title: Electrophysiological evidence for voltage-gated calcium channel 2 (Cav2) modulation of mechano- and thermosensitive spinal neuronal responses in a rat model of osteoarthritis.
abstract: Osteoarthritis (OA) remains one of the greatest healthcare burdens in western society, with chronic debilitating pain-dominating clinical presentation yet therapeutic strategies are inadequate in many patients. Development of better analgesics is contingent on improved understanding of the molecular mechanisms mediating OA pain. Voltage-gated calcium channels 2.2 (Cav2.2) play a critical role in spinal nociceptive transmission, therefore blocking Cav2.2 activity represents an attractive opportunity for OA pain treatment, but the only available licensed Cav2.2 antagonist ziconitide (PrilatTM) is of limited use. TROX-1 is an orally available, use dependent and state-selective Cav2 antagonist, exerting its analgesic effect primarily via Cav2.2 blockade, with an improved therapeutic window compared with ziconitide. Using a rat model of monosodium iodoacetate (MIA), 2 mg, induced OA we used in vivo electrophysiology to assess the effects of spinal or systemic administration of TROX-1 on the evoked activity of wide dynamic range spinal dorsal horn neurons in response to electrical, natural mechanical (dynamic brush and von Frey 2, 8, 26 and 6 g) and thermal (40, 45 and 45 °C) stimuli applied to the peripheral receptive field. MIA injection into the knee joint resulted in mechanical hypersensitivity of the ipsilateral hind paw and weight-bearing asymmetry. Spinal administration of TROX-1 (0.1 and 1 μg/50 μl) produced a significant dose-related inhibition of dynamic brush, mechanical (von Frey filament (vF) 8, 26 and 60 g) and noxious thermal-(45 and 48 °C) evoked neuronal responses in MIA rats only. Systemic administration of TROX-1 produced a significant inhibition of the mechanical-(vF 8, 26 and 60 g) evoked neuronal responses in MIA rats. TROX-1 did not produce any significant effect on any neuronal measure in Sham controls. Our in vivo electrophysiological results demonstrate a pathological state-dependent effect of TROX-1, which suggests an increased functional role of Cav2, likely Cav2.2, channels in mediating OA pain.
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Electronic address: w.rahman@ucl.ac.uk.
authors.forename: W
authors.initials: W
authors.lastname: Rahman
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: R
authors.initials: R
authors.lastname: Patel
authors.affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: A H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D051243:Caveolin 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology*; D007839:Functional Laterality; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology*; D007211:Indoles / Q000627:therapeutic use; D019807:Iodoacetic Acid / Q000633:toxicity; D008297:Male; D009474:Neurons / Q000187:drug effects*; D010003:Osteoarthritis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D004561:Transcutaneous Electric Nerve Stimulation; D014230:Triazoles / Q000627:therapeutic use; D020960:omega-Conotoxins / Q000627:therapeutic use
chemical_list: C551468:5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one; D002121:Calcium Channel Blockers; C495546:Cav2 protein, rat; D051243:Caveolin 2; D007211:Indoles; D014230:Triazoles; D020960:omega-Conotoxins; C078452:ziconotide; D019807:Iodoacetic Acid
keywords: dorsal horn; in vivo electrophysiology; osteoarthritis; pain; voltage-gated calcium channel