Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological selectivity and effect of training dose on agonist and antagonist effects of mu opioids
24
Citation
0
Reference
10
Related Paper
Citation Trend
Keywords:
Nalorphine
Nalbuphine
Opioid antagonist
Stimulus generalization
Stimulus (psychology)
The discriminative stimulus effects of enadoline were characterized in pigeons responding under a fixed-ratio 20 schedule of food presentation and discriminating between intramuscular injections of the kappa opioid agonist enadoline and saline. Cumulative doses of enadoline dose-dependently increased drug-key responding with the training dose of enadoline (0.178 mg/kg) producing > or = 90% drug key responding (% DR). In time course studies, doses of enadoline larger than 0.32 mg/kg produced > or = 90% DR for more than 40 min. Naltrexone antagonized both the discriminative stimulus and the rate-decreasing effects of enadoline (pA2 = 6.79 and 6.73, respectively); in some pigeons, naltrexone produced an unsurmountable antagonism of the enadoline discriminative stimulus. Substitution tests using the kappa agonists U-50,488, spiradoline, U-69,593 and ethylketocyclazocine resulted in > or = 90% DR in most, but not all, pigeons; at larger doses, all compounds markedly decreased response rates. Up to rate-decreasing doses, nalorphine, dynorphin A(1-13) amide (DYN), nalbuphine, butorphanol, morphine and ketamine failed to occasion > or = 90% DR; nalbuphine, nalorphine, butorphanol, but not DYN, antagonized the discriminative stimulus and the rate-decreasing effects of enadoline. This study established stimulus control with enadoline in pigeons and results from substitution studies in these pigeons support the view that the enadoline discriminative stimulus is mediated by kappa opioid receptors; these results further demonstrate that nalbuphine and butorphanol have kappa antagonist actions in pigeons. The negative results obtained with DYN are in contrast to previous demonstrations of kappa agonist effects for DYN and might provide support for the hypothesized importance of nonopioid systems in the effects of this peptide.
Nalorphine
Nalbuphine
Butorphanol
κ-opioid receptor
Opioid antagonist
Cite
Citations (14)
The discriminative stimulus effects of nalbuphine were studied in 15 male Sprague-Dawley rats trained to discriminate 3.2 mg/kg of nalbuphine from saline under a fixed-ratio 15 schedule of food delivery. Cumulative doses of nalbuphine produced nalbuphine lever responding at doses of 1.0 to 10 mg/kg and rate-suppressing effects at doses of 3.2 to 32 mg/kg. Experiments to evaluate the contribution of opioid receptor activity suggested that the stimulus effects of nalbuphine were mediated through mu systems, inasmuch as mu agonists (etorphine, fentanyl, morphine, buprenorphine, GPA 1657 and nalorphine) produced nalbuphine lever responding, whereas kappa agonists [EKC and U-50,488H (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl] benzeneacetamide methanesulfonate hydrate)] and nonopioids (d-pentazocine, d-amphetamine and ketamine) produced saline lever responding. dl-Pentazocine produced nalbuphine lever responding in one-half the rats tested. Both high and low efficacy agonists produced nalbuphine lever responding, but the antagonist naltrexone produced predominantly saline lever responding. Increasing the training dose of nalbuphine by a 0.50 log unit failed to alter the potency of nalbuphine or any other compound to produce nalbuphine lever responding, suggesting that these training doses produce a maximum amount of stimulation at the mu receptor. Naltrexone antagonized the discriminative stimulus but not the rate-decreasing effects of nalbuphine, suggesting that only the discriminative stimulus effects of nalbuphine are mediated by a mu opioid mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)
Nalbuphine
Nalorphine
Etorphine
Pentazocine
Cite
Citations (39)
In opioid-dependent subjects, the low-efficacy μ agonist nalbuphine generally precipitates withdrawal or withdrawal-like stimulus effects. To provide a more complete characterization of the discriminative stimulus effects of nalbuphine in opioid-treated subjects, seven White Carneux pigeons were treated daily with 10 mg/kg morphine i.m. and trained 6 h later to discriminate among 10 mg/kg morphine, 1.0 mg/kg nalbuphine, and saline by responding on one of three different keys. When tested, morphine produced morphine-key responding and nalbuphine produced nalbuphine-key responding. Replacing the daily morphine injection with saline produced nalbuphine-key responding, and this effect was reversed by the administration of morphine. In substitution tests with other compounds, the antagonists naltrexone (i.m.) and CTAP (d-Phe-Cys-Tyr-d-Tryp-Lys-Thr-Pen-Thr-NH2) (i.c.v.) produced nalbuphine-key responding. High-efficacy agonists fentanyl and etorphine produced morphine-key responding. The intermediate-efficacy agonists buprenorphine, dezocine, and butorphanol produced a pattern of morphine-, saline-, and/or nalbuphine-key responding that differed across individual pigeons. The lower efficacy agonists nalorphine and levallorphan produced predominantly nalbuphine-key responding. The κ agonists spiradoline and U50,488 [trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate], the nonopioid d-amphetamine, and saline produced predominantly saline-key responding. Naltrexone and nalbuphine dose dependently reversed the morphine-key responding produced by the training dose of morphine. Together, these data suggest that the discriminative-stimulus effects of the low-efficacy μ agonist nalbuphine in morphine-treated pigeons are similar to those of other low-efficacy agonists, naltrexone, and the termination of daily morphine treatment.
