(299) Therapeutic morphine prolongs neuropathic pain in Fischer 344 rats: a role for TLR4 and inflammasome signaling in the lumbar spinal cord

Abstract

Despite their status as gold-standard therapeutic analgesics for neuropathic pain, opioids initiate microgliosis and proinflammatory cytokine release via Toll Like Receptor 4 (TLR4) in naïve animals, which enhances pro-nociceptive neuroexcitability. However, the behavioral and molecular impact of opioid-induced gliosis has not been defined in the presence of peripheral nerve injury, which also induces lumbar spinal gliosis per se. We hypothesized that sciatic chronic constriction injury (CCI)-allodynia would be enhanced by subsequent repeated morphine, in an inflammasome-dependent fashion involving TLR4, the purinergic receptor P2X7, and caspase-1, which facilitates release of mature interleukin (IL)-1b. Beginning 10 days after CCI surgery in male Fischer 344 rats, s.c. morphine (5 mg/kg b.i.d.) or equivolume saline was administered for 5 consecutive days. Compared to vehicle, morphine treatment significantly prolonged the duration of CCI-induced allodynia from 5 to 11 weeks (n=6/group; p<0.05). Continuous intrathecal infusion of inhibitors of TLR4 ([+]-naloxone; 60 mcg/h), P2X7 (Brilliant Blue G; 30 ng/h), or caspase-1 (ac-YVAD-cmk; 1 mcg/h) prevented morphine-prolonged CCI-allodynia when administered concomitantly with morphine, and, except for ac-YVAD-cmk, completely reversed established morphine-prolonged CCI-allodynia when administered 5 weeks after morphine dosing (n=6/group; p<0.05). Morphine treatment induced significant release of tumor necrosis factor (TNF)a and IL-1b (p<0.05) from lumbar dorsal spinal cords (p<0.05). Furthermore, a single intrathecal dose of soluble TNF receptor (100 mcg; Amgen), IL-1 receptor antagonist (100 mcg; Amgen) or IL-6 (10 mcg; K. Rice) transiently attenuated morphine-prolonged CCI-allodynia (n=6/group; p<0.05). These data suggest that morphine may paradoxically contribute to the incidence of chronic neuropathic pain due to an interaction between morphine and the products of nerve injury, resulting in sustained inflammasome signaling. These data further present an opportunity to pharmacologically inhibit paradoxical pain enhancement while retaining the analgesic properties of morphine, as each is mediated via different receptors and underlying mechanisms.