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PubMed1997

Pharmacokinetic interaction between butorphanol nasal spray and oral metoclopramide in healthy women.

The pharmacokinetics of butorphanol nasal spray, with and without the coadministration of metoclopramide, were studied in 24 healthy women. In this crossover study all volunteers received 3 treatments: a single, 1-mg dose of butorphanol nasal spray, a single, 10-mg oral dose of metoclopramide, and a combination of a single, 1-mg dose of butorphanol nasal spray and a single, 10-mg oral dose of metoclopramide. There was at least a one-week washout period between sessions. Serial blood samples were collected and plasma samples analyzed using a validated radioimmunoassay to determine the concentration of butorphanol, or a high-performance liquid chromatography/ultraviolet procedure was used to determine the concentration of metoclopramide. There were no statistically significant differences in the pharmacokinetic parameters, Cmax, tmax, AUC, and t1/2, for butorphanol with or without metoclopramide. Similarly, except for a delay in tmax of metoclopramide with coadministration of butorphanol, the pharmacokinetic parameters of metoclopramide were not significantly different between two treatments. Thus, the pharmacokinetics of both butorphanol and metoclopramide were not significantly altered when administered in combination. The incidence of nausea/vomiting after butorphanol administration was substantially reduced by coadministration of metoclopramide. Based on the pharmacokinetic and safety results, it can be concluded that butorphanol nasal spray and metoclopramide can be administered in combination without altering the dose regimen of either drug.

Administration, Oral↗

PubMed1995

Increased locus coeruleus glutamate levels are associated with naloxone-precipitated withdrawal from butorphanol in the rat.

Extracellular fluid levels of glutamate were measured in the locus coeruleus during butorphanol (a mixed agonist at mu-, delta-, and kappa-opioid receptors) withdrawal by using microdialysis in conscious butorphanol-dependent Sprague-Dawley rats. Guide cannulae were implanted chronically and rats were given intracerebroventricular (i.c.v.) infusions of butorphanol (26 nmol/1 microliter/hr) or saline (1 microliter/hr) for 3 days. Microdialysis probes (2 mm tip) were inserted into the locus coeruleus 24 hr before precipitation of withdrawal by i.c.v. injection of naloxone (48 nmol/5 microliters). A separate series of rats was rendered dependent by peripheral injection of butorphanol (20 mg/kg, s.c., b.i.d.) for 5 days and naloxone (5 mg/kg, i.p.) was given to precipitate withdrawal. Single injections of butorphanol (26 nmol/5 microliters, i.c.v.) had no effect on the extracellular fluid levels of glutamate, compared to rats injected with vehicle. Behavioral evidence of withdrawal was detected following naloxone challenge in butorphanol-dependent rats (both i.c.v. and s.c. models), but not in non-dependent, vehicle-treated rats. Significant increases (P < 0.05) in levels of glutamate were noted after naloxone-precipitated withdrawal only in the butorphanol group. The glutamate levels in the locus coeruleus increased from 8.37 +/- 2.01 before, to 21.93 +/- 4.58 microM in the first 15 min sample following i.c.v. injections of 48 nmol/5 microliters naloxone and from 10.84 +/- 1.74 before, to 26.01 +/- 6.19 microM in the 15-30 min sample following i.p. injections of 5 mg/kg naloxone in the butorphanol-dependent rats, respectively. These results provide direct evidence to support the role of excitatory amino acids within the locus coeruleus in butorphanol withdrawal.

Animals↗

PubMed1996

Mu- and delta-opioid receptor antagonists precipitate similar withdrawal phenomena in butorphanol and morphine dependence.

The relative involvement of mu- and delta-opioid receptors in the mediation of butorphanol-, as compared to morphine-, dependence was examined with the use of highly selective antagonists at mu- and delta-opioid receptors. Extracellular fluid levels of glutamate (Glu) and aspartate (Asp) were measured within the pontine locus coeruleus following precipitation of withdrawal from dependence on either butorphanol or morphine in conscious Sprague-Dawley rats. Dependence was induced by intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/mu l/h), morphine (26 nmol/mu l/h) or saline vehicle (1 mu l/h) for 3 days by means of an osmotic minipump. Microdialysis probes (2 mm tip) were inserted into the locus coeruleus 24 h before precipitation of withdrawal by i.c.v. injection of either the mu-opioid receptor antagonist, D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; 48 nmol/5 mu l or 48 nmol/5 mu l), or the delta-opioid receptor antagonist, naltrindole (17-cyclopropy;methyl-6,7-dehydro-4,5-epoxy-3, 14-dihydroxy-6,7,2'3'-indolmorphinan hydrochloride; 48 nmol/5 mu l or 100 nmol/5 mu l). Baseline levels of Glu ranged from 9.59 + or - 1.27 to 12.84 + or - 3.01 mu M in the various treatment groups. Levels of Asp were similar. Precipitation of withdrawal by CTOP elicited significant increases of Glu and Asp in both morphine- and butorphanol-dependent rats. Maximal increases in Glu of 425% and 258% above baseline levels were elicited in the first 15 min microdialysis sample following i.c.v. injection of CTOP in morphine- and butorphanol-dependent rats, respectively. Behavioral signs of withdrawal were greater in morphine than butorphanol-dependent groups. The i.c.v. treatment with naltrindole elicited increases in Glu and Asp that were similar, although less marked, than those precipitated by CTOP treatment. Administration of naltrindole produced equivalent signs of withdrawal in both morphine- and butorphanol-dependent rats. Withdrawal from dependence on both morphine and butorphanol is characterized by elevations in coerulear levels of excitatory amino acids. Responses elicited following the use of selective mu- and delta-opioid receptor antagonists to precipitate withdrawal suggest that the role played by these receptors in mediation of the signs and symptoms of withdrawal do not differ greatly between butorphanol- and morphine-dependent rats.

