type calcium channels in a manner similar to that observed with NK1 receptors (Russo et al., 1997). Paradoxically, mglur agonists have been reported to exert a depressant e ect on the synaptic transmission of myelinated and unmyelinated a erent bres but this e ect is apparently mediated by presynaptic receptors and the action of these compounds on the postsynaptic neurones is excitatory (Cao et al., 1995; King and Liu, 1996). Wind-up studied in spinal class 2 neurones was also enhanced after activation of metabotropic glutamate receptors by the iontophoretic application of (1S,3R)- 1-amino-cyclopentane-1,2-dicarboxylic acid. The e ect was reduced by the application of (S)-4- carboxy-3- hydroxyphenyl-glycine, a phenylglycine derivative that is a selective antagonist of the group 1 metabotropic glutamate receptor (Budai and Larson, 1998). This e ect was probably produced by a positive modulation of ionotropic glutamate receptors since it was accompanied by an increase in the neuronal responses to ionotropic glutamate receptors agonists Non-steroidal anti-in ammatory drugs (NSAIDs) The non-steroidal anti-in ammatory drugs have potent analgesic actions, especially in situations of hyperalgesia induced by in ammation. These kinds of drugs also have a depressive action on wind-up, though this e ect depends on the type of NSAID as well as the route of administration. The NSAID ketoprofen, (member of the group of 2- arylpropionic acids), is e ective in the reduction of wind-up when studied in spinal cord nociceptive re exes (Herrero et al., 1997; Mazario et al., 1998). The e ect of this NSAID was dose-dependent and very e ective either in animals with monoarthritis or in soft-tissue in ammation. The e ect of dexketoprofen trometamol, a derivative of ketoprofen that crosses the gastric barrier rapidly is illustrated in Fig. 11. However, not all NSAIDs are able to induce an e ect on re ex wind-up. The cyclooxygenase-2 (COX-2) preferring NSAID, meloxicam did not a ect re ex windup in monoarthritic rats (Laird et al., 1997), though its e ect on nociceptive responses evoked by natural stimulation was very potent. This perhaps re ects a low penetration in the central nervous system (CNS) (Laird et al., 1997). The intrathecal administration of both indomethacin (non-selective COX inhibitor) and SC58125 (selective for the inducible cyclooxygenase, COX-2) dosedependently inhibited re ex wind-up (Willingale et al., 1997). In these experiments, neither the shape of the wind-up curve nor the initial level of excitability was modi ed. However, other authors have not observed e ects of indomethacin after application directly to the spinal cord. Thus in experiments in vivo recording dorsal horn neurones, even high doses of indomethacin (250 g) had no e ect on wind-up, although they blocked responses to formalin injection (Chapman and Dickenson, 1992a). Similarly, in studies in vitro performed in our laboratory we found that indomethacin was devoid of e ects on the ventral root responses to repetitive stimulation in spinal cords isolated from naive or in amed rats (Lopez-Garcia and Laird, 1998). However, in this study meloxicam was found to signi cantly decrease the wind-up in the same conditions (Lopez-Garcia and Laird, 1998). These results suggest that the inhibition of wind-up by some particular NSAIDs may not be due to inhibition of the COX enzyme but rather to actions on other transmitter systems, and depends crucially on access to the spinal cord.

19 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169± Fig. 11. Single motor unit wind-up recorded in rats treated with the non-steroidal anti-in ammatory drug dexketoprofen trometamol. Dexketoprofen induced a dose- dependent reduction of the wind-up without in uencing the initial excitability of the units (modi ed from Mazario et al., 1998) Opioids and nociceptin In general terms, opioids induce a depression of the excitability of the spinal cord, thus an inhibitory action of opioids on wind-up is not surprising. The mechanism of this inhibition of wind-up is, however, not well understood. When opioids are administered directly onto the spinal cord, they produce a depression of wind-up in dorsal horn neurones (Dickenson and Sullivan, 1986; Chapman et al., 1994). It seems that morphine reduces the initial input to class 2 neurones and therefore delays the onset without a ecting the eventual rate of wind-up. The e ect observed is an inhibition of the baseline C- bre response, since the depression caused by morphine is more intense in the inhibition of the input at low intrathecal doses (5 mg) and it is necessary to inject a high dose (50 mg) in order to observe a depression of both input and windup (Chapman and Dickenson, 1992b). Similarly, intrathecal administration of endomorphins 1 and 2 induced a signi cant reduction in wind-up responses of dorsal horn neurones but they also were e ective on the non-potentiated C- bre responses (Chapman et al., 1997). This type of e ect has also been observed after systemic administration of the selective - opioid agonist fentanyl on spinal cord nociceptive re exes (Mazario et al., 1998, Fig. 12). Endogenous opioids also seem to be important in the modulation of wind-up. The opioid antagonist naloxone induces a dose-dependent increase in windup evoked in withdrawal re exes of spinalised anaesthetised rats (Hartell and Headley, 1991). This enhancement likely re ects the endogenous opioid tonic control on the processing of information in the spinal cord leading to nociceptive re exes. An interaction between NMDA and opioid systems might explain, at least in part, the role of opioids in the modulation of wind-up. This is based on results from experiments in which a potentiation of the e ect of morphine is induced by the co-administration of low doses of morphine (5 mg) and submaximal doses of the selective antagonist of the glycine site of the NMDA receptor, 7-chlorokynureate (7CK) (2.5 g intrathecal). In this case, a strong inhibition of windup was observed, although no e ect, or very little, was induced by the two drugs when administered separately (Chapman and Dickenson, 1992b). However, since a similar potentiation was observed between morphine and the local anaesthetic lidocaine (Fraser et al., 1992, see below) the inhibitory action of these compounds seems to be more related to a non-speci c depression of the spinal cord excitability rather than a speci c e ect on wind-up. Orphanin FQ/nociceptin a heptadecapeptide, proposed to be the endogenous ligand for the ORL1 receptor (Meunier et al., 1995; Reinscheid et al., 1995), also has some e ect on wind-up. When administered directly onto the spinal cord (Stanfa et al., 1996) nociceptin depressed wind-up of dorsal horn neurones when administered intrathecally, in a naloxone-reversible manner. The e ect was di erent depending on the dose studied such that 50 mg of nociceptin reduced wind-up but not the baseline C- bre response, whereas 225 mg reduced both the wind-up and the basal ring rate Local anaesthetics The local anaesthetic lidocaine when applied directly onto the spinal cord produced a signi cant depression of wind-up in deep dorsal horn class 2 neurones, to around 60% of the control response, presumably due to a general reduction of spinal cord excitability since Fig. 12. Single motor unit wind-up in anaesthetised rats administered with the m-opioid agonist fentanyl. Fentanyl induced a dose-dependent reduction of wind-up. Note in this case the progressive reduction of the initial excitability of the units in contrast to the data shown in Fig. 11 (modi ed from Mazario et al., 1998).

