Muscle pain in models of chemotherapy‐induced and alcohol‐induced peripheral neuropathy

Abstract

Objective While inflammatory pain is well described in skeletal muscle, neuropathic muscle pain remains to be clarified. We used three well-established rodent models of peripheral neuropathy to evaluate for muscle pain. Methods In rats exposed to either of two neurotoxic cancer chemotherapies, paclitaxel or oxaliplatin, or to alcohol consumption, we assessed the evolution of mechanical hyperalgesia in skeletal muscle and skin, in the same animal. To explore the involvement of protein kinase C epsilon (PKCε), a second messenger implicated in some forms of neuropathic pain, oligodeoxynucleotides (ODN) antisense (AS) or mismatch (MM) for PKCε were administered intrathecally. Results Rats submitted to models of chemotherapy- and alcohol-induced neuropathy developed persistent muscle hyperalgesia, which evolved in parallel in muscle and skin. The administration of PKCε AS, which has been shown to mediate cutaneous hyperalgesia in paclitaxel and ethanol models of neuropathic pain, also inhibited muscle hyperalgesia induced by these agents. Stopping AS-ODN was associated with the reappearance of hyperalgesia at both sites. The AS-ODN to PKCε treatment was devoid of effect in both muscle and skin in the oxaliplatin neuropathy model. Interpretation Our results support the suggestion that neuropathic muscle pain may be a greater clinical problem than generally appreciated.

Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel

“…The mechano-hyperalgesia was reported to last for at least 40 days, which seems far too long for oxaliplatin’s acute reaction. However, a more recent study suggests that it lasts for 12 days or less (Alvarez et al, 2011). Ling et al (2007b, 2008) did not find any mechano-hyperalgesia (paw pressure test) or heat hyperalgesia after a single injection of oxaliplatin.…”

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

“…This phenomenon appears to be dependent on the release of catecholamines and beta-adrenoceptor activation [31], a hallmark in models of stress-induced widespread muscle pain [5; 40]. Furthermore, paclitaxel chemotherapy, which produces robust muscle pain in humans [28; 33; 43] and rodents [3; 22], is associated with a marked increase in serum levels of MCP-1 in humans [52] and enhanced expression of MCP-1 in nociceptors and dorsal horn neurons in rodents [66]. While these observations strongly suggest a role for MCP-1 as a pro-nociceptive mediator in skeletal muscle, evidence supporting this view is still lacking.…”

Antihyperalgesic effect of tetrodotoxin in rat models of persistent muscle pain

“…The effect of cumulative doses of TTX on mechanical hyperalgesia induced by the neurotoxic antineoplastic chemotherapy agent oxaliplatin, a model of chemotherapy induced neuropathic muscle pain (Alvarez et al, 2011), was evaluated in the gastrocnemius muscle of the adult rat. Consistent with our previous observations, rats displayed a robust muscle mechanical hyperalgesia at 4 and 15 days after intravenous injection of oxaliplatin (Alvarez et al, 2011) ( P < 0.001, n=12/group, Fig.…”

“…As previously reported (Alvarez et al, 2011; Joseph and Levine, 2009), oxaliplatin was freshly dissolved in normal saline at a concentration of 2 mg/ml and immediately administered by intravenous route (1 ml/kg) to isoflurane-anesthetized rats.…”