Effects of Buprenorphine, Methylnaltrexone, and Their Combination on Gastrointestinal Transit in Healthy New Zealand White Rabbits.

Among the many analgesic agents available, buprenorphine appears to be the analgesic used most often in rabbits. Unfortunately, deleterious side effects of opioids, such as gastrointestinal stasis and anorexia, may discourage the use of these agents. Methylnaltrexone is a peripheral opioid antagonist that ameliorates opioid-induced gastrointestinal stasis in others species yet preserves the analgesic effects of buprenorphine. We evaluated whether methylnaltrexone reversed buprenorphine-induced gastrointestinal stasis in 8 healthy male New Zealand White rabbits. To measure gastrointestinal transit time, each rabbit received 20 barium-filled spheres through an orogastric tube. Rabbits then received 4 treatments in random order: buprenorphine (0.05 mg/kg SC), methylnaltrexone (1 mg/kg SC), both agents combined (B+M), or normal saline (control) every 12 h for 2 d. Fecal production was measured every 6 h, and water and food consumption, and body weight, were measured daily, for 5 d after each treatment. The time to appearance of the first sphere was significantly longer for buprenorphine group than for control and methylnaltrexone groups. Daily fecal output was lowest for buprenorphine and B+M, intermediate for control, and highest for methylnaltrexone. Water and food consumption were lower for groups buprenorphine and B+M than for control and methylnaltrexone. Body weight was not affected. In conclusion, treatment with buprenorphine 0.05 mg/kg BID for 2 d in healthy rabbits decreased food and water consumption, prolonged gastrointestinal transit time and decreased the fecal output. Coadministration of methylnaltrexone at 1 mg/kg did not alleviate these negative side effects.

Characteristics and comparative severity of respiratory response to toxic doses of fentanyl, methadone, morphine, and buprenorphine in rats.

Opioids are known to induce respiratory depression. We aimed to characterize in rats the effects of four opioids on arterial blood gases and plethysmography after intraperitoneal administration at 80% of their LD(50) in order to identify opioid molecule-specific patterns and classify response severity. Opioid-receptor (OR) antagonists, including intravenous 10 mg kg(-1)-naloxonazine at 5 min [mu-OR antagonist], subcutaneous 30 mg kg(-1)-naloxonazine at 24 h [mu1-OR antagonist], subcutaneous 3 mg kg(-1)-naltrindole at 45 min [delta-OR antagonist], and subcutaneous 5 mg kg(-1)-Nor-binaltorphimine at 6 h [kappa-OR antagonist] were pre-administered to test the role of each OR. Methadone, morphine, and fentanyl significantly decreased PaO(2) (P<0.001) and increased PaCO(2) (P<0.05), while buprenorphine only decreased PaO(2) (P<0.05). While all opioids significantly increased inspiratory time (T(I), P<0.001), methadone and fentanyl also increased expiratory time (T(E), P<0.05). Intravenous 10 mg kg(-1)-naloxonazine at 5 min completely reversed opioid-related effects on PaO(2) (P<0.05), PaCO(2) (P<0.001), T(I) (P<0.05), and T(E) (P<0.01) except in buprenorphine. Subcutaneous 30 mg kg(-1)-naloxonazine at 24 h completely reversed effects on PaCO(2) (P<0.01) and T(E) (P<0.001), partially reversed effects on T(I) (P<0.001), and did not reverse effects on PaO(2). Naltrindole reversed methadone-induced T(E) increases (P<0.01) but worsened fentanyl's effect on PaCO(2) (P<0.05) and T(I) (P<0.05). Nor-binaltorphimine reversed morphine- and buprenorphine-induced T(I) increases (P<0.001) but worsened methadone's effect on PaO(2) (P<0.05) and morphine (P<0.001) and buprenorphine's (P<0.01) effects on pH. In conclusion, opioid-related respiratory patterns are not uniform. Opioid-induced hypoxemia as well as increases in T(I) and T(E) are caused by mu-OR, while delta and kappa-OR roles appear limited, depending on the specific opioid. Regarding severity of opioid-induced respiratory effects at 80% of their LD(50), all drugs increased T(I). Methadone and fentanyl induced hypoxemia, hypercapnia, and T(E) increases, morphine caused both hypoxemia and hypercapnia while buprenorphine caused only hypoxemia.

