title: A novel combination of opiates and endothelin antagonists to manage pain without any tolerance development.
abstract: Several neurotransmitter mechanisms have been proposed as playing a role in the development of morphine tolerance. We provide evidence for the first time that endothelin antagonists can restore morphine analgesia in morphine-tolerant rats and prevent the development of tolerance to morphine. Studies were carried out in rats and mice treated with implanted placebo or implanted morphine pellet. The maximal tail-flick latency in morphine pellet + vehicle-treated rats (7.54 seconds) was significantly lower when compared with placebo pellet + vehicle-treated rats (10 seconds), indicating that tolerance developed to the analgesic effect of morphine. BQ123 potentiated tail-flick latency by 30.0% in placebo-tolerant rats and 94.5% in morphine-tolerant rats compared with respective controls. BMS182874 potentiated tail-flick latency by 30.2% in placebo-tolerant rats and 66.7% in morphine-tolerant rats. The enhanced analgesic effect of morphine after treatment with endothelin antagonists could be blocked by naloxone, indicating an opiate-mediated effect; but naloxone binding to brain membranes was not affected by BQ123. Guanosine triphosphate binding was stimulated by morphine and endothelin-1 in non-tolerant mice and not in morphine-tolerant mice; however, guanosine triphosphate binding was stimulated by BQ123 in morphine-tolerant mice and was unaffected in non-tolerant mice. These results suggest that uncoupling of G-protein occurs in morphine tolerance and endothelin antagonist restores the coupling of G-protein to its receptors. A combination use of endothelin antagonist and opiates could provide a novel approach in improving analgesia and eliminating tolerance.
authors.affiliation: Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA. gulati@uic.edu
authors.forename: Anil
authors.initials: A
authors.lastname: Gulati
authors.forename: Shaifali
authors.initials: S
authors.lastname: Bhalla
authors.forename: George
authors.initials: G
authors.lastname: Matwyshyn
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003619:Dansyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004361:Drug Tolerance; D065130:Endothelin A Receptor Antagonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D013462:Sulfur Radioisotopes; D013997:Time Factors
chemical_list: D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D003619:Dansyl Compounds; D065130:Endothelin A Receptor Antagonists; D009292:Narcotic Antagonists; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; D009270:Naloxone; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)