Morphine amplifies mechanical allodynia via TLR4 in a rat model of spinal cord injury.

Central neuropathic pain (CNP) is a pervasive, debilitating problem that impacts thousands of people living with central nervous system disorders, including spinal cord injury (SCI). Current therapies for treating this type of pain are ineffective and often have dose-limiting side effects. Although opioids are one of the most commonly used CNP treatments, recent animal literature has indicated that administering opioids shortly after a traumatic injury can actually have deleterious effects on long-term health and recovery. In order to study the deleterious effects of administering morphine shortly after trauma, we employed our low thoracic (T13) dorsal root avulsion model (Spinal Neuropathic Avulsion Pain, SNAP). Administering a weeklong course of 10mg/kg/day morphine beginning 24h after SNAP resulted in amplified mechanical allodynia. Co-administering the non-opioid toll-like receptor 4 (TLR4) antagonist (+)-naltrexone throughout the morphine regimen prevented morphine-induced amplification of SNAP. Exploration of changes induced by early post-trauma morphine revealed that this elevated gene expression of TLR4, TNF, IL-1ß, and NLRP3, as well as IL-1ß protein at the site of spinal cord injury. These data suggest that a short course of morphine administered early after spinal trauma can exacerbate CNP in the long term. TLR4 initiates this phenomenon and, as such, may be potential therapeutic targets for preventing the deleterious effects of administering opioids after traumatic injury.

Prior exposure to repeated morphine potentiates mechanical allodynia induced by peripheral inflammation and neuropathy.

Opioids, such as morphine, induce potent analgesia and are the gold standard for the treatment of acute pain. However, opioids also activate glia, inducing pro-inflammatory cytokine and chemokine production, which counter-regulates the analgesic properties of classical opioid receptor activation. It is not known how long these adverse pro-inflammatory effects last or whether prior morphine could sensitize the central nervous system (CNS) such that responses to a subsequent injury/inflammation would be exacerbated. Here, multiple models of inflammation or injury were induced two days after morphine (5mg/kg b.i.d., five days , s.c.) to test the generality of morphine sensitization of later pain. Prior repeated morphine potentiated the duration of allodynia from peripheral inflammatory challenges (complete Freund's adjuvant (CFA) into either hind paw skin or masseter muscle) and from peripheral neuropathy (mild chronic constriction injury (CCI) of the sciatic nerve). Spinal cord and trigeminal nucleus caudalis mRNAs were analyzed to identify whether repeated morphine was sufficient to alter CNS expression of pro-inflammatory response genes, measured two days after cessation of treatment. Prior morphine elevated IL-1ß mRNA at both sites, MHC-II and TLR4 in the trigeminal nucleus caudalis but not spinal cord, but not glial activation markers at either site. Finally, in order to identify whether morphine sensitized pro-inflammatory cytokine release, spinal cord was isolated two days after morphine dosing for five days , and slices stimulated ex vivo with lipopolysaccharide. The morphine significantly induced TNFα protein release. Therefore, repeated morphine is able to sensitize subsequent CNS responses to immune challenges.