(321) Role of microglia and P2X7 receptors in arthritis pain

Abstract

Joint pain associated with arthritis is among the most common and debilitating chronic pain conditions. Although joint pathology is an underlying factor, some patients with severe joint degeneration report little to no pain, while others with minor joint pathology experience debilitating and unremitting pain. The discordance between pain severity and peripheral pathology of the arthritic joint suggests joint damage is not necessarily a direct predictor of ensuing chronic pain. Rather, new evidence suggests altered pain processing within the spinal cord as being a key determinant of joint pain. In this study we examined the involvement of spinal microglia and ATP-gated P2X7 receptors (P2X7R) in chronic arthritis pain. To induce arthritis pain in rats, we administered an intra-articular injection of monosodium iodoacetate (MIA), which resulted in a reduction in both mechanical and thermal nociceptive thresholds. The onset of mechanical allodynia and thermal hyperalgesia occurred as early as day 3 post-MIA injection. On day 7 post-MIA, we detected an increase in expression of microglial markers, Iba-1 and Cd11b, on the ipsilateral spinal dorsal horn. Given that P2X7Rs have a peripheral and central mechanism of action, and they are a locus through which microglia contribute to chronic pain, we asked whether spinal P2X7Rs are causally involved in the development and expression of MIA-induced arthritic pain behaviours. We found that 7 day intrathecal osmotic pump administration of the selective P2X7R antagonist A740003 attenuated the development of mechanical allodynia and thermal hyperalgesia in MIA-injected rats. In addition, we discovered that a single acute injection of A740003 in animals with established MIA-induced arthritis pain transiently reversed both the mechanical and thermal hypersensitivity. Collectively our results suggest that spinal P2X7Rs are causally involved in the development and ongoing expression of arthritis pain. Supported by grants from NSERC, CIHR, and the Rita Allen Foundation/American Pain Society.