Donepezil reverses buprenorphine-induced central respiratory depression in anesthetized rabbits.

Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphine-induced respiratory depression shows a marked ceiling effect at higher doses, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is an excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an Index of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 +/- 4.8 %, 92.3% +/- 22.8 % of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.

Donepezil reverses buprenorphine-induced central respiratory depression in anesthetized rabbits

Buprenorphine is a mixed opioid receptor agonist-antagonist used in acute and chronic pain management. Although this agent's analgesic effect increases in a dose-dependent manner, buprenorphine-induced respiratory depression shows a marked ceiling effect at higher doses, which is considered to be an indicator of safety. Nevertheless, cases of overdose mortality or severe respiratory depression associated with buprenorphine use have been reported. Naloxone can reverse buprenorphine-induced respiratory depression, but is slow-acting and unstable, meaning that new drug candidates able to specifically antagonize buprenorphine-induced respiratory depression are needed in order to enable maximal analgesic effect without respiratory depression. Acetylcholine is an excitatory neurotransmitter in central respiratory control. We previously showed that a long-acting acetylcholinesterase inhibitor, donepezil, antagonizes morphine-induced respiratory depression. We have now investigated how donepezil affects buprenorphine-induced respiratory depression in anesthetized, paralyzed, and artificially ventilated rabbits. We measured phrenic nerve discharge as an Índex of respiratory rate and amplitude, and compared discharges following the injection of buprenorphine with discharges following the injection of donepezil. Buprenorphine-induced suppression of the respiratory rate and respiratory amplitude was antagonized by donepezil (78.4 ± 4.8 percent, 92.3 percent ± 22.8 percent of control, respectively). These findings indicate that systemically administered donepezil restores buprenorphine-induced respiratory depression in anesthetized rabbits.

Anxiolytic-like effects of morphine and buprenorphine in the rat model of fear-potentiated startle: tolerance, cross-tolerance, and blockade by naloxone.

RATIONALE: Morphine and buprenorphine have analgesic and anxiolytic-like properties. While their analgesic effects have been well characterized, their anxiolytic-like properties have not. OBJECTIVES: Effects of acute morphine and buprenorphine on the expression of acoustic fear-potentiated startle (FPS) and naloxone pretreatment were assessed. Effects of chronic morphine and buprenorphine on tolerance, cross-tolerance, and withdrawal were also examined. MATERIALS AND METHODS: Fear-conditioned rats were given subcutaneous drug treatment immediately before testing for FPS. Experiment 1, rats were administered morphine (0.03, 0.25, 0.63, 2.5, or 10 mg/kg) or buprenorphine (0.004, 0.0075, 0.015, 0.03, or 0.25 mg/kg). Experiment 2, rats were given saline or naloxone (0.5 mg/kg) and 5 min later given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg). Experiment 3, rats received once-daily injections of saline, morphine (10 mg/kg), or buprenorphine (0.25 mg/kg) for 7 days. Immediately before testing, saline-treated rats were given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg), morphine-treated rats were given morphine (2.5 mg/kg) or buprenorphine (0.03 mg/kg), and buprenorphine-treated rats were given buprenorphine (0.03 mg/kg) or morphine (2.5 mg/kg). Tolerance and cross-tolerance in analgesia were assessed via the tail-flick test, as were naloxone-precipitated withdrawal. RESULTS: Morphine and buprenorphine had parallel dose-response curves in blocking FPS, with buprenorphine 40 times more potent than morphine. Naloxone reversed these effects. Morphine and buprenorphine showed tolerance and cross-tolerance in their anxiolytic-like and analgesic effects. Chronic buprenorphine produced less withdrawal than chronic morphine. CONCLUSIONS: Cross-tolerance between morphine and buprenorphine suggests a common receptor mediating their anxiolytic-like and analgesic effects.

