Activation of Peripheral μ-opioid Receptors by Dermorphin [<scp>d</scp>-Arg2, Lys4] (1–4) Amide Leads to Modality-preferred Inhibition of Neuropathic Pain

Background Opioids have long been regarded as the most effective drugs for the treatment of severe acute and chronic pain. Unfortunately, their therapeutic efficacy and clinical utility have been limited because of central and peripheral side effects. Methods To determine the therapeutic value of peripheral μ-opioid receptors as a target for neuropathic pain treatment, the authors examined the effects of dermorphin [d-Arg2, Lys4] (1–4) amide (DALDA), a hydrophilic, peripherally acting μ-opioid receptor agonist, in male and female rats with spinal nerve ligation–induced neuropathic pain. The authors also utilized behavioral, pharmacologic, electrophysiologic, and molecular biologic tools to characterize DALDA’s possible mechanisms of action in male rats. Results DALDA, administered subcutaneously, had 70 times greater efficacy for inhibiting thermal (n = 8 to 11/group) than mechanical hypersensitivity (n = 6 to 8/group) in male rats. The pain inhibitory effects of DALDA on mechanical and heat hypersensitivity were abolished in animals pretreated with systemic methylnaltrexone (n = 7 to 9/group), a peripheral μ-opioid receptor antagonist. In the spinal wide-dynamic range neurons, systemic DALDA inhibited C-fiber–mediated, but not A-fiber–mediated, response in neuropathic male rats (n = 13). In primary sensory neurons, DALDA inhibited the capsaicin-induced [Ca2+] increase more than the β-alanine–induced [Ca2+] increase (n = 300); capsaicin and β-alanine activate subpopulations of neurons involved in the signaling of heat and mechanical pain, respectively. DALDA-treated rats (n = 5 to 8/group) did not exhibit motor deficits and locomotor impairment suggesting that it does not induce central side effects. Conclusions These findings suggest that DALDA may represent a potential alternative to current opioid therapy for the treatment of neuropathic pain and is likely to be associated with minimal adverse effects.