A subanalgesic dose of morphine eliminates nalbuphine anti-analgesia in postoperative pain.

UNLABELLED: The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by coadministration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by coadministering a dose of morphine low enough that it does not produce analgesia. After extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of 2 low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low-dose morphine may act as an anti-analgesia opioid receptor antagonist. PERSPECTIVE: Previously, we reported that the nalbuphine produces both analgesic and anti-analgesic effects and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism.

Clocinnamox distinguishes opioid agonists according to relative efficacy in normal and morphine-treated rats trained to discriminate morphine.

High doses of insurmountable antagonists or frequent administration of high doses of agonists are required to alter the potency of opioid agonists to produce discriminative stimuli. In the present study, insurmountable antagonism and repeated agonist treatment were combined to remove or disable a large enough proportion of mu-opioid receptors to alter the potency or maximal effect for four agonists in male Sprague-Dawley rats trained to discriminate 3.2 mg/kg morphine from saline under a fixed-ratio 15 schedule of food reinforcement. All agonists produced 88 to 100% morphine responding and were differentially sensitive to clocinnamox antagonism (fentanyl < morphine < or = buprenorphine = nalbuphine). Repeated treatment with 20 mg/kg per day morphine for 6 days decreased by 2- to 3-fold the potency of fentanyl, morphine, and buprenorphine to produce morphine responding. After morphine treatment, 3.2 mg/kg clocinnamox produced a 7-fold further decrease in morphine potency. Clocinnamox (10 mg/kg) produced a 7- and 12-fold further decrease in morphine and fentanyl potency, respectively, a reduction in the slope of the morphine dose-response curve, and a suppression of the maximal morphine responding for buprenorphine. Repeated treatment with 10 mg/kg per day morphine for 6 days failed to alter the potency of nalbuphine to produce morphine responding. In these morphine-treated rats, doses of 3.2 or 10 mg/kg clocinnamox suppressed the maximal morphine responding. Taken together, these data indicate that combined insurmountable antagonist and repeated agonist treatment produce additive effects at mu-opioid receptors to diminish discriminative stimulus effects in a manner predicted by the relative efficacy of opioid agonists.

Effects of morphine, nalbuphine and pentazocine on gastric emptying of indigestible solids.

The effects of morphine (CAS 57-27-2), nalbuphine (CAS 20594-83-6) and pentazocine (CAS 359-83-1) on gastric emptying of indigestible solids were studied. In rats, which were fasted for 24 h, either morphine, nalbuphine, pentazocine or saline was injected intraperitoneally, and ten steel balls (1.0 mm in diameter) were inserted into the stomach. At 3 h, the number of balls which had passed into the small intestine was counted. If these drugs inhibited gastric emptying, naloxone was injected concurrently to study the mechanisms of the inhibitory effect. Morphine, nalbuphine and pentazocine significantly inhibited gastric emptying (ED50:0.041 [95% confidence interval: 0.0078-0.14] mg kg-1, 0.0012 [0.00037-0.0081] mg kg-1 and 0.81 [0.41-1.30] mg kg-1, respectively). Naloxone 0.3 mg kg-1 antagonized the inhibitory effect of both morphine 1.3 mg kg-1 (ED75) and nalbuphine 0.005 mg kg-1 (ED75). In contrast, naloxone 0.3 or 1.0 mg kg-1 did not antagonize the effect of pentazocine 1.9 mg kg-1 (ED75), but a higher dose of naloxone (3.0 mg kg-1) did so. Therefore, in the rat, morphine, nalbuphine and pentazocine inhibit gastric emptying of indigestible solids, and it is likely that morphine and nalbuphine inhibit the emptying through the same opioid receptor, whereas pentazocine does so through a different receptor interaction.

Antagonistic effect of MR2266 and MR2267 on morphine or nalbuphine analgesia at the spinal levels in rats.

The aim of this paper was to study the effect of two benzomorphan derivatives MR2266 and MR2267 with predominant antagonism to kappa-opioid receptors administered intrathecally on the analgesic action of morphine and nalbuphine. Both compounds attenuated the analgesia elicited by examined opioid agonists. Our results support the hypothesis that the spinal opioid receptors take part in analgesic effect of morphine and nalbuphine. It was for the first time described that MR2267, considered as inactive enantiomer of MR2266, is an active opioid antagonist when administered intrathecally.