Thienorphine: receptor binding and behavioral effects in rhesus monkeys.

Thienorphine is an oripavine with long-lasting antinociceptive effects in mice that are thought to be mediated by mu-opioid receptors. This study examined the receptor binding of thienorphine in cell membrane homogenates and its behavioral effects in rhesus monkeys (Macaca mulatta). Affinity and potency were determined using radioligand displacement and stimulation of guanosine 5'-O-(3-[35S]thio)triphosphate binding in C6 (mu, delta) and Chinese hamster ovary (kappa) cell membranes. Thienorphine displayed high affinity for kappa-, mu-, and delta-opioid receptors with K(i) values of 0.14, 0.22, and 0.69 nM, respectively. Thienorphine partially stimulated kappa-opioid (75%) and mu-opioid (19%) receptors and not delta-opioid receptors. Thienorphine dose-dependently increased tail-withdrawal latency for 50 degrees C water and not 55 degrees C water with effects lasting for more than 7 days. The kappa-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (3.2 mg/kg) and a large dose (1.0 mg/kg) of naltrexone prevented thienorphine-induced antinociception. Thienorphine enhanced the antinociceptive effects of morphine and U50,488 [trans-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide] with 50 degrees C water; with 55 degrees C water, thienorphine enhanced the effects of morphine and attenuated the effects of U50,488. In other monkeys, thienorphine decreased responding in both components of a multiple schedule of food presentation and stimulus shock termination for up to 8 days; naltrexone and nor-BNI partially prevented these rate-decreasing effects. In morphine-treated monkeys discriminating naltrexone, thienorphine, and U50,488 neither substituted for nor modified the naltrexone discriminative stimulus. Thienorphine and U50,488 produced the same directly observable signs. These results show that thienorphine has long-lasting effects that seem to be mediated by low-efficacy agonism at kappa-opioid receptors, both in vitro and in vivo.

Naloxone reversal of buprenorphine-induced respiratory depression.

BACKGROUND: The objective of this investigation was to examine the ability of the opioid antagonist naloxone to reverse respiratory depression produced by the mu-opioid analgesic, buprenorphine, in healthy volunteers. The studies were designed in light of the claims that buprenorphine is relatively resistant to the effects of naloxone. METHODS: In a first attempt, the effect of an intravenous bolus dose of 0.8 mg naloxone was assessed on 0.2 mg buprenorphine-induced respiratory depression. Next, the effect of increasing naloxone doses (0.5-7 mg, given over 30 min) on 0.2 mg buprenorphine-induced respiratory depression was tested. Subsequently, continuous naloxone infusions were applied to reverse respiratory depression from 0.2 and 0.4 mg buprenorphine. All doses are per 70 kg. Respiration was measured against a background of constant increased end-tidal carbon dioxide concentration. RESULTS: An intravenous naloxone dose of 0.8 mg had no effect on respiratory depression from buprenorphine. Increasing doses of naloxone given over 30 min produced full reversal of buprenorphine effect in the dose range of 2-4 mg naloxone. Further increasing the naloxone dose (doses of 5 mg or greater) caused a decline in reversal activity. Naloxone bolus doses of 2-3 mg, followed by a continuous infusion of 4 mg/h, caused full reversal within 40-60 min of both 0.2 and 0.4 mg buprenorphine-induced respiratory depression. CONCLUSIONS: Reversal of buprenorphine effect is possible but depends on the buprenorphine dose and the correct naloxone dose window. Because respiratory depression from buprenorphine may outlast the effects of naloxone boluses or short infusions, a continuous infusion of naloxone may be required to maintain reversal of respiratory depression.

