Uncovering the analgesic effects of a pH-dependent mu-opioid receptor agonist using a model of nonevoked ongoing pain. Issue 12 (December 2020)

• Record Type: Journal Article
• Authors: Massaly, Nicolas; Temp, Julia; Machelska, Halina; Stein, Christoph
• Is Part Of: Pain. Volume 161:Issue 12(2020)
• Publication Date: 2020-12
• Subjects: Ongoing pain -- Inflammatory pain -- Mu-opioid receptor -- Conditioned place preference -- Analgesia; Pain -- Periodicals; Douleur -- Périodiques; Anesthésie -- Périodiques; Pain; Electronic journals; Periodicals; Electronic journals; 616.0472
• DOI: 10.1097/j.pain.0000000000001968
• Languages: English
• ISSNs: 0304-3959

Abstract

Abstract : Abstract: Currently, opioids targeting mu-opioid receptors are the most potent drugs for acute and cancer pain. However, opioids produce adverse side effects such as constipation, respiratory depression, or addiction potential. We recently developed (±)- N -(3-fluoro-1-phenethylpiperidine-4-yl)- N -phenyl propionamide (NFEPP), a compound that does not evoke central or intestinal side effects due to its selective activation of mu-opioid receptors at low pH in peripheral injured tissues. Although we demonstrated that NFEPP effectively abolishes injury-induced pain, hyperalgesia, and allodynia in rodents, the efficacy of NFEPP in nonevoked ongoing pain remains to be established. Here, we examined reward, locomotor activity, and defecation in rats with complete Freund's adjuvant-induced paw inflammation to compare fentanyl's and NFEPP's potentials to induce side effects and to inhibit spontaneous pain. We demonstrate that low, but not higher, doses of NFEPP produce conditioned place preference but not constipation or motor disturbance, in contrast to fentanyl. Using a peripherally restricted antagonist, we provide evidence that NFEPP-induced place preference is mediated by peripheral opioid receptors. Our results indicate that a low dose of NFEPP produces reward by abolishing spontaneous inflammatory pain. Abstract : Supplemental Digital Content is Available in the Text.Using a combination of conditioned place preference and classic pharmacology, we demonstrate that selective activation of opioid receptors in peripheral injured tissue through a novel pH-dependent agonist (NFEPP) inhibits ongoing nonevoked pain, while lacking adverse side effects. These data indicate a potential for translational application of NFEPP to relieve ongoing pain in humans without deleterious consequences.