Abstract
Enhancement of endocannabinoid signaling has emerged as an attractive strategy for the treatment of pain. In addition to the well-characterized hydrolytic pathways, cyclooxygenase-2 (COX-2) mediated oxygenation is thought to be an alternative route for endocannabinoid metabolism and therefore provides a new avenue for drug intervention. In this study, we examined the therapeutic effect of indomethacin morpholinamide (IMMA), a novel substrate-selective COX-2 inhibitor, in the chronic constriction injury (CCI) mouse model. Treatment with IMMA significantly alleviated hyperalgesia and mechanical allodynia demonstrated by increased thermal withdrawal latency in Hargreaves test and tactile thresholds in Von Frey test. Accumulation of astrocytes and microglia in spinal cord dorsal horn and infiltration of macrophages into the dorsal root ganglion and sciatic nerve were reduced by drug treatment. Co-administration of the CB2 receptor antagonist, but not the CB1 receptor antagonist partially reversed the inhibitory effect of IMMA on pain sensitivity and inflammatory infiltrates. IMMA downregulated the mRNA expression of TNF-α and IL-1β and the production of IL-6 and MCP-1 proteins in the ipsilateral sciatic nerve. The enhanced NF-κB DNA binding activity in the CCI mouse dorsal spinal cord was also significantly reduced, suggesting that inactivation of NF-κB contributes to the anti-inflammatory property of IMMA. However, different from the previous reports showing that IMMA can increase endocannabinoids without interfering with arachidonic acid metabolism, treatment with IMMA failed to elevate the endogenous levels of AEA and 2-AG, but significantly reduced the production of prostaglandin E2 (PGE2). Furthermore, the mRNA expression of enzymes involved in PGE2 production, COX-2 and prostaglandin E synthase 2 in the ipsilateral sciatic nerve was also suppressed by IMMA treatment. Taken together, these results suggested that IMMA might exert anti-nociceptive effects through multiple mechanisms which include, but are not limited to, CB2 receptor activation and reduced PGE2 production.
Highlights
Neuropathic pain is a debilitating form of chronic pain caused by traumatic nerve injury, toxic insults and various disease states (Donvito et al, 2018)
For the dose of 20 mg/kg, a significant increase of thermal withdrawal latency was only observed on day 14 in the indomethacin morpholinamide (IMMA) treatment group with the value of 15.6 s compared to the constriction injury (CCI) vehicle group with the value of 13.1 s (Figure 1B; #p < 0.05)
There were no significant differences in both thermal hyperalgesia and mechanical allodynia between the 5 mg/kg treatment group and the CCI vehicle group (Figures 1A,B)
Summary
Neuropathic pain is a debilitating form of chronic pain caused by traumatic nerve injury, toxic insults and various disease states (Donvito et al, 2018). Endogenous cannabinoids are not stored in vesicles and are produced when/where they are needed This “on demand” synthesis suggests that the production of endocannabinoids is able to activate cannabinoid receptors in a time- and region-specific manner without activating all accessible receptors indiscriminately (Hwang et al, 2010). Following the induction of inflammatory and neuropathic pain, cannabinoid receptors and their endogenous ligands AEA and 2-AG are increased in dorsal root ganglion (DRG) and spinal cord dorsal horn on the ipsilateral side of injury (Mitrirattanakul et al, 2006; Drew et al, 2009). In the formalin model, selective inhibitor of 2-AG hydrolysis increases the level of 2-AG to exert analgesic effect (Bisogno et al, 2009) All of these findings indicate that inflammatory and neuropathic pain involves peripheral and central endocannabinoid alteration, suggesting that manipulation of the endocannabinoid system may play a predominant role in the pain treatment
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