Interaction of mu-opioid receptor agonists and antagonists with the analgesic effect of buprenorphine in mice.

Buprenorphine is a potent opioid analgesic with partial agonistic properties at mu-opioid receptors. This study investigated the interaction potential with several full mu-agonists in the tail-flick test in mice. We further examined the reversibility of buprenorphine antinociception by different mu-opioid receptor antagonists. Combination of buprenorphine with morphine, oxycodone, hydromorphone and fentanyl in the analgesic dose range resulted in additive or synergistic effects. When given after the decline of the acute buprenorphine effect, both morphine and fentanyl also showed full efficacy. A moderate antagonistic effect according to the partial mu-agonistic properties of buprenorphine was only seen when high doses exceeding the therapeutic dose ranges were combined. Under these conditions antinociception of morphine was reduced to the effect of buprenorphine alone. Prophylactic administration of naloxone (10 mg/kg i.v.), naltrexone (1 mg/kg i.v.) and clocinnamox (5 mg/kg s.c.) fully and persistently blocked the antinociception of a high dose of buprenorphine. An established effect of buprenorphine was less sensitive, although repeated administration of naloxone induced complete antagonism, as did the irreversible antagonist clocinnamox under prophylactic and curative treatment conditions. Our results suggest that the antinociceptive effect of buprenorphine is mainly, if not exclusively, mediated by activation of mu-opioid receptors. They confirm clinical experience that in the analgesic dose range a switch between buprenorphine and full mu-agonists is possible without loss of analgesic efficacy and without a refractory period between the termination of buprenorphine analgesia and the onset of action of the new mu-opioid treatment. Antinociception of buprenorphine is sensitive towards mu-opioid receptor antagonists and incomplete inhibition can be improved by increasing the dose or repetitive dosing.

Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in mu-opioid receptor knockout mice.

Buprenorphine is a relatively nonselective opioid receptor partial agonist that is used in the management of both pain and addiction. To improve understanding of the opioid receptor subtypes important for buprenorphine effects, we now report the results of our investigation on the roles of mu-, delta-, and kappa-opioid receptors in antinociceptive responses and place preferences induced by buprenorphine. Buprenorphine antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous mu-opioid receptor knockout (MOR-KO) mice and abolished in homozygous MOR-KO mice. In contrast, buprenorphine retained its ability to establish a conditioned place preference (CPP) in homozygous MOR-KO, although the magnitude of place preference was reduced as the number of copies of wild-type mu-opioid receptor genes was reduced. The remaining CPP of buprenorphine was abolished by pretreatment with the nonselective opioid antagonist naloxone, but only partially blocked by pretreatment with either the delta-selective opioid antagonist naltrindole or the kappa-selective opioid antagonist norbinaltorphimine. These data, and biochemical confirmation of buprenorphine actions as a partial delta-, mu-, and kappa-agonist, support the ideas that mu-opioid receptors mediate most of analgesic properties of buprenorphine, but that mu- and delta- and/or kappa-opioid receptors are each involved in the rewarding effects of this drug.

Potency differences for D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 as an antagonist of peptide and alkaloid micro-agonists in an antinociception assay.

