Long-Term Blockade of Nociceptive Na_v1.7 Channels Is Analgesic in Rat Models of Knee Arthritis

Abstract

The voltage gated sodium channels (Nav) 1.7, 1.8, and 1.9 are primarily located on nociceptors where they are involved in signalling neuropathic pain. This study examined the effect of Nav1.7 blockade on joint pain using either the small molecule inhibitor PF05089771 or an antibody directed towards the intracellular domain of the ion channel. Male Wistar rats were assigned to one of three experimental groups consisting of either intra-articular injection of 3 mg sodium monoiodoacetate (MIA—joint degeneration group), intra-articular injection of 100 μg lysophosphatidic acid (LPA—joint neuropathy group), or transection of the medial meniscus (MMT—posttraumatic osteoarthritis group). G-ratio calculations were performed to determine potential demyelination and immunohistochemistry was used to measure Nav1.7 expression on joint afferent cell bodies. Pain behaviour was evaluated over 3 h by von Frey hair algesiometry and hindlimb weight bearing before and after local administration of PF05089771 (0.1 mg/50 µL). Chronic pain behaviour was assessed over 28 days following peripheral treatment with a Nav1.7 antibody (Ab) in conjunction with the transmembrane carrier peptide Pep1. Demyelination and increased Nav1.7 channel expression were observed in MIA and LPA rats, but not with MMT. Acute secondary allodynia was diminished by PF05089771 while a single injection of Nav1.7 Ab-Pep1 reduced pain up to 28 days. This analgesia only occurred in MIA and LPA animals. Hindlimb incapacitance was not affected by any treatment. These data indicate that joint pain associated with neural demyelination can be alleviated somewhat by Nav1.7 channel blockade. Biologics that inactivate Nav1.7 channels have the potential to reduce arthritis pain over a protracted period of time.

Keywords

• Arthritis
• biologics
• demyelination
• neuropathic pain
• voltage-gated sodium channels