Animals↗

PubMed1991

Post-caesarean section analgesia: a comparison of epidural butorphanol and morphine.

Epidural butorphanol 1, 2 and 4 mg were compared with morphine, 5 mg, for postoperative analgesia in 92 consenting, healthy, term parturients who had undergone Caesarean section under epidural lidocaine anaesthesia in a randomized double-blind study. Postoperative pain was assessed using a visual analogue scale and recorded with heart rate, blood pressure and respiratory rate. The demographic characteristics, and the incidences of primary and repeat Caesarean sections, were not different among the four treatment groups. At 15, 30, 45 and 60 min after treatment the median pain scores following butorphanol were similar and lower than those following morphine (P less than 0.05). Calculated median percentage pain relief values for butorphanol were higher than morphine at each of these times (P less than 0.05). At 90 min and 2 hr the pain scores and pain relief values were similar. Beyond 45 min the number of patients requesting supplemental medication and dropping out of the study increased progressively in both the butorphanol and morphine treated patients. The attrition profiles for butorphanol were different from morphine (P less than 0.01). The median time in the study was greater than 24 hr for morphine, and 3, 2.5 and 4 hr for butorphanol, 1, 2 or 4 mg, respectively. No patient developed a clinically important change in heart rate or blood pressure, and none experienced a decrease in respiratory rate below 12 breaths.min-1. One of 69 patients (1.4 per cent) who received butorphanol developed pruritus compared with ten (43 per cent) of 23 patients who received morphine. The global assessments of the adequacy of analgesia were indistinguishable between morphine and butorphanol. Epidural butorphanol provides safe, effective postoperative analgesia, has a prompt onset, and a limited duration.

Adult↗

PubMed1999

Antinociceptive effects of opioids following acute and chronic administration of butorphanol: influence of stimulus intensity and relative efficacy at the mu receptor.

RATIONALE: A common treatment strategy for the management of severe pain involves the co-administration of multiple opioid analgesics. Due to the increasing popularity of this practice, it is becoming increasingly important to understand the interactions between clinically employed opioids under a wide range of conditions. OBJECTIVE: The purpose of the present investigation was to examine the effects of opioid combinations following acute and chronic administration of the low-efficacy mu-opioid butorphanol, and to determine if the effects of these combinations are modulated by the intensity of the nociceptive stimulus. METHODS: In a warm-water, tail-withdrawal procedure, rats were restrained and the latencies to remove their tails from 50 degrees C (low temperature) and 55 degrees C (high temperature) water were measured following both acute and chronic administration of butorphanol. Opioids possessing both high (etorphine, levorphanol, morphine) and low [dezocine, (-)-pentazocine, nalbuphine] relative efficacy at the mu receptor were examined. RESULTS: Under acute conditions, etorphine, levorphanol, morphine and dezocine increased tail-withdrawal latencies at both low and high temperatures, whereas (-)-pentazocine, nalbuphine and butorphanol increased latencies only at the low temperature. A dose of 30 mg/kg butorphanol increased the effects produced by these opioids at the low temperature, but antagonized the effects of etorphine, levorphanol, morphine and dezocine at the high temperature. During chronic treatment with 30 mg/kg per day butorphanol, tolerance was conferred to the antinociceptive effects of all the opioids examined, with greater degrees of tolerance conferred to those opioids possessing low efficacy at the mu receptor. During butorphanol treatment, etorphine, levorphanol and morphine increased tail-withdrawal latencies at both water temperatures, dezocine increased latencies at only the low temperature, and (-)-pentazocine, nalbuphine and butorphanol failed to increase latencies at either temperature. A dose of 30 mg/kg butorphanol antagonized the antinociceptive effects of etorphine, levorphanol, morphine and dezocine during chronic treatment, and these effects were observed at both water temperatures. CONCLUSIONS: These findings indicate that the interactions between butorphanol and other mu opioids vary quantitatively between low and high stimulus intensities, and between acute and chronic conditions. In most instances, however, these interactions can be predicted from the effects of the drugs when administered alone.