D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) is a peptide antagonist that demonstrates potent and selective affinity for micro-opioid receptors in radioligand binding assays and in vitro bioassays. However, previous studies indicate that CTAP may possess unusual pharmacology under certain conditions. Therefore, CTAP was evaluated as an antagonist of the antinociceptive effects of a range of structurally diverse high- and low-efficacy peptide and alkaloid opioid agonists and compared with the traditional antagonist naltrexone. Male Sprague-Dawley rats (N = 227) were loosely restrained and the latency for tail withdrawal from 55 degrees C water was measured. Morphine s.c. and i.c.v., buprenorphine s.c., etorphine s.c. and i.c.v., [N-Me-Phe3,D-Pro4]-morphiceptin and [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin produced antinociceptive effects. CTAP was at least 10-fold more potent than naltrexone as an antagonist of the antinociceptive effects of all five agonists. High doses of CTAP produced a noncompetitive antagonism of etorphine s.c. and morphine s.c. suggesting that CTAP may interact with additional opioid receptors in vivo or produce insurmountable antagonism at these doses. CTAP was approximately 300-fold more potent as an antagonist of DAMGO than the other agonists, indicating that CTAP may distinguish some peptide agonists such as DAMGO from other agonists based on binding interactions within the micro-opioid receptor or pharmacodynamic properties of these peptides. Naltrexone, however, administered by either s.c. or i.c.v. routes of administration was approximately equipotent as an antagonist of the antinociceptive effects of most agonists. Taken together, these data indicate that the peptide antagonist CTAP possesses a unique pharmacology unlike traditional opioid antagonists such as naltrexone

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.

Characterization of the discriminative stimulus effects of buprenorphine in pigeons.

RATIONALE: Buprenorphine is a low-efficacy mu opioid agonist that can reduce drug taking in opioid abusers; however, the mechanism by which buprenorphine modifies the actions of other drug taking and the consequences of repeated treatment with buprenorphine are not fully understood. OBJECTIVE: The purposes of this study were to evaluate the time- and dose-dependence of discriminative stimulus effects in pigeons receiving buprenorphine repeatedly and to examine possible interactions between buprenorphine and heroin. METHODS: Six pigeons discriminated between vehicle and 0.178 mg/kg buprenorphine while responding under an FR schedule for food. Substitution and drug combination studies characterized the potency and time course for buprenorphine, as well as interactions between buprenorphine and heroin. RESULTS: Stimulus control by buprenorphine was maintained throughout the study and was not changed by repeated daily dosing or by an acute injection of large doses of buprenorphine. Mu opioid agonists substituted for buprenorphine with the following order of potency: heroin > or = butorphanol > nalbuphine > or = morphine. Ketamine, enadoline, spiradoline, amphetamine and cocaine failed to substitute completely for buprenorphine. The discriminative stimulus effects of buprenorphine lasted 2-72 h, depending on dose, and naltrexone prevented but did not reverse the effects of buprenorphine. CONCLUSION: Despite a very long duration of action and apparent irreversibility, under these conditions in pigeons, buprenorphine does not modulate the discriminative stimulus effects of itself or heroin. Thus, simple agonism might account for the therapeutic effectiveness of buprenorphine in opioid abusers.

Effects of medetomidine and buprenorphine administered for sedation in dogs.

Medetomidine at doses of 10, 20 or 30 microg/kg was administered along with 10 microg/kg buprenorphine intramuscularly to 48 dogs requiring sedation for various diagnostic or therapeutic procedures. The heart rate, respiratory rate and degree of sedation were recorded before and 30 minutes after administration of the drugs. Heart rate fell by a mean of 55 per cent and respiratory rate by a mean of 62 per cent. Mean sedation scores were increased in all groups. Administration of atipamezole at the end of the period of sedation produced rapid recoveries, with a mean time to standing of 12 minutes. Animals that were anaesthetised required much less thiopentone than the 10 mg/kg recommended after premedication with acepromazine maleate.

Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver microsomes.

Buprenorphine is a long acting analgesic of the opiate family. Recently, it has been proposed for the opioid dependency treatment at a large scale. The drug is extensively metabolized by the hepatic cytochrome P450 in man, yielding a N-dealkylated metabolite, norbuprenorphine. The specific forms of P450 involved in this oxidative N-demethylation were examined in a panel of 18 human liver microsomal preparations previously characterized with respect to their P450 contents. Buprenorphine was N-dealkylated with an apparent Km of 89 +/- 45 microM (n = 3). The metabolic rates were 3.46 +/- 0.43 nmol/(min x mg of protein). This metabolic pathway was strongly correlated with 6 catalytic activities specific to P450 3A4 and with the immunodetectable P450 3A content of liver microsomal samples (r = 0.87). Buprenorphine metabolism was 62-71% inhibited by three mechanism-based inhibitors (TAO, erythralosamine, gestodene), by nifedipine as competitive inhibitor (Ki = 129 microM) and by ketoconazole 0.6 microM (25% residual activity), all these inhibitors specific to P450 3A. Among 10 heterologously expressed P450s tested, only P450 3A4 was able to dealkylate buprenorphine with a turnover number of 9.6 min(-1). Morever, this catalytic activity was inhibited up to 80% (vs control) by anti-rat P450 3A antibody. Taken together, all these data demonstrate that P450 3A4 is the major enzyme involved in hepatic buprenorphine N-dealkylation.

