buprenorphine and beta-funaltrexamine

Antagonistic properties of buprenorphine for epsilon- and micro -opioid receptors were characterized in beta-endorphin- and [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO)-induced antinociception, respectively, with the tail-flick test in male ICR mice. epsilon-Opioid receptor agonist beta-endorphin (0.1-1 micro g), micro -opioid receptor agonist DAMGO (0.5-20 ng), or buprenorphine (0.1-20 micro g) administered i.c.v. dose dependently produced antinociception. The antinociception induced by 10 micro g of buprenorphine given i.c.v. was completely blocked by the pretreatment with beta-funaltrexamine (beta-FNA) (0.3 micro g i.c.v.), indicating that the buprenophine-induced antinociception is mediated by the stimulation of the micro -opioid receptor. The antinociceptive effects induced by beta-endorphin (1 micro g i.c.v.) and DAMGO (16 ng i.c.v.) were dose dependently blocked by pretreatment with smaller doses of buprenorphine (0.001-1 micro g i.c.v.), but not by a higher dose of buprenorphine (10 micro g i.c.v.). beta-FNA at a dose (0.3 micro g i.c.v.) that strongly attenuated DAMGO-induced antinociception had no effect on the antinociception produced by beta-endorphin (1 micro g i.c.v.). However, pretreatment with buprenorphine (0.1-10 micro g) in mice pretreated with this same dose of beta-FNA was effective in blocking beta-endorphin-induced antinociception. beta-FNA was 226-fold more effective at antagonizing the antinociception induced by DAMGO (16 ng i.c.v.) than by beta-endorphin (1 micro g i.c.v.). The antinociception induced by delta-opioid receptor agonist [d-Ala2]deltorphin II (10 micro g i.c.v.) or kappa1-opioid receptor agonist trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamine methanesulfonate salt [(-)-U50,488H] (75 micro g i.c.v.) was not affected by pretreatment with buprenorphine (0.1-1.0 micro g i.c.v.). It is concluded that buprenorphine, at small doses, blocks epsilon-opioid receptor-mediated beta-endorphin-induced antinociception and micro -opioid receptor-mediated DAMGO-induced antinociception, and at high doses produces a micro -opioid receptor-mediated antinociception.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; beta-Endorphin; Buprenorphine; Disease Models, Animal; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Time Factors

Previous research has demonstrated that, in male rats, the magnitude of contact hypersensitivity (CHS) can be enhanced by morphine treatment. The present experiments test the hypothesis that the mu-opioids morphine, etorphine, and buprenorphine would produce significant sex differences in the magnitude of 2,4-dinitrofluorobenzene-induced CHS. During tests conducted over a 192-h period, morphine, etorphine, and buprenorphine administered before elicitation of CHS on the external surface of the ear (pinna) potentiated the CHS response, and the magnitude of this enhancement was significantly greater in females than males. By contrast, morphine had no effect on croton oil-induced irritant contact dermatitis, indicating that morphine's effects on CHS do not generalize to immunologically nonspecific forms of contact dermatitis. Activation of brain mu-opioid receptors is responsible for the effects of morphine on CHS, because intracerebroventricular treatment with the mu-opioid receptor antagonist beta-funaltrexamine blocked morphine potentiation of CHS in females and males. The sex differences in morphine potentiation of CHS appear to be a result of the gonadal hormonal milieu, because castration enhanced the CHS response following vehicle and morphine treatment, whereas ovariectomy significantly attenuated the enhancement of CHS by morphine. Because ovariectomy had no effect on the CHS response following vehicle treatment, the presence of female gonadal hormones may underlie the sex differences in morphine potentiation of CHS in gonadally intact animals. Overall, these results support an increased sensitivity to the modulatory effects of opioids on the CHS response in females that depends on the interaction between gonadal hormones and the central mu-opioid system.

