The mixed kappa and delta opioid receptor agonist, MP1104, attenuates chemotherapy-induced neuropathic pain. (1st March 2021)

• Record Type: Journal Article
• Authors: Atigari, Diana Vivian; Paton, Kelly Frances; Uprety, Rajendra; Váradi, András; Alder, Amy Frances; Scouller, Brittany; Miller, John H.; Majumdar, Susruta; Kivell, Bronwyn Maree
• Is Part Of: Neuropharmacology. Volume 185(2021)
• Publication Date: 2021-03-01
• Subjects: Mixed opioid receptor agonist -- Neuropathic pain -- Paclitaxel -- Respiratory depression -- Tolerance -- Tail-withdrawal; β-FNA β-Funaltrexamine -- CINP chemotherapy-induced neuropathic pain -- DMSO dimethyl sulfoxide -- DOP delta opioid receptor -- i.p. intraperitoneal -- KOP kappa opioid receptor -- MOP mu opioid receptor -- MP1104 17-Cyclopropylmethyl-3-hydroxy-4, 5α-epoxy-7, 8-en-6-β-[(3′-iodo)benzamido]-morphinan -- nor-BNI nor-binaltorphimine -- s.c. subcutaneous; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2020.108445
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Effective treatments for chronic pain without abuse liability are urgently needed. One in 5 adults suffer chronic pain and half of these patients report inefficient treatment. Mu opioid receptor agonists (MOP), including oxycodone, tramadol and morphine, are often prescribed to treat chronic pain, however, use of drugs targeting MOP can lead to drug dependency, tolerance and overdose deaths. Kappa opioid receptor (KOP) agonists have antinociceptive effects without abuse potential; however, they have not been utilised clinically due to dysphoria and sedation. We hypothesise that mixed opioid receptor agonists targeting the KOP and delta opioid receptor (DOP) would have a wider therapeutic index, with the rewarding effects of DOP negating the negative effects of KOP. MP1104, an analogue of 3-Iodobenzoyl naltrexamine, is a novel mixed opioid receptor agonist with potent antinociceptive effects mediated via KOP and DOP in mice without rewarding or aversive effects. In this study, we show MP1104 has potent, long-acting antinociceptive effects in the warm-water tail-withdrawal assay in male and female mice and rats; and is longer acting than morphine. In the paclitaxel-induced neuropathic pain model in mice, MP1104 reduced both mechanical and cold allodynia and unlike morphine, did not produce tolerance when administered daily for 23 days. Moreover, MP1104 did not induce sedative effects in the open-field locomotor activity test, respiratory depression in mice using whole-body plethysmography, or have cross-tolerance with morphine. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOP/DOP agonists, as non-addictive pain medications with reduced tolerance. Graphical abstract: Image 1 Highlights: MP1104 is a mixed opioid receptor agonist. MP1104 exerts long-acting antinociceptive effects in the warm-water tail-withdrawal assay. In a paclitaxel-induced neuropathic pain model, MP1104 reduced responding to non-disease levels. MP1104 did not induce sedative or respiratory side-effects.