Nalbuphine
Nalorphine
Etorphine
Butorphanol
Cite
Citations (15)
Rats learned to discriminate cyclazocine (2 mg/kg, i.p.) from saline using a two-lever operant (FR-4) procedure within 10 sessions under each drug condition. The cyclazocine discriminative stimulus (DS) was both dose- and time-related, being antagonized by naloxone at doses approximately 80 times that necessary to block the discriminative stimulus effect of morphine. Cyclazocine also generalized to nalorphine, but not to morphine, pentazocine or LSD. These data suggest that cyclazocine produced DS control of behavior by acting at CNS sites different from those affected by morphine or LSD.
Nalorphine
Pentazocine
Stimulus generalization
Stimulus (psychology)
Opiate
Cite
Citations (7)
Nalorphine
Nalbuphine
Pentazocine
Narcotic antagonists
Narcotic antagonists
Thebaine
Narcotic
Cite
Citations (5)
Pentazocine
Nalorphine
Nalbuphine
Narcotic antagonists
Dose
Cite
Citations (1)
The respiratory depressant capacities of intravenous nalbuphine, a potent analgesic of the narcotic antagonist type, and of morphine were compared in 23 healthy subjects using displacement of CO2 response by a steady-state method as the index of respiratory depression. At equianalgesic doses of 10 mg/70 kg, respiratory depression by nalbuphine was equal to that by morphine. When increments of 10 mg/70 kg were given hourly the dose-effect curve for respiratory depression by nalbuphine was flatter than that of morphine, and maximum respiratory depression occurred after 30 mg/70 kg. In a separate study of 10 subjects nalbuphine was administered in 10 mg/70 kg increments to a total dose of 60 mg/70 kg; doses in excess of 30 mg/70 kg failed to increase respiratory depression beyond that induced by morphine 20 mg/70 kg. A ceiling effect for respiratory depression previously known to exist only for nalorphine was thereby demonstrated to apply to nalbuphine. The respiratory depression of nalbuphine was readily antagonized by naloxone 0.4 mg, nalorphine 10 mg, and levallorphan 1.0 mg. Subjective effects of nalbuphine were milder than those of morphine, and dysphoria suggestive of the psychotomimetic effects of narcotic antagonists was reported only 4 times in 24 subject exposures. The ceiling effect for respiratory depression by nalbuphine provides a unique safety factor among potent analgesics. Clinical Pharmacology and Therapeutics (1980) 27, 478–485; doi:10.1038/clpt.1980.67
Nalbuphine
Nalorphine
Narcotic antagonists
Ceiling effect
Narcotic
Cite
Citations (250)
Pentazocine (PZ), buprenorphine, butorphanol, cyclazocine, and nalbuphine are known to have opioid agonistic and opiate antagonistic effects. The analgesic efficacies of these drugs are generally high, and the relative potencies against morphine in humans are, in the above order, 1/3, 20-40, 5, 10-20, 1, and 1/7-1/10. The relative potencies of the antagonistic effect against nalorphine in humans are 1/50, 10, none, 5-7, 1, and 1/7-1/10 respectively. However, both in animals and humans, the synergism between morphine and PZ is observable when the doses of both drugs are relatively low.
Nalbuphine
Nalorphine
Pentazocine
Butorphanol
Narcotic antagonists
Opiate
Cite
Citations (1)
Nalbuphine is a narcotic antagonist and analgesic. A dose of 8 mg. per 70 Kg. of nalbuphine in man produces subjective effects which resemble those of 10 mg. per 70 Kg. of morphine. Nalbuphine, in doses of 24 and 72 mg. per 70 Kg., produces mild effects which more closely resemble those of nalorphine. Nalbuphine is ¼ as potent as nalorphine in precipitating abstinence in subjects dependent on 60 mg. of morphine per day. Chronic administration of nalbuphine produces physical dependence which resembles that produced by pentazocine, since it has elements of both morphine and nalorphine dependence. It is concluded that nalbuphine has an abuse potential which approximates that of pentazocine, but equianalgesic doses of nalbuphine produce less nalorphine‐like effects than does pentazocine.
Nalbuphine
Nalorphine
Pentazocine
Narcotic antagonists
Physical dependence
Narcotic
Cite
Citations (110)
Nalbuphine
Nalorphine
Pentazocine
Narcotic antagonists
Agonist-antagonist
Cite
Citations (197)