Analgesics, Opioid↗

PubMed2002

The bindings of [3H]muscimol and [3H]flunitrazapam are elevated in discrete brain regions of butorphanol-withdrawal rats.

We have investigated the effects of continuous infusion of butorphanol on the modulation of GABA(A) receptor binding. Butorphanol was infused continuously into intracerebroventricle (ICV) at a constant rate of 26 nmol/microl/h for 3 days, and the withdrawal from opioid was rendered 7 h after the cessation of infusion. The GABA(A) receptor bindings in rat brain slices were analyzed by quantitative autoradiography using [3H]muscimol and [3H]flunitrazepam. In the rats withdrawn from butorphanol, the levels of [3H]muscimol binding were significantly elevated in cortex, thalamus, and part of the hippocampus. The levels of [3H]flunitrazepam binding were elevated in almost all of brain regions including cortex, caudate putamen, thalamus, hippocampus, brainstem, and cerebellum in the rats withdrawn from butorphanol. The levels of binding of either [3H]muscimol or [3H]flunitrazepam were not changed in the rats tolerant to butorphanol. However, the activity of GABAergic neuron was not found to have been modulated by butorphanol withdrawal, because the level of glutamic acid decarboxylase was not changed markedly either in rats that were tolerant to or withdrawn from butorphanol by Western blot and immunohistochemical data. These results suggest that the withdrawal from butorphanol infusion markedly elevates the binding of [3H]muscimol and [3H]flunitrazepam throughout the brain in a region-specific manner, and that the regulatory mechanisms in butorphanol tolerance and withdrawal may be different.

Animals↗

PubMed1996

Pharmacokinetics of butorphanol nasal spray in patients with renal impairment.

1. The pharmacokinetics of butorphanol were evaluated in 18 female volunteers with varying degrees of renal function following a single, 1 mg transnasal dose of butorphanol tartrate. The creatinine clearance (CLCR) values for subjects in the normal (NOR), moderately impaired (MI), and severely impaired (SI) groups were > or = 70 ml min-1, 30-60 ml min-1, and < or = 30 ml min-1, respectively. 2. Serial blood and urine samples were collected immediately after dosing for 48 h. Plasma concentrations of butorphanol were determined using a specific radioimmunoassay. Urine concentrations of butorphanol and its metabolites (hydroxy-butorphanol, norbutorphanol and their glucuronide conjugates) were determined using h.p.l.c. with fluorescence detection. 3. There was no significant difference between the three treatments for peak plasma concentration of butorphanol and time to peak. Statistically significant differences were detected among the study groups for AUC, t1/2, MRT, and CLR with the mean values for severely impaired subjects significantly different from those of normal renal subjects; mean values for moderately impaired subjects were not significantly different from either the normal or severely impaired groups for all respective parameters. 4. The elimination half-life of butorphanol increased from 5.75 h in NOR to 10.48 h in SI. A similar trend was observed for MRT. Creatinine clearance (CLCR) significantly correlated with CLR (r = 0.563, P = 0.019), CLT/F (r = 0.505, P = 0.033), t1/2 (r = -0.554, P = 0.017) and lambda (r = 0.606, P = 0.008). 5. Although the exposure of butorphanol was greater in subjects with renal impairment, there was no trend for an increase in the number of adverse experiences reported by subjects with renal dysfunction. 6. Patients with less than 30 ml min-1 creatinine clearance may require less frequent administration of transnasal butorphanol as compared with subjects with normal or moderately impaired renal function.

Administration, Intranasal↗

PubMed2005

Bioavailability of intranasal butorphanol administered from a single-dose sprayer.

PURPOSE: The bioavailability and tolerability of single doses of intranasal butorphanol tartrate using a single-dose, metered sprayer were studied. METHODS: In this open-label, randomized, three-way crossover study, 24 healthy volunteers received three treatments: (1) 2 mg of i.v. butorphanol (treatment A), (2) 2 mg of intranasal butorphanol (treatment B), and (3) 1 mg of intranasal butorphanol (treatment C). The three treatments received by each subject were separated by six-day washout periods. Venous blood samples (10 mL each) were obtained from an indwelling catheter at 0 (predose), 5, 10, 15,20,30, and 45 minutes and 1,2,3,4,6,8, 12, and 16 hours after butorphanol administration. Pharmacokinetic parameters were determined using standard noncompartmental methods with log-linear least-squares regression analysis to determine the elimination-rate constants. RESULTS: Intranasal butorphanol 1 and 2 mg administered using unit dose sprayers had a mean bioavailability of approximately 80%, which is higher than the percentage reported with the commercially available multidose product (61-69%). The absorption of intranasal butorphanol was rapid, with a median time to reach maximum concentration of 20 minutes (range, 10-60 minutes). Elimination profiles were comparable among all treatments. There were no clinically significant changes in the results of physical examinations, nasal evaluations, or laboratory tests related to butorphanol treatment. Most adverse effects reported were mild to moderate and as expected for this drug. CONCLUSION: Single-dose intranasal butorphanol was rapidly absorbed and had high absolute bioavailability in healthy volunteers.

