Involvement of Nav 1.8 sodium ion channels in the transduction of mechanical pain in a rodent model of osteoarthritis.
BACKGROUND
A subgroup of voltage gated sodium channels including Nav1.8 are exclusively expressed on small diameter primary afferent neurons and are therefore believed to be integral to the neurotransmission of nociceptive pain. The present study examined whether local application of A-803467, a selective blocker of the Nav 1.8 sodium channel, can reduce nociceptive transmission from the joint in a rodent model of osteoarthritis (OA).


METHODS
OA-like changes were induced in male Wistar rats by an intra-articular injection of 3 mg sodium monoiodoacetate (MIA). Joint nociception was measured at day 14 by recording electrophysiologically from knee joint primary afferents in response to non-noxious and noxious rotation of the joint both before and following close intra-arterial injection of A-803467. The effect of Nav1.8 blockade on joint pain perception and secondary allodynia were determined in MIA treated animals by hindlimb incapacitance and von Frey hair algesiometry respectively.


RESULTS
A-803467 significantly reduced the firing rate of joint afferents during noxious rotation of the joint but had no effect during non-noxious rotation. In the pain studies, peripheral injection of A-803467 into OA knees attenuated hindlimb incapacitance and secondary allodynia.


CONCLUSIONS
These studies show for the first time that the Nav1.8 sodium channel is part of the molecular machinery involved in mechanotransduction of joint pain. Targeting the Nav1.8 sodium channel on joint nociceptors could therefore be useful for the treatment of OA pain, avoiding the unwanted side effects of non-selective nerve blocks.
Department of Physiology & Pharmacology, University of Calgary, 3330, Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
Niklas
N
Schuelert
Jason J
JJ
McDougall
D000704:Analysis of Variance; D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D018771:Arthralgia / Q000503:physiopathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005663:Furans / Q000008:administration & dosage / Q000494:pharmacology; D006120:Grooming / Q000187:drug effects; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control; D007270:Injections, Intra-Articular; D019807:Iodoacetic Acid; D007719:Knee Joint / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000187:drug effects / Q000502:physiology*; D062559:NAV1.8 Voltage-Gated Sodium Channel / Q000502:physiology*; D020370:Osteoarthritis, Knee / Q000139:chemically induced / Q000503:physiopathology*; D010147:Pain Measurement; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology
C520740:A 803467; D000814:Aniline Compounds; D005663:Furans; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568319:Scn10a protein, rat; D026941:Sodium Channel Blockers; D019807:Iodoacetic Acid