Loperamide, a peripheral Mu-Opioid receptor agonist, attenuates chemotherapy-induced neuropathic pain in rats

Opioids are employed in the management of chemotherapy-induced neuropathic pain (CINP) when other pain management approaches have failed and proven ineffective. However, their use in CINP is generally considered as a second-line or adjunctive therapy owing to their central side effects and development of tolerance with their long-term usage. Targeting peripheral sites may offer several advantages over the conventional CNS-based approaches as peripheral targets modulate pain signals at their source, thereby relieving pain with higher specificity, efficacy and minimizing adverse effects associated with off-site CNS actions. Therefore, present study was designed with an aim to investigate the effect of loperamide, a peripherally acting mu-opioid receptor agonist, on paclitaxel-induced neuropathic pain in rats and elucidate its underlying mechanism. Loperamide treatment significantly attenuated mechanical, and cold hypersensitivity and produced significant place preference behaviour in neuropathic rats indicating its potential to treat both evoked and spontaneous pain. More importantly, loperamide treatment in naive rats did not produce place preference to drug-paired chamber pointing towards its non-addictive analgesic potential. Further, molecular investigations revealed increased expression of ion channels such as TRPA1, TRPM8; voltagegated sodium channels (VGSCs) and neuroinflammatory markers in the dorsal root ganglion (DRG) and lumbar (L4-L5) spinal cord of neuropathic rats, which was significantly downregulated upon loperamide treatment. These findings collectively suggest that activation of peripheral muopioid receptors contributes to the amelioration of both evoked and spontaneous pain in neuropathic rats by downregulating TRP channels and VGSCs along with suppression of oxidonitrosative stress and neuro-inflammatory cascade.