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Objective. To determine whether local administration of the cannabinoid 1 (CB 1 ) receptor agonist arachidonyl-2-chloroethylamide (ACEA) can modulate joint nociception in control rat knee joints and in experimental osteoarthritis (OA).Methods. OA was induced in male Wistar rats by intraarticular injection of 3 mg of sodium monoiodoacetate, with a recovery period of 14 days. Electrophysiologic recordings were made of knee joint primary afferent nerve fibers in response to normal rotation and noxious hyperrotation of the joint both before and after close intraarterial injection of different doses of ACEA.Results. Local application of the CB 1 agonist significantly reduced the firing rate of afferent nerve fibers by up to 50% in control knee joints (n ‫؍‬ 19) and up to 62% in OA knee joints (n ‫؍‬ 29; P < 0.01). Coadministration of the CB 1 receptor antagonist AM251 or the transient receptor potential vanilloid 1 (TRPV-1) ion channel antagonist SB366791 significantly reduced the desensitizing effect of ACEA. The CB 1 receptor antagonist AM251 by itself had no effect in the control joint but significantly increased the firing rate of afferent nerve fibers in the OA joint.Conclusion. These findings indicate that activation of peripheral CB 1 receptors reduces the mechanosensitivity of afferent nerve fibers in control and OA knee joints. Blockade of either the CB 1 receptor or the TRPV-1 channel significantly reduced the efficacy of ACEA, which suggests that both receptors are involved in cannabinoid-mediated antinociception. The increased nerve activity observed following CB 1 receptor antagonism suggests a tonic release of endocannabinoids during OA. As such, peripheral CB 1 receptors may be important targets in controlling OA pain.

These data indicate that GW405833 reduces the mechanosensitivity of afferent nerve fibres in control joints but causes nociceptive responses in OA joints. The observed pro-nociceptive effect of GW405833 appears to involve TRPV1 receptors.

These findings indicate that VIP is involved in peripheral sensitization of knee joint afferents especially in response to normal joint movements. OA-induced sensitization of knee joint afferents was inhibited by local administration of VIP(6-28), indicating that VIP is released into OA knee joints, potentially contributing to joint pain. As such, VIP(6-28) may prove to be a beneficial agent for the treatment of arthritis pain.

IntroductionA 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).MethodsOA-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.ResultsA-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.ConclusionsThese 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.