Dermorphin [D-Arg2, Lys4] (1-4) Amide Attenuates Burn Pain by Inhibiting TRPV1/NR2B Mediated Neuroinflammatory Signalling.

Burn injury-induced chronic pain is a highly debilitating condition that profoundly impacts the well-being of military veterans and the general population. Current pain management for burn injured patients mainly relies on central opioids, often causing sedation, addiction, and physical dependence. This study aims to investigate the effects of Dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripherally acting μ-opioid receptor (MOR) agonist in an animal model of burn injury-induced chronic pain while unravelling the underlying mechanisms. Soldering apparatus was used to induce burn pain in Sprague Dawley rats followed by testing for both evoked and ongoing pain behaviours. Molecular investigations were performed for TRPV1, NR2B, neuro-inflammatory and glia cell markers (TNF-α, IL-6, Iba-1 & ICAM-1), and neuropeptides (CGRP), using western blotting and RT-PCR analysis. Burn-injured rats exhibited significant hypersensitivity to mechanical, thermal, and cold stimuli, along with severe ongoing pain. Systemic administration of DALDA significantly reduced evoked pain behaviour in a dose-dependent manner (1, 3, and 10 mg/kg), with the 10 mg/kg s.c. dose effectively alleviating spontaneous pain without causing drug addiction. DALDA also restored antioxidant enzyme levels in the sciatic nerve and downregulated burn injury-induced molecular changes, including TRPV1, NR2B, and CGRP, as well as neuroinflammatory markers such as TNF-α and IL-6 in the DRG and spinal cord of rats. Activation of peripheral μ-opioid receptors efficiently mitigates both evoked and spontaneous pain in burn-injured rats, without causing central nervous system (CNS)-related side effects. Findings from the present study demonstrate a promising approach to mitigate burn pain, overcoming the limitations associated with centrally acting opioids.