Paradoxical Effects of the Opioid Antagonist Naltrexone on Morphine Analgesia, Tolerance, and Reward in Rats
| Autor: | Asha Jhamandas, Noura S. Abul-Husn, Mary C. Olmstead, Kelly J. Powell, Richard J. Beninger, Khem Jhamandas |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Male
medicine.drug_class Narcotic Antagonists Physical dependence (+)-Naloxone Pharmacology Naltrexone Rats Sprague-Dawley Mice Reward Drug tolerance Animals Medicine Rats Wistar Injections Spinal Pain Measurement Morphine Naloxone business.industry Drug Tolerance Conditioned place preference Rats Analgesics Opioid Opioid Conditioning Operant Molecular Medicine medicine.symptom business Injections Intraperitoneal Opioid antagonist medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 300:588-596 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 microg) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 microg i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 microg) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations. |
| Databáze: | OpenAIRE |
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