Role for monocyte chemoattractant protein-1 in the induction of chronic muscle pain in the rat

Abstract

While raised levels of monocyte chemoattractant protein 1 (MCP-1) have been observed in patients with chronic muscle pain, direct evidence for its role as an algogen in skeletal muscle is still lacking. In the rat, MCP-1 induces a dose-dependent mechanical hyperalgesia lasting for up to 6weeks. Following recovery, rats exhibited a markedly prolonged hyperalgesia to an intramuscular injection of prostaglandin E2, hyperalgesic priming. Intrathecal pretreatment with isolectin B4 (IB4)-saporin, which selectively destroys IB4-positive (IB4+) nociceptors, markedly decreased MCP-1-induced hyperalgesia and prevented the subsequent development of priming. To evaluate the involvement of MCP-1 in stress-induced chronic pain we administered, intrathecally, antisense (AS) or mismatch oligodeoxynucleotides directed against CCR2 (the canonical receptor for MCP-1) mRNA, during the exposure to water-avoidance stress, a model of stress-induced persistent muscle pain. The AS treatment attenuated this hyperalgesia, whereas IB4-saporin abolished water-avoidance stress-induced muscle hyperalgesia and prevented stress-induced hyperalgesic priming. These results indicate that MCP-1 induces persistent muscle hyperalgesia and a state of latent chronic sensitization to other algogens, by action on its cognate receptor on IB4+ nociceptors. Because MCP-1 also contributes to stress-induced widespread chronic muscle pain, it should be considered as a player in chronic musculoskeletal pain syndromes.

Keywords: Fibromyalgia; Inflammation; Myalgia; Nociceptor; Stress.

Figure 1

MCP-1 induces muscle hyperalgesia and hyperalgesic priming dependent on IB4+ nociceptors. (A) Effect of a single injection of rrMCP-1 (1-1000 ng/20 μl, n=6/group) into the gastrocnemius muscle. The dotted line indicates the average mechanical nociceptive threshold observed in naïve rats. (B) Effect of PGE₂ (1 μg/20 μl) injected into the gastrocnemius muscle of rats previously with rrMCP-1 (ng/20 μl, n=6/group) or saline (n=6). (C) Effect of treatment with intrathecal IB4-saporin (n=6) on baseline nociceptive threshold compared to control treatment (i.t. saline, n=6), and muscle hyperalgesia induced by i.m. rrMCP-1 (100 ng/20 μl). (D) Effect of treatment with intrathecal IB4-saporin and control treatment on PGE₂ (1 μg/20 μl) induced hyperalgesia in rats previously injected with rrMCP-1.

Figure 2

Water avoidance stress produces a persistent muscle hyperalgesia dependent on CCR2 expressed by IB4+ nociceptors. (A) Effect of intrathecal pre-treatment with IB4-saporin (n=6) or control treatment (saline 20 μl, n=6) on water avoidance stress-induced muscle hyperalgesia. (B) Effect of intrathecal IB4-saporin (open circle, n=6) or control treatment (i.t. saline 20 μl, n=6, solid circle) on water avoidance stress-induced hyperalgesic priming. PGE₂ (1 μg/20 μl) was injected into the gastrocnemius muscle of rats previously exposed to water avoidance stress. (C) Effect of CCR2 AS/MM (n=6/group) in water avoidance stress-induced muscle pain. (D) Effect of CCR2 AS/MM (n=6/group) in rrMCP-1 (100 ng/20 μl) induced muscle hyperalgesia in naïve rats.