Abstract
The mechanisms underlying the transition from acute nociceptive pain to centrally maintained chronic pain are not clear. We have studied the contributions of the peripheral and central nervous systems during the development of osteoarthritis (OA) pain. Male Sprague-Dawley rats received unilateral intra-articular injections of monosodium iodoacetate (MIA 1 mg) or saline, and weight-bearing (WB) asymmetry and distal allodynia measured. Subgroups of rats received intra-articular injections of, QX-314 (membrane impermeable local anaesthetic) + capsaicin, QX-314, capsaicin or vehicle on days 7, 14 or 28 post-MIA and WB and PWT remeasured. On days 7&14 post-MIA, but not day 28, QX-314 + capsaicin signficantly attenuated changes in WB induced by MIA, illustrating a crucial role for TRPV1 expressing nociceptors in early OA pain. The role of top-down control of spinal excitability was investigated. The mu-opioid receptor agonist DAMGO was microinjected into the rostroventral medulla, to activate endogenous pain modulatory systems, in MIA and control rats and reflex excitability measured using electromyography. DAMGO (3 ng) had a significantly larger inhibitory effect in MIA treated rats than in controls. These data show distinct temporal contribtuions of TRPV1 expressing nociceptors and opioidergic pain control systems at later timepoints.
Highlights
Osteoarthritis (OA) is a common form of degenerative joint disease and a major cause of joint pain worldwide[1]
We hypothesised that there are differential contributions of the peripheral and central nervous system to mono-sodium iodoacetate (MIA) induced OA pain over time, which are relevant to the development of novel treatment approaches
Targeted inactivation of joint nociceptors attenuates pain evoked by intra-articular injection of NGF
Summary
Osteoarthritis (OA) is a common form of degenerative joint disease and a major cause of joint pain worldwide[1]. Synovitis is significantly associated with OA pain[7,8] and increased levels of pro-inflammatory mediators in synovial fluid sensitise nociceptors[9]. These nociceptors are primary afferent sensory neurons which innervate multiple components of the joint and detect changes in the local environment, as well as being potential sources of nociceptive factors themselves. Concomitant MIA-induced pain behaviour (weight bearing asymmetry (WB) and lowered paw withdrawal thresholds (PWT)) models aspects of activity-related pain and altered distal pain pressure thresholds in OA patients[19,22]. This model is associated with hallmarks of of spinal[20,23] and supraspinal[24] sensitization. We hypothesised that there are differential contributions of the peripheral and central nervous system to MIA induced OA pain over time, which are relevant to the development of novel treatment approaches
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