Afferent drive elicits ongoing pain in a model of advanced osteoarthritis

Abstract

Osteoarthritis (OA) is a chronic condition characterized by pain during joint movement. Additionally, patients with advanced disease experience pain at rest (i.e., ongoing pain)that is generally resistant to non-steroidal anti-inflammatory drugs (NSAIDs). Injection of monosodium iodoacetate (MIA) into the intra-articular space of the rodent knee is a well-established model of OA that elicits weight-bearing asymmetry and referred tactile and thermal hypersensitivity. Whether ongoing pain is present in this model is unknown. Additionally, the possible relationship of ongoing pain to MIA dose is not known. MIA produced weight asymmetry, joint osteolysis, and cartilage erosion across a range of doses (1, 3, and 4.8 mg). However, only rats treated with the highest dose of MIA showed conditioned place preference to a context paired with intra-articular lidocaine, indicating relief from ongoing pain. Diclofenac blocked the MIA-induced weight asymmetry but failed to block MIA-induced ongoing pain. Systemic AMG9810, a TRPV1 antagonist, effectively blocked thermal hypersensitivity, but failed to block high dose MIA-induced weight asymmetry or ongoing pain. Additionally, systemic or intra-articular HC030031, a TRPA1 antagonist, failed to block high dose MIA-induced weight asymmetry or ongoing pain. Our studies suggest that a high dose of intra-articular MIA induces ongoing pain originating from the site of injury that is dependent on afferent fiber activity but apparently independent of TRPV1 or TRPA1 activation. Identification of mechanisms driving ongoing pain may enable development of improved treatments for patients with severe OA pain and diminish the need for joint replacement surgery.

Pain relief produces negative reinforcement through activation of mesolimbic reward–valuation circuitry

“…PNB at the site contralateral to the injured hind paw did not result in CPP (Fig. S1), confirming that lidocaine at the dose used for PF injection does not produce systemic effects on pain relief, as demonstrated previously (23). These data suggest that relief of postsurgical, ongoing (i.e., spontaneous) pain is rewarding.…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Chronic neuropathic pain is an even better example. Although the loss-of-function TRPV1 variant I585V was reported to confer decreased risk for painful OA (Valdes et al, 2011), neither the selective TRPV1 antagonist AMG9810, nor the TRPA1 blocker HC-030031, ameliorated ongoing spontaneous pain in a model of advanced OA (Okun et al, 2012). Moreover, the TRPV1 antagonist ABT-116 failed to provide pain relief in client-owned dogs with hip OA (Malek et al, 2012), and a clinical trial with AZD1386 involving 241 patients with OA in seven different countries had to be terminated prematurely for lack of efficacy (Svensson et al, 2010;Miller et al, 2014).…”

Targeting the Transient Receptor Potential Vanilloid Type 1 (TRPV1) Assembly Domain Attenuates Inflammation-induced Hypersensitivity

“…Although we can not ascertain whether central or peripheral TRPV1 is the major contributor of mechanical hypersensitivity in our model, our findings with the intrathecal administration of the peptide support that spinal inhibition of TRPV1 channel enables pain relief in MIA-induced osteoarthritis. Of note, others have shown that antagonists of TRPV1 block MIA-induced thermal hyperalgesia but not weight asymmetry or ongoing pain (37). Finally, stimulation of capsaicinsensitive sensory neurons appeared to reduce both pain and bone lesions in the MIA model (42).…”