Involvement of Nav 1.8 sodium ion channels in the transduction of mechanical pain in a rodent model of osteoarthritis

Abstract

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.

The Role of Peripheral Nociceptive Neurons in the Pathophysiology of Osteoarthritis Pain

“…In addition, systemic (s.c.) or intraplantar administration of A-803467 resulted in a decreased response by spinal neurons. This supports a previous study demonstrating the ability of an IA injection of A-803467 to inhibit the firing of knee joint afferents in response to noxious rotation of the joint and to inhibit mechanical allodynia and weight-bearing deficits in rats 14 days after induction of OA via MIA injection (59). Together, these studies suggest that targeting peripheral sodium channels may be an effective treatment option in treating persistent OA pain.…”

Chemogenetic Inhibition of Pain Neurons in a Mouse Model of Osteoarthritis

“…Both studies focused on day 14, which is in the NSAID-sensitive phase of the model. This inhibitor was able to reduce the mechanosensitivity of joint afferent fibers during noxious rotation of the joint (36), reverse weight-bearing and mechanical allodynia (36), and block spinal neuron responses to mechanical and thermal stimuli (37). These results suggest that at least some of the observed effects may in fact be mediated by Na V 1.8 itself.…”

Towards a mechanism-based approach to pain management in osteoarthritis

“…44 In addition, experiments in the rat monoiodoacetate (MIA) model, which is frequently used to model OA pain pathways, 45 have found a role for the voltage-gated sodium channel Nav1.8 in noxious mechanosensation in the joint. 46 Nav1.8 is restricted in its expression to small primary afferent neurons 47 and has been implicated in noxious mechanosensation in mice. 48 Approximately 50% of C-fibres and 10% of Aδ-fibres in normal rats express Nav1.8, 49 and expression levels were shown to be increased in afferent neurons that innervate inflamed rat knees.…”