beta-funaltrexamine and Opioid-Related-Disorders

Topics: Animals; Aorta, Thoracic; Cocaine; Cyclic AMP; Electric Stimulation; Guinea Pigs; Humans; Ileum; In Vitro Techniques; Male; Mice; Muscle, Smooth; Opioid-Related Disorders; Rats; Receptors, Dopamine; Receptors, Opioid; Receptors, Serotonin; Substance-Related Disorders

Nalbuphine, an opioid mixed agonist-antagonist, prevents many morphine-related side effects. In this study, we compared the effects of nalbuphine versus naloxone on the prevention of morphine tolerance and dependence in Sprague-Dawley rats. Group 1 received a morphine 5 mg/kg intraperitoneal (I.P.) injection. Groups 2 and 3 received single doses of nalbuphine (0.01 to 5 mg/kg I.P.) or naloxone (1 to 500 microg/kg I.P.) coadministered with morphine (5 mg/kg I.P.), respectively. Group 4 received a saline I.P. injection. Treatments were continued for 4 days. The occurrence of tolerance was estimated by comparing the antinociceptive effect of morphine on Day 1 (Group 1) and Day 5 (each group). The severity of dependence was determined by precipitated withdrawal signs (incidence of diarrhea and teeth chattering) induced by naloxone (10 mg/kg I.P.). We found that coadministration of nalbuphine or naloxone with morphine dose-dependently blocked the development of morphine tolerance and dependence. However, unlike naloxone, nalbuphine did not attenuate the antinociceptive effect of morphine.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug Tolerance; Male; Morphine; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Pyrrolidines; Rats; Rats, Sprague-Dawley

Butorphanol has been known to act on mu-, delta-, and kappa-opioid receptors, mu- and possibly delta-receptors are thought to mediate morphine dependence. Relative to morphine, butorphanol has a higher affinity for mu- and delta-receptors. In the present study, beta-funaltrexamine (beta-FNA) and naltrindole (NTI) (nonequilibrium mu- and delta-antagonist, respectively) were used to precipitate withdrawal in butorphanol-dependent rats. It was found that beta-FNA (12, 24, 48, and 100 nM) did not elicit significant withdrawal behaviors, while NTI caused teeth-chattering (100 nM), wet shakes (100 nM), forepaw tremors (24 nM), yawning (48 and 100 nM), ejaculation (24 nM), and urination (100 nM). The present results indicate that delta-opioid receptors may be involved in mediating butorphanol dependence, while the involvement of mu-opioid receptors needs to be further investigated.

Topics: Animals; Behavior, Animal; Butorphanol; Indoles; Injections, Intraventricular; Male; Morphinans; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Receptors, Opioid, mu; Substance Withdrawal Syndrome

We have previously reported that chicken embryos injected with a single dose of methadone (Meth) on day 3, 7 or 11 of embryogenesis fail to show dependence on day 14, measured as a significant overshoot in motility above baseline after challenge with the opioid antagonist naloxone (Nx). Constant infusion of Meth from day 7 to 14 also failed to produce evidence of dependence on day 14. To address the question of whether the 14-day-old embryo is capable of expressing withdrawal, isobutylmethylxanthine (IBMX), a compound that produces quasi-opioid withdrawal, was injected directly into the embryo, resulting in a significant increase in motility. To determine whether the 14-day-old embryo could also express true opioid withdrawal, the embryos were injected with various doses of Meth or morphine (Morph), followed at different time intervals by injections of varying doses of Nx. A high dose of Morph followed 24 hours later by a low dose of Nx produced evidence of withdrawal, as did a low dose of Meth followed 1 hour later by a higher dose of Nx, U50488H, a selective kappa agonist, had no effect on motility in the 14-day-old embryo, suggesting that the decrease in motility seen after Meth was not mediated by a kappa receptor. Pretreatment with the irreversible mu antagonist, beta-funaltrexamine (B-FNA), blocked the decrease in motility seen after Meth and also prevented the overshoot in motility when Nx was given 1 hour post-Meth. We were also able to demonstrate dependence/withdrawal in the 12-day-old embryo, but higher doses of both Meth and Nx were required.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 1-Methyl-3-isobutylxanthine; 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Chick Embryo; Methadone; Morphine Dependence; Motor Activity; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Pyrrolidines; Receptors, Opioid; Substance Withdrawal Syndrome

Topics: Animals; Drug Tolerance; Naltrexone; Narcotic Antagonists; Narcotics; Opioid-Related Disorders; Rats; Receptors, Opioid; Spinal Cord

The acute administration of morphine produces a characteristic increase in plasma corticosterone. By using the male rat with a chronic i.v. catheter, a stereotaxically placed cannula in the lateral ventricle and a sound-attenuated one-way vision chamber, the effects of prototypic kappa and sigma opiate receptor agonists were studied. Both ethyl-ketocyclazocine (EKC) and N-allyl-normetazocine [SKF 10047] (SKF) also produced such a rise in hormone level after i.v. or i.c.v. administration. The former effect was blocked by concurrent treatment with naloxone (NX), 0.4 mg/kg. The latter effect was not blocked by i.c.v. pretreatment with beta-funaltrexamine, a long-acting mu receptor antagonist, whereas the response to i.c.v. morphine was attenuated significantly. The development of acute dependence and short-term tolerance to EKC and SKF was also studied. Priming with either drug (i.v.) did not result in a NX-precipitated plasma corticosterone withdrawal response 3 hr later. Similar studies priming with morphine (i.c.v.) did result in the plasma corticosterone-elevated response when NX was administered i.c.v. after 3 hr. When EKC or SKF was substituted for morphine, no NX-induced response was observed. Short-term tolerance to the effects of EKC and SKF on the hypothalamo-pituitary-adrenal axis did not appear to occur. These data support the notion that stimulation of several subclasses of opiate receptors will result in the activation of the hypothalamo-pituitary-adrenal axis. Furthermore, it appears that the mu opiate receptor is involved in the initiation of acute opiate dependence.

Topics: Animals; Brain; Corticosterone; Cyclazocine; Ethylketocyclazocine; Humans; Hypothalamo-Hypophyseal System; Male; Morphine; Naloxone; Naltrexone; Opioid-Related Disorders; Phenazocine; Pituitary-Adrenal System; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu; Receptors, sigma