20 188 J.F. Herrero et al. / Progress in Neurobiology 61 (2000) 169±203 the initial response of the cells was also reduced to a similar extent (Fraser et al., 1992). This result is perhaps to be expected since lidocaine blocks voltagedependent sodium channels, and therefore the generation of action potentials Alpha-2 adrenergic and imidazoline I2 receptors The alpha2-adrenoceptor agonist, dexmedetomidine, produces a strong depression of wind-up responses in dorsal horn neurones, when administered directly onto the spinal cord (Sullivan et al., 1992). This e ect was reversed by the alpha2 adrenoceptor antagonist, atipamezole. Wind-up was still observed after the administration of dexmedetomidine but to a lesser extent, whereas there was a depression of the initial ring rate or of the basal responses. Similarly, the imidazoline I2 receptor agonist, 2-(4,5-dihydroimidazol-2yl)-quinoline hydrochloride (BU-224), when applied directly onto the spinal cord reduced the nociceptive responses of dorsal horn neurones and induced a dose-dependent inhibition of C- bre mediated responses including wind-up of the cells. The e ect was totally blocked by the previous administration of idazoxan (an antagonist of both alpha2-adrenoceptors and imidazoline I2 receptors) (Diaz et al., 1997). These results suggest that the inhibitory e ects on wind-up of the activation of either alpha2-adrenoceptors or imidazoline I2 receptors are secondary to e ects on the basal C- bre mediated input, rather than directly on the process of wind-up Serotonin Despite the clear involvement of 5-HT (serotonin) in the descending systems controlling somatosensation and nociception very few studies have examined the e ects of 5-HT on wind-up. We have recently performed a series of experiments studying the e ects of 5-HT on the cumulative depolarisations seen in the dorsal root-ventral root re ex during repetitive stimulation using the hemisected spinal cord in vitro (Hedo and Lopez-Garcia, 1999). We found that 5-HT had a concentration-dependent inhibitory action but did not reduce the slope of the cumulative depolarisation at concentrations up to 10 mm. At higher concentrations 5-HT produced a substantial depression of the response, which also a ected the slope of the excitability increase (see Fig. 13). Gjerstad et al. (1996), Gjerstad et al. (1997) have studied the roles of 5-HT1A and 1B receptors on the action potential wind-up developed by class 2 (multireceptive) neurones of the rat dorsal horn in vivo. They observed that activation of the 5-HT1A receptor reduced the long latency (presumably C- bre-evoked) spikes and the after-discharge. This reduction was greater for neurones with large receptive elds and moderate wind up index. In contrast the activation of 5-HT1B receptors increased the after-discharge without modifying C- bre mediated responses. The possible roles of other 5-HT receptors remain unexplored Thyrotropin-releasing hormone (TRH) Neuropeptides like thyrotropin-releasing hormone (TRH) and galanin occur naturally in the spinal cord and though their actions are not established, it is believed that they along with the many other identi ed neuropeptides, have a role as modulators in the nociceptive system. TRH induces a potentiation of wind-up both in dorsal horn neurones (Chizh and Headley, 1996) and spinal cord nociceptive re exes (Chizh and Headley, 1994). The actions of TRH appear to be produced by a positive modulation of the NMDA receptor, since the e ect was reversed by ketamine and was also associated with a potentiation of neuronal responses to iontophoretic application of NMDA (Chizh and Headley, 1996). Fig. 13. E ect of serotonin on the generation of wind-up in the immature rat hemisected spinal cord preparation in vitro. The administration of 5-HT produced a concentration-dependent reduction of the ventral root re ex responses to repetitive dorsal root stimulation at C- bre intensity.

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