Topics: Animals; Buprenorphine; Castration; Dermatitis, Contact; Etorphine; Female; Gonadal Steroid Hormones; Male; Morphine; Naltrexone; Rats; Rats, Inbred F344; Receptors, Opioid, mu; Sex Characteristics

The purpose of the present study was to determine the relative intrinsic efficacy of various opioids using the irreversible mu opioid antagonist beta-funaltrexamine (betaFNA). To this end, pigeons were trained to discriminate 3.0 (n=6) or 1.8 (n=1) mg/kg morphine from distilled water in a two-key, food-reinforced, drug discrimination procedure. The mu opioids fentanyl, l-methadone, buprenorphine, butorphanol, nalorphine, nalbuphine and levallorphan, as well as the delta opioid BW373U86, substituted completely for the morphine stimulus. The stimulus effects of morphine were antagonized (i.e., produced a significant increase in the ED50 value) by a 10 mg/kg but not a 5 mg/kg dose of betaFNA. Antagonist effects of betaFNA were observed following a 2-h pretreatment, but not following 26-, 50-, 74-, 98- or 146-h pretreatments. The stimulus effects produced by fentanyl, l-methadone and buprenorphine were not antagonized by doses of betaFNA as high as 20, 10 and 10 mg/kg, respectively. The lowest dose of betaFNA required to antagonize the stimulus effects of butorphanol was 10 mg/kg, whereas the effects of nalorphine, nalbuphine and levallorphan were antagonized by a dose of betaFNA as low as 5 mg/kg. The delta BW373U86 substituted for the morphine stimulus, and this effect was not antagonized by 10 mg/kg betaFNA. The pkB values for naloxone (1.0 mg/kg) against the stimulus effects of fentanyl (6.70) and morphine (6.52) were considerably higher than that for BW373U86 (4.60), indicating further that the morphine-like stimulus effects produced by BW373U86 were not mediated by activity at the mu opioid receptor. These findings indicate that the strategy of irreversible antagonism can be used effectively to differentiate opioids with varying degrees of intrinsic efficacy at the mu opioid receptor in a pigeon drug discrimination procedure. In particular, the ranking of these drugs by relative intrinsic efficacy at the mu opioid receptor is: l-methadone=fentanyl> or =buprenorphine> or =morphine> or =butorphanol>nalorphine=nalbuphine=levallorphan. Additionally, the short-acting effect of betaFNA in the pigeon suggests that the recovery of mu opioid receptor function varies across species.

Topics: Animals; Buprenorphine; Butorphanol; Columbidae; Discrimination Learning; Female; Fentanyl; Levallorphan; Methadone; Morphine; Nalbuphine; Nalorphine; Naltrexone; Narcotic Antagonists; Receptors, Opioid, mu

The antinociceptive effect of buprenorphine was examined in mu1-opioid receptor-deficient CXBK mice. I.p. administration of buprenorphine at a dose of 3 mg/kg produced marked antinociception in the tail-flick test in C57BL/6 mice, a progenitor strain of CXBK mice. The antinociceptive effect of buprenorphine in C57BL/6 mice was antagonized by pretreatment with either beta-funaltrexamine (beta-FNA), a mu-opioid receptor antagonist, or naloxonazine (NXZ), a selective mu1-opioid receptor antagonist. The antinociceptive effect of buprenorphine (3 mg/kg, i.p.) in CXBK mice was significantly less than that in C57BL/6 mice. Neither beta-FNA nor NXZ reduced the antinociceptive effect of buprenorphine in CXBK mice. There was no significant difference between the buprenorphine-induced antinociceptive effect in CXBK mice and NXZ-treated C57BL/6 mice. Furthermore, neither naltrindole, a selective delta-opioid receptor antagonist, nor norbinaltorphimine, a selective kappa-opioid receptor antagonist, had a significant effect on the antinociceptive effects of buprenorphine in both CXBK and C57BL/6 mice. These results support our previous hypothesis that mu1- rather than mu2-, delta- or kappa-opioid receptors are involved in the antinociceptive effects of buprenorphine.

Topics: Animals; Buprenorphine; Male; Mice; Mice, Inbred C57BL; Naloxone; Naltrexone; Narcotic Antagonists; Receptors, Opioid, mu; Species Specificity

beta-Funaltrexamine (beta-FNA), an irreversible antagonist at the mu-opioid receptor, was administered intracisternally to rats discriminating between subcutaneous injections of saline and 3.0 mg/kg of morphine in order to reduce the size of the receptor reserve. beta-FNA alone (10 micrograms) occasioned substantial morphine-appropriate responding for at least 6 h but mainly saline-appropriate responding 24 h after administration, the pretreatment interval for most experiments. beta-FNA (3.0-30 micrograms) dose-dependently shifted to the right stimulus-generalization curves for morphine and fentanyl; 10 micrograms also shifted to the right the curves for meperidine and buprenorphine. In all cases, antagonism was fully surmounted by higher doses of the agonist, even after inactivation of more than 75% of mu-opioid receptors. This antagonist effect of beta-FNA is smaller than that reported previously in tests of analgesia, suggesting that the receptor reserve for the discriminative effects of morphine-like drugs is larger than the receptor reserve for their analgesic effects. beta-FNA produced larger rightward displacements of the morphine and buprenorphine curves than of the fentanyl curve and inactivated a larger fraction of the receptors acted upon by those drugs compared to fentanyl. Results with meperidine were intermediate. This suggests that the receptor population mediating morphine-like discriminative effects of fentanyl is not identical to the receptor population mediating these effects of morphine and buprenorphine.