Nalbuphine, a mixed kappa 1 and kappa 3 analgesic in mice.

Nalbuphine is a mixed opioid agonist/antagonist analgesic. It labels mu receptors most potently where it acts as an antagonist. Nalbuphine is analgesic in the tail-flick assay after systemic (ED50, 41.8 mg/kg s.c.), i.c.v. (ED50, 21.3 micrograms) or intrathecal administration (ED50, 11.2 micrograms). Analgesia elicited by systemic nalbuphine was reversed by nor-binaltorphimine, but not by beta-funaltrexamine or naltrindole despite their ability to antagonize morphine and [D-Pen2,D-Pen5]enkephalin analgesia, respectively. This insensitivity toward beta-funaltrexamine and naltrindole argued strongly against either a mu or delta component of analgesia. Nor-binaltorphimine antagonized systemic nalbuphine analgesia over 10-fold more potently after intrathecal injection of the antagonist than after i.c.v. administration, implying a role for kappa 1 receptors at the spinal level. The presence of analgesic cross-tolerance between nalbuphine and both naloxone benzoylhydrazone and nalorphine indicated an analgesic role for kappa 3 receptors, which act supraspinally. Additional studies revealed synergistic interactions between spinal kappa 1 and supraspinal kappa 3 receptors when nalbuphine was given both intrathecally and i.c.v. In conclusion, these studies suggest that nalbuphine elicits analgesia through a complex interaction of supraspinal kappa 3 and spinal kappa 1 mechanisms.

The possible involvement of alpha-adrenoceptors in the intestinal effect of nalbuphine in mice.

In the present study, intestinal motility was measured by the transit of charcoal meal through the small intestine in mice. Nalbuphine, given subcutaneously, caused a dose-dependent inhibition of the intestinal transit in mice. This inhibitory effect of nalbuphine was antagonized by prior s.c. administration of naloxone and MR2266. In addition, the inhibitory effect of nalbuphine was also suppressed by prior administration of yohimbine, an alpha 2-adrenoceptor antagonist, and phentolamine, an antagonist for both alpha 1- and alpha 2-adrenoceptors. Unlike morphine, the intestinal inhibitory effect of nalbuphine was also antagonized by prazosin, a selective alpha 1-adrenoceptor antagonist. However, prior administration of propranolol did not alter this effect of nalbuphine. These adrenoceptor antagonists by themselves, at the doses used, had no effect on the rate of intestinal transit of a charcoal meal in mice. These results suggest that both alpha 1- and alpha 2-adrenoceptors may be involved in the intestinal effect of nalbuphine while beta-adrenoceptors do not appear to play any significant role in this aspect of nalbuphine's action.

Pressor effect of nalbuphine in hemorrhagic shock is dependent on the sympathoadrenal system.

Nalbuphine, an analgesic with opiate agonist and antagonist properties, increases heart rate, mean arterial pressure (MAP), and cardiac function following a moderate hemorrhage in the rat. The interaction between opiate receptors and the sympathoadrenal system was examined in control, beta receptor-blocked, and adrenal-demedullated animals. MAP and heart rate were measured continuously in chronically instrumented conscious animals. Hemorrhage decreased MAP in the control group by 50%, and nalbuphine (1 mg/kg) returned this to prehemorrhage values within 5 min. MAP remained significantly greater in the nalbuphine-treated animals for 120 min. Heart rate fell with hemorrhage and increased above prehemorrhage values in the nalbuphine-treated animals. The pressor response to nalbuphine was abolished in both beta-blocked and adrenal-demedullated animals. Plasma catecholamines were not significantly elevated in the nalbuphine-treated as compared to control animals, which suggests that nalbuphine effects do not result from an enhancement of central mediated sympathoadrenal discharge. The opiate receptor antagonist naloxone, in a concentration that was not by itself effective in alleviating the hypotensive effects of hemorrhage, prevented the pressor response with nalbuphine. These results suggest that nalbuphine's beneficial effects in hemorrhagic shock depend on an intact sympathoadrenal system and on an interaction with opiate receptor sites, possibly in the heart.

Ceiling effect for respiratory depression by nalbuphine.

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.