Buprenorphine increases intake of freely available and operant-contingent food in satiated rats.

Opiate administration increases short-term free feeding in satiated rats. The feeding effects of the mixed opioid receptor agonist/antagonist buprenorphine were examined in both free-feeding and operant chamber paradigms. Buprenorphine (0.1 and 0.3 mg/kg) produced significant increases in short-term free feeding (i.e., 4 h), an effect enhanced by repeated administration. Buprenorphine's effects on operant responding were examined in satiated rats using a fixed ratio (FR) 80 (initial pellet) FR 3 (subsequent pellets) reinforcement schedule. Buprenorphine (0.03-0.3 mg/kg) decreased latency to begin responding for food, and increased total number of pellets consumed in a 1-h session. Increases in food intake relative to control were caused by continued responding for food as sessions progressed. Naloxone suppressed both the free-feeding and operant-contingent intake induced by buprenorphine. Thus, buprenorphine increases both freely available and lever-press contingent food intake.

Cardiorespiratory effects of four opioid-tranquilizer combinations in dogs.

The cardiorespiratory effects of four opioid-tranquilizer combinations were evaluated in six dogs. The four combinations were administered to each dog in a randomized order. Buprenorphine (BUP; 0.01 mg/kg IV) or oxymorphone (OXY; 0.1 mg/kg IV) was followed in 10.4 +/- 1.3 minutes by midazolam (MID; 0.3 mg/kg IV) or acepromazine (ACE; 0.05 mg/kg IV). Nalbuphine (0.16 mg/kg IV) was administered 94.1 +/- 2.3 minutes after the tranquilizer was given. Heart rate (HR) and mean arterial blood pressure (MAP) decreased significantly (P < .05) after each combination. MAP was significantly lower with combinations using ACE. Most dogs panted after opioid administration; this was associated with increased minute volume (VM) and decreased tidal volume (VT). After administration of the tranquilizer, mean breathing rate and VM index (VMI) were significantly lower with ACE combinations. There were no significant changes in pH and blood gas variables after BUP-ACE. The other three combinations were associated with significant (P < .05) decreases in pH and increases in PaCO2. Mean PaO2 decreased significantly (P < .05) with OXY combinations but not BUP combinations. Dysrhythmias (atrial or ventricular escape complexes) were seen with each combination. HR increased significantly (P < .05) after nalbuphine in dogs receiving OXY, but not BUP. Dogs receiving OXY became more alert after nalbuphine on six of 12 occasions, whereas dogs receiving BUP became less alert on six of 12 occasions. OXY-ACE provided the most chemical restraint/sedation and BUP-MID provided the least.

Buprenorphine as a stimulus in drug discrimination learning: an assessment of mu and kappa receptor activity.

