Yeşilyurt Ozgür, Dogrul Ahmet
Department of Medical Pharmacology, Gülhane Military Academy of Medicine, 06018 Etlik, Ankara, Turkey.
Neurosci Lett. 2004 Nov 23;371(2-3):122-7. doi: 10.1016/j.neulet.2004.08.052.
Opioids and cannabinoids produce antinociception through activity at spinal, supraspinal and peripheral sites. Tolerance to the antinociceptive effects of both the opioids and the cannabinoids develop when these agents are administered chronically. Although mutual potentiation of antinociceptive effects have been reported between opioids and cannabinoids, the development of antinociceptive cross-tolerance between these systems has not been demonstrated consistently. In the present investigation, we explored the possibility of antinociceptive cross-tolerance between systemic or topical morphine and systemic or topical cannabinoids in mice. Mice were made tolerant to morphine either by the subcutaneous (s.c.) implantation of a morphine pellet or repeated topical administration and then challenged with the mixed CB(1) and CB(2) receptor agonist WIN 55, 212-2 given s.c. or topically. Antinociception was indicated by increased tail-flick latencies to noxious radiant heat. Implantation with morphine pellets did not attenuate the antinociceptive potency of systemic or topical WIN 55,212-2. Moreover, twice-daily topical administration of morphine did not attenuate the antinociceptive potency of WIN 55,212-2 applied topically. These observations suggest that opioids and cannabinoids produce antinociception through mechanisms that are independent of each other at either the systemic or peripheral levels.
阿片类药物和大麻素通过在脊髓、脊髓上和外周部位发挥作用产生抗伤害感受。当长期给予这些药物时，会产生对阿片类药物和大麻素抗伤害感受作用的耐受性。虽然已有报道阿片类药物和大麻素之间存在抗伤害感受作用的相互增强，但这些系统之间抗伤害感受交叉耐受性的发展尚未得到一致证实。在本研究中，我们探讨了全身或局部应用吗啡与全身或局部应用大麻素在小鼠中产生抗伤害感受交叉耐受性的可能性。通过皮下（s.c.）植入吗啡丸或重复局部给药使小鼠对吗啡产生耐受性，然后用混合的CB(1)和CB(2)受体激动剂WIN 55,212-2进行皮下或局部给药挑战。通过对有害辐射热的甩尾潜伏期延长来表明抗伤害感受。植入吗啡丸并未减弱全身或局部应用WIN 55,212-2的抗伤害感受效力。此外，每天两次局部应用吗啡并未减弱局部应用WIN 55,212-2的抗伤害感受效力。这些观察结果表明，阿片类药物和大麻素在全身或外周水平通过相互独立的机制产生抗伤害感受。
