A novel combination of opiates and endothelin antagonists to manage pain without any tolerance development

J Cardiovasc Pharmacol. 2004 Nov;44 Suppl 1:S129-31. doi: 10.1097/01.fjc.0000166242.43616.c2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Non-Narcotic / administration & dosage
  • Analgesics, Non-Narcotic / pharmacology*
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Dansyl Compounds / administration & dosage
  • Dansyl Compounds / pharmacology*
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Drug Tolerance*
  • Endothelin A Receptor Antagonists*
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Injections, Intraventricular
  • Male
  • Mice
  • Morphine / pharmacology*
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Pain / drug therapy*
  • Pain / metabolism
  • Pain / physiopathology
  • Pain Measurement
  • Pain Threshold / drug effects
  • Peptides, Cyclic / administration & dosage
  • Peptides, Cyclic / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Endothelin A / metabolism
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / metabolism
  • Sulfur Radioisotopes
  • Time Factors

Substances

  • Analgesics, Non-Narcotic
  • Analgesics, Opioid
  • Dansyl Compounds
  • Endothelin A Receptor Antagonists
  • Narcotic Antagonists
  • Peptides, Cyclic
  • Receptor, Endothelin A
  • Receptors, Opioid, mu
  • Sulfur Radioisotopes
  • 5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide
  • Naloxone
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Morphine
  • cyclo(Trp-Asp-Pro-Val-Leu)