The bifunctional μ opioid agonist/antioxidant [Dmt(1)]DALDA is a superior analgesic in an animal model of complex regional pain syndrome-type i.
Reactive oxygen species (ROS) play an important role in the development of complex regional pain syndrome-Type I (CRPS-I), as also demonstrated with the chronic post ischemia pain (CPIP) animal model of CRPS-I. We show that morphine and the antioxidant N-acetylcysteine (NAC) act synergistically to reduce mechanical allodynia in CPIP rats. The tetrapeptide amide [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) is a potent and selective μ opioid receptor (MOR) agonist with favorable pharmacokinetic properties and with antioxidant activity due to its N-terminal Dmt (2',6'-dimethyltyrosine) residue. In the CPIP model, [Dmt(1)]DALDA was 15-fold more potent than morphine in reversing mechanical allodynia and 4.5-fold more potent as analgesic in the heat algesia test. The results indicate that bifunctional compounds with MOR agonist/antioxidant activity have therapeutic potential for the treatment of CRPS-I.
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Quebec Canada H2W 1R7.|Department of Pharmacology, Université de Montréal , Montreal, Quebec, Canada H3C 3J7.
Peter W
PW
Schiller
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Ave. West, Montreal, Quebec Canada H2W 1R7.
Thi M-D
TM
Nguyen
Department of Psychology, McGill University , 1205 Dr. Penfield Ave., Montreal, Quebec, Canada H3A 1B1.
Amy
A
Saray
Anesthesia Research Unit, Department of Anesthesia, McGill University , 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
Annie Wing Hoi
AW
Poon
Anesthesia Research Unit, Department of Anesthesia, McGill University , 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
André
A
Laferrière
Anesthesia Research Unit, Department of Anesthesia, McGill University , 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
Terence J
TJ
Coderre
D000111:Acetylcysteine / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D019540:Area Under Curve; D059350:Chronic Pain / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D020318:Rats, Long-Evans; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D012019:Reflex Sympathetic Dystrophy / Q000188:drug therapy* / Q000378:metabolism; D014110:Touch
C424424:2',6'-dimethyltyrosyl-arginyl-phenylalanyl-lysinamide; D000701:Analgesics, Opioid; D000975:Antioxidants; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D009020:Morphine; D000111:Acetylcysteine
CRPS-I therapeutics; [Dmt1]DALDA; bifunctional μ opioid/antioxidant peptide; chronic post ischemia pain (CPIP) rat model; complex regional pain syndrome-type I (CRPS-I); μ opioid-antioxidant synergy