Using the conditioned taste aversion baseline of drug discrimination learning, different groups of animals were trained to discriminate either buprenorphine or morphine from distilled water. Specifically, animals were injected with buprenorphine or morphine prior to a saccharin-LiCl pairing and the drug vehicle prior to saccharin alone. By the fifth conditioning trial, animals differentially consumed saccharin on the basis of administration of the drug or its vehicle. In subsequent generalization tests, buprenorphine stimulus control generalized completely to the mu agonist morphine in four of the five subjects tested, while morphine stimulus control completely generalized to buprenorphine in two of five subjects and partially generalized in the remaining three. Buprenorphine failed to generalize to the relatively selective kappa antagonist MR2266 and the broad-based antagonist diprenorphine. Morphine also failed to generalize to MR2266, but did generalize to diprenorphine. That morphine and buprenorphine displayed some degree of cross-generalization suggests that these compounds share some stimulus property, presumably their agonist activity at the mu receptor, and that the mu activity of these compounds was used in the establishment of the discrimination, a conclusion supported by the fact that compounds with mu antagonist activity (e.g., naloxone, MR2266) blocked both buprenorphine and morphine stimulus control. That buprenorphine failed to generalize to compounds with kappa antagonist activity suggests that animals trained to discriminate buprenorphine from its vehicle do not use the kappa antagonist activity of the drug in the establishment of the discrimination. The basis for the differential ability of various receptor subtypes to mediate the discriminative properties of compounds with mixed receptor activity was discussed.

The ambulation-increasing effect of buprenorphine in mice: comparison with the effect of morphine.

Effects of buprenorphine on ambulatory activity in mice were studied, and the result s were compared with those of morphine. Buprenorphine, at 0.01-3 mg/kg s.c., increased the mouse's ambulatory activity in a dose-dependent manner with Straub tail-reaction. The effect reached to the maximum level at 10-20 min and persisted for 2-3 hr after the administration. The overall activity counts for 3 hr were almost identical when 1 mg/kg of buprenorphine and 10 mg/kg of morphine were administered. Naloxone, 0.01-1 mg/kg s.c., reduced the ambulation-increasing effect of both buprenorphine and morphine, but the reducing-action of naloxone was stronger for morphine than for buprenorphine. However, the combined administration of buprenorphine and morphine demonstrated no significant modification in individual drug effects. On the other hand, the ambulation-increasing effect of buprenorphine and morphine were enhanced by combined s.c. administration of methamphetamine (1 mg/kg), cocaine (10 mg/kg), scopolamine (0.5 mg/kg), or caffeine (10 mg/kg). Such enhancing effects of methamphetamine and cocaine were much greater for buprenorphine than for morphine. In contrast, haloperidol (0.05 mg/kg), pilocarpine (2 mg/kg), and N6-(L-2-phenylisopropyl)-adenosine (0.1 mg/kg) reduced the ambulation-increasing effect of buprenorphine or morphine. The modification by pilocarpine was more marked for morphine than for buprenorphine. The present results indicate that buprenorphine and morphine possess differential effectiveness on dopaminergic and/or cholinergic systems.

1,4-Benzodiazepines antagonize opiate-induced antinociception in mice.

The influence of diazepam, midazolam, and flunitrazepam on the antinociceptive effect of morphine, fentanyl, and buprenorphine was studied using the hot-plate test and the tail-flick test in mice. Diazepam and midazolam induced a dose-dependent attenuation of the effect of all three opiates in both tests of nociception. Flunitrazepam antagonized the antinociceptive effect only in the tail-flick test. The benzodiazepine effect could not be explained by altered tail-skin temperature. The antagonism did not correlate well with the sedative or muscle-relaxing properties of the benzodiazepines, and a different mechanism may therefore be involved. It is proposed that the antagonism represents an interaction between benzodiazepines and opioid systems in the brain participating in modulation of nociceptive inputs.

[Effect of buprenorphine on external pancreatic secretion in rats]. / Action de la buprénorphine sur la sécrétion pancréatique externe chez le rat.

2-deoxyglucose stimulates pancreatic secretion through a mainly vagal neural pathway. Buprenorphine antagonized this stimulation in a dose-related fashion between 0.017 and 0.45 mg/kg. i.v. The effect of buprenorphine was suppressed by naloxone, but not by alpha and beta-adrenoceptor blocking agents. The effect of methadone was similar, at doses about ten times larger.