Topics: Analgesics, Opioid; Animals; Buprenorphine; Cisterna Magna; Discrimination Learning; Fentanyl; Injections; Male; Meperidine; Morphine; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

Buprenorphine produced a dose-dependent antagonism of the selective kappa opioid agonist U50,488 in squirrel monkeys responding under the shock titration procedure. In one group of four monkeys, 0.003-0.01 mg/kg buprenorphine produced dose-dependent rightward shifts in the individual U50,488 dose-effect curves and increased the A50 value for U50,488 more than 2-fold in each monkey. Furthermore, 0.01 mg/kg buprenorphine antagonized a maximally effective dose of U50,488 in these monkeys. Buprenorphine (0.01-0.1 mg/kg) also produced rightward shifts in the group U50,488 dose-effect curve for a second group of three monkeys. Buprenorphine's antagonism of U50,488 was probably not a consequence of any mu opioid antagonist properties of buprenorphine in this procedure since (1) buprenorphine produced an inconsistent antagonism of the selective mu agonist fentanyl, and (2) the selective mu antagonist beta-funaltrexamine did not antagonize U50,488. These results support the hypothesis that buprenorphine has kappa antagonist activity in the shock titration procedure.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Buprenorphine; Electroshock; Fentanyl; Male; Naltrexone; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Saimiri

Buprenorphine was studied for its antagonist activity against the specific kappa-opioid agonist U-50,488H in pigeons responding under a multiple schedule of grain presentation and in mice in an antinociception test. U-50,488H decreased rates of responding of pigeons over the dose range (2.5-20 mg/kg i.m.). In the presence of 0.32 mg/kg of buprenorphine, the U-50,488H dose-effect curve was shifted to the right approximately two-fold. Buprenorphine alone (0.01-0.08 mg/kg s.c.) inhibited in mice the abdominal stretching induced by i.p. acetic acid. beta-Funaltrexamine pretreatment blocked the mu-like agonist analgesic effect of buprenorphine and revealed an antagonist action of buprenorphine against 2.5 mg/kg of U-50,488H over the same dose range that it produced antinociception at the mu-receptor. Thus, buprenorphine is a potent kappa-opioid receptor antagonist, producing the kappa-antagonist activity over the same dose range that it produces its mu-mediated partial agonist activity.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Buprenorphine; Columbidae; Male; Mice; Muscle Contraction; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Reinforcement Schedule

Buprenorphine was studied for its effects on urinary output to determine if it was an agonist, partial agonist, or antagonist at the kappa receptor. Buprenorphine was a potent antagonist of bremazocine-induced urination and had no kappa agonist activity. Thus, the high affinity that buprenorphine has for the kappa receptor results in potent kappa receptor antagonist activity in vivo.

Topics: Animals; Benzomorphans; Buprenorphine; Diuresis; Drug Combinations; Male; Naltrexone; Rats; Rats, Inbred Strains; Receptors, Opioid

Systemic administration of beta-funaltrexamine (beta-FNA) 24 hr before analgesic testing produced approximately a 10-fold parallel shift in the dose-response curves of the prototypic mu agonists morphine, I-methadone, fentanyl and etorphine in the mouse abdominal constriction test. In contrast, prior administration of beta-FNA produced no appreciable shift in the analgesic dose-response curve of the selective kappa agonist, U-50, 488H. These results suggest that beta-FNA is selective for mu over kappa receptors under the conditions used in this study. The dose-response curves for ethylketazocine and proxorphan were affected only to a small extent by beta-FNA pretreatment, suggesting that these compounds have analgesic actions mediated primarily through nonmu, probably kappa receptors. The dose-response curves for cyclazocine, buprenorphine, butorphanol, nalorphine and nalbuphine were shifted markedly to the right and frequently not in a parallel fashion by the prior administration of beta-FNA. These results seem to indicate a major role for the mu receptor in the analgesic actions of these compounds.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Animals; Biological Assay; Buprenorphine; Butorphanol; Cyclazocine; Dose-Response Relationship, Drug; Ethylketocyclazocine; Etorphine; Fentanyl; Methadone; Mice; Morphine; Muscle Contraction; Nalbuphine; Nalorphine; Naltrexone; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, mu