Administration, Intranasal↗

PubMed1997

Continuous brachial plexus infusion of butorphanol-mepivacaine mixtures for analgesia after upper extremity surgery.

We have recently reported that continuous administration of butorphanol into the brachial plexus neurovascular sheath provided superior analgesia compared with that obtained with continuous i.v. administration. Furthermore, we found that analgesia was most pronounced when a mixture of mepivacaine and butorphanol was given and that butorphanol alone ranked next. In this study, we increased the dose of butorphanol, compared with that used in our previous reports, and an initial bolus dose of butorphanol was administered into the brachial plexus neurovascular sheath just after surgery had ended. Thereafter, postoperative pain relief was estimated. In patients undergoing upper extremity surgery with continuous axillary brachial plexus block, group A received a bolus of 1 ml of physiological saline with 1.5% mepivacaine, 10 ml into the brachial plexus sheath followed by a continuous brachial plexus infusion of 0.5% mepivacaine with butorphanol 6 mg at a rate of 144 ml/ 72 h. Group B was given a bolus of butorphanol 1 mg (1 ml) with 1.5% mepivacaine, 10 ml into the brachial plexus sheath and a continuous brachial plexus infusion of 0.5% mepivacaine with butorphanol 6 mg at a rate of 144 ml/72 h. After operation, VAS scores did not differ between the two groups. The time to first use of supplementary analgesia did not differ significantly between the two groups and there were no significant differences in the number of patients who required supplementary analgesia. These results indicate that continuous butorphanol 2 mg day-1 with 0.5% mepivacaine provided sufficient postoperative analgesia after upper limb surgery.

Analgesia↗

PubMed2002

Effects of medetomidine-midazolam, midazolambutorphanol, or acepromazine-butorphanol as premedicants for mask induction of anesthesia with sevoflurane in dogs.

OBJECTIVE: To characterize the effects of medetomidine-midazolam, midazolam-butorphanol, or acepromazine-butorphanol as premedicants for mask induction of anesthesia with sevoflurane in dogs. ANIMALS: 10 healthy Beagles. PROCEDURE: The following premedicants were administered intramuscularly: medetomidine-midazolam (20 microg/kg and 0.3 mg/kg, respectively), midazolam-butorphanol (0.1 and 0.2 mg/kg, respectively), and acepromazine-butorphanol (0.05 and 0.2 mg/kg, respectively). Saline (0.9% NaCI) solution (0.1 ml/kg) was administered intramuscularly as a control. Anesthesia was induced in each dog with sevoflurane in a 100% O2 at a flow rate of 4 L/min developed by a facemask. Vaporizer settings were increased by 0.8% at 15-second intervals until the value corresponding to 4.8% sevoflurane was achieved. Time to onset and cessation of involuntary movements, loss of the palpebral reflex, negative response to tail-clamp stimulation, and endotracheal intubation were recorded, and the cardiopulmonary variables were measured. RESULTS: Mask induction with sevoflurane in dogs that received each premedicant resulted in a shorter induction time and milder changes in heart rate, mean arterial blood pressure, cardiac output, and respiratory rate, compared with mask induction without premedicants. Treatment with medetomidine-midazolam resulted in a shorter and smoother induction, compared with acepromazine-butorphanol or midazolam-butorphanol treatment, whereas the cardiovascular changes were greater. Cardiopulmonary variables of dogs during induction following treatment with acepromazine-butorphanol or midazolam-butorphanol were maintained close to the anesthetic maintenance values for sevoflurane, with the exception of mild hypotension that was observed in dogs following acepromazine-butorphanol treatment. CONCLUSION AND CLINICAL RELEVANCE: In dogs use of premedicants provides a smoother and better quality mask induction with sevoflurane.

Analgesics, Opioid↗

PubMed2000

Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs.

OBJECTIVE: To evaluate the effects of butorphanol and carprofen, alone and in combination, on the minimal alveolar concentration (MAC) of isoflurane in dogs. DESIGN: Randomized complete-block crossover study. ANIMALS: 6