Therapeutic Effect of the Substrate-Selective COX-2 Inhibitor IMMA in the Animal Model of Chronic Constriction Injury

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.

A Guide to Targeting the Endocannabinoid System in Drug Design

“…CB2 antagonist, AM630 (3 mg/kg intraperitoneally), partially reversed IMMA's action. This compound has a complex MOA, including reduction in prostaglandin E 2 (PGE2) synthesis and CB2 activation [86]. Other studies focused on aripiprazole, an antypsychotic drug and a ligand of multiple dopamine (DA) and serotonin (5-HT) receptors.…”

Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats

“…Many studies have indicated that persistent mechanical hypersensitivity was induced in the hind paw following sciatic nerve injuries along with microglial cell accumulation in the spinal dorsal horn (SDH), and the suppression of microglial cell activation in the spinal cord significantly alleviated mechanical hypersensitivity [11][12][13]. In SDH, the increased Iba1 immunoreactivity that indicates the hyperactive states of microglia was reported to be detected as early as 20 min, peaking on day 3, and remaining at a significant level on day 7 following peripheral nerve injury [14].…”

Protocatechuic acid as an inhibitor of the JNK/CXCL1/CXCR2 pathway relieves neuropathic pain in CCI rats

“…Repair and regeneration after nerve injury involves a complex process of change, including inflammatory reaction, adhesion reaction, extracellular matrix synergy, regulation of neurotrophic factors on regeneration, synthesis and release of neurotransmitters, formation and extension of growth cones, and regeneration of neurons. It has been reported that drug treatment can reduce the aggregation of astrocytes and microglia in spinal dorsal horn and the infiltration of macrophages into dorsal root ganglion and sciatic nerve [36]. Anethole inhibited the activation of glial cells, decreased the secretion of pro-inflammatory cytokines to relieve the chronic nerve injury in mice [37].…”

“…in the treatment of nerve injury [36,[45][46][47][48]. In addition, the NF-κB signaling pathway is also reported as being involved in nerve injury.…”