TRPV1-related modulation of spinal neuronal activity and behavior in a rat model of osteoarthritic pain.
The TRPV1 receptor functions as a molecular integrator, and blockade of this receptor modulates enhanced somatosensitivity across several animal models of pathological pain, including models of osteoarthritic (OA) pain. In order to further characterize the contributions of TRPV1 to OA-related pain, we investigated the systemic effects of a selective TRPV1 receptor antagonist, A-889425, on grip force behavior, and on the evoked and spontaneous firing of spinal wide dynamic range (WDR) and nociceptive specific (NS) neurons in the monoiodoacetate (MIA) model of OA. Administration of A-889425 (10-300 μmol/kg, p.o.) alleviated grip force impairment in OA rats 3 weeks after the MIA injection. Also at 3 weeks post-MIA injection, the responses of WDR and NS neurons to 300 g von Frey hair stimulation of the knee joint were significantly reduced by A-889425 administration (10 and 30 μmol/kg, i.v.) in OA, but not sham-OA rats. Spontaneous firing of WDR neurons was elevated in the OA rats compared to sham-OA rats and may reflect ongoing discomfort in the OA animal. In addition to an effect on mechanotransmission, systemic administration of A-889425 reduced the elevated spontaneous firing of WDR neurons in OA rats but did not alter spontaneous firing in sham rats. The present data demonstrate that blockade of TRPV1 receptors modulates the firing of two important classes of spinal nociceptive neurons in a rat model of OA. The effect of A-889425 on neuronal responses to intense mechanical stimulation of the knee and on the spontaneous firing of WDR neurons adds to the growing appreciation for the role of TRPV1 receptors in pathological mechanotransmission and possibly non-evoked discomfort, respectively.
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6118, USA.
Katharine L
KL
Chu
Prasant
P
Chandran
Shailen K
SK
Joshi
Michael F
MF
Jarvis
Philip R
PR
Kym
Steve
S
McGaraughty
D000818:Animals; D004195:Disease Models, Animal; D004594:Electrophysiology; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D010003:Osteoarthritis / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D010146:Pain / Q000378:metabolism* / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000187:drug effects / Q000378:metabolism*
C540006:A-889425; D011725:Pyridines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat