Chronic pain: glutamate dysfunction, treatments, and need for glutamate biomarkers

Transcription

1 Chronic pain: glutamate dysfunction, treatments, and need for glutamate biomarkers BRIAN E. CAIRNS, RPh, ACPR, PhD Faculty of Pharmaceutical Sciences The University of British Columbia Vancouver, Canada

2 Topics: How do glutamate and glutamate receptors contribute to pain in chronic pain conditions. What are the challenges in using centrally acting NMDA receptor antagonists (e.g. ketamine) as treatments for chronic pain conditions. Do peripheral glutamate and glutamate receptors contribute significantly to the development & maintenance of chronic pain: focus on temporomandibular disorders.

3 Chronic pain conditions > 6 months pain Not clear how the transition occurs from acute pain Many chronic pain conditions (e.g. migraine, neuropathic pain, fibromyalgia) show evidence of altered central pain processing e.g. exagerated summation of experimentally induced pain. Central sensitization, a prolonged increase in the excitability of nociceptive neurons in the CNS, induced by sustained, repetitive, high frequency input from nociceptors Increased response to pain (hyperalgesia), novel inputs (eg. Low threshold) causing pain (allodynia), referral of pain

4 Central sensitization is initiated by NMDA receptor activation NMDA receptor blockade reduces pain and referral Ketamine (uncompetitive NMDA receptor antagonist) for chronic pain: low dose (< 1mg/kg or 20 ug/kg/h) ketamine efficacious for neuropathic pain, orofacial pain, cancer pain, complex regional pain syndrome, phantom limb and fibromyalgia Not possible to separate pain relief from CNS side-effects: learning and memory impairment, sedation, ataxia & psychotomimetic effects such as hallucinations in humans

5 Is there a way to capitalize on the analgesic potential of NMDA receptor antagonists but limit side effects? Low affinity NMDA antagonist neramexane shows some promise.but memantine has not been particulary efficacious NR2B subunit selective antagonists may be free of psychomimetic effects Another possibility is to target the peripheral pain transduction mechanisms to avoid CNS effects: glutamate and glutamate receptors contribute to peripheral pain mechanisms

6 Temporomandibular Disorders Chronic, craniofacial pain condition characterized by pain in the TMJ and/or muscles of mastication ~75% of TMD patients have muscle pain ~ 85% women pain on palpation limited jaw movement pain upon jaw opening Pathogenesis unclear

7 Interstitial concentrations of glutamate are elevated in patients with chronic myofascial TMD. 20 Masseter Muscle Serum glutamate (µm) * TMD patients Healthy controls 0 Castrillon et al, 2010

8 Systemic injection of 50 mg/kg MSG increases masseter muscle interstitial glutamate concentrations 2-3 times over baseline and decreases masseter muscle afferent fiber mechanical threshold. Glutamate Concentration ( µm) MSG 50 mg/kg Time (s) Relative Mechanical Threshold (%) MSG 50 mg/kg * Time (sec)

9 Intramuscular injection of glutamate evokes pain that is mediated through activation of peripheral NMDA receptors Control Ketamine VAS Score G 1.0 M G 1.0 M G 1.0 M G 1.0 M & K10mM 10 min S 1.0 M S 1.0 M S 1.0 M S1.0M & K 10 mm

10 ~40% of masseter ganglion neurons express the NR2B subunit ~15% of masseter ganglion neurons express the NR2A subunit NR2B Fast Blue

11 Glutamate-evoked masticatory muscle afferent discharge is mediated through activation of peripheral NR2B subunit containing NMDA receptors. Relative Cumulative Activity C Control APV Ketamine min Ifenprodil * C I 10 Hz Log Concentration (mm)

12 In 10 female myofascial TMD patients, 8 reported a greater than 50% reduction in pain 1 h after a single injection of 10mM ketamine into the masseter muscle. 250 Pain relief Pain increase VAS/NRS pain relative changes compared to baseline (%) Placebo Ketamine Baseline -15 min 5 min 15 min 1hr 3hr 24 hr Castrillon et al, 2008

13 Conclusions Glutamate concentrations in the muscles increase in chronic pain and could contribute to pain and sensitivity through activation of peripheral NR2B containing NMDA receptors Need to further characterize the role of elevated tissue glutamate levels in other chronic pain conditions (e.g. migraine) biomarker? Need to develop and test peripherally restricted NMDA receptor antagonists to determine whether this mechanism is an important component of pain pathophysiology

14 Center for Sensory-Motor Interaction University of Aalborg, Denmark Lars Arendt-Nielsen Thomas Graven-Nielsen Kelun Wang Parisa Gazerani Faculty of Dentistry University of T oronto, Canada Barry J. Sessle James W. Hu David Lam Harvard Medical School, USA Charles B. Berde School of Dentistry University of Aarhus, Denmark Peter Svensson Eduardo Castrillon Lene Baad-Hansen Karolinska Institute, Sweden Malin Ernberg Faculty of Pharmaceutical Sciences & Brain Research Center, UBC, Canada Xudong Dong Ujendra Kumar Mandeep Mann David Sung Akhlaq Hakim Mianwei Wang Support: NIH/NIDCR, CIHR/IMHA, Canadian Pain Society