The effect of the irreversible opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on antinociception produced by mu- and kappa-receptor agonists was studied in the rat. beta-FNA, 20 to 80 mg kg-1, s.c., given 24 h before testing, produced a dose-related antagonism of the effects of morphine in the paw pressure, hotplate and tail-flick tests. Following the 80 mg kg-1 dose, the degree of antagonism of morphine was stable for up to 48 h after dosing, but was reduced by 5 days and had disappeared by 8 days. In the paw pressure test, beta-FNA, 40 mg kg-1, s.c., antagonized the effects of fentanyl, buprenorphine, tifluadom, ethylketocyclazocine and proxorphan; it was without effect against the highly selective kappa-agonist, U-50,488. In light of these results, the possible opioid receptor selectivities of both the agonists and beta-FNA are reassessed.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzodiazepines; Buprenorphine; Cyclazocine; Ethylketocyclazocine; Fentanyl; Male; Naltrexone; Pain; Pyrrolidines; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu

The effects of buprenorphine were examined under a shock titration procedure and compared to the effects of morphine. Under this procedure shock increased every 15 sec from 0 to 2.0 mA in 30 increments. Five responses within a 15-sec shock period decreased shock intensity by one increment. Both buprenorphine and morphine increased the level at which shock was maintained without decreasing rates of responding in the presence of shock. Buprenorphine-induced increases in median shock level occurred over a 10-fold dose range and were apparent for 6 to 12 hr. Dose-effect curves for morphine and buprenorphine were shifted to the right by prior administration of diprenorphine (0.001-1.0 mg/kg), naloxone (0.001-1.0 mg/kg) and beta-funaltrexamine (1.0-16.0 mg/kg), with the dose of antagonist required to restore responding to control levels being 1 to 2 log U larger for buprenorphine than for morphine. Buprenorphine-induced increases in median shock level were also restored to control levels when naloxone (1.0 mg/kg) was administered as much as 110 min after buprenorphine. Buprenorphine was not effective in antagonizing the effects of morphine. When a dose of buprenorphine which increased median shock level was administered once daily, median shock levels returned to control level within 6 to 15 days. When the morphine dose-effect curve was then redetermined in the presence of chronic buprenorphine, it exhibited a 10-fold shift to the right.

Topics: Animals; Buprenorphine; Conditioning, Operant; Diprenorphine; Dose-Response Relationship, Drug; Drug Interactions; Electroshock; Male; Morphinans; Morphine; Naloxone; Naltrexone; Saimiri

Pigeons trained to peck a key on a fixed-ratio 20 schedule of food presentation were used to evaluate the antagonistic and rate-suppressing effects of several opioid antagonists. Antagonism was measured as an increase in the dose of morphine necessary to suppress responding. Antagonist pretreatments increased the suppressing dose of morphine, although the magnitude of the increase varied markedly among different antagonists. Rank order of the maximum increase in the suppressing dose of morphine that each antagonist produced was: naltrexone = WIN 44,441 greater than beta-funaltrexamine greater than naloxone = buprenorphine greater than MR 2266 greater than diprenorphine. The time course of morphine antagonism also differed among antagonists. For example, buprenorphine was not an effective antagonist when administered 10 min before morphine, but was effective when administered either 2 or 12 hr before morphine. beta-Funaltrexamine and WIN 44,441 had the longest durations of antagonist action; each antagonized the rate-suppressing effects of morphine from 10 min to 24 hr. The effective antagonistic dose range (i.e., doses which blocked the rate-suppressing effects of morphine without affecting response rate when administered alone) and maximum increase in the suppressing dose of morphine were highly correlated, suggesting that the direct effects of most of these antagonists on responding may limit their effectiveness as morphine antagonists.

Topics: Animals; Azocines; Benzomorphans; Buprenorphine; Columbidae; Conditioning, Operant; Diprenorphine; Dose-Response Relationship, Drug; Morphine; Naloxone; Naltrexone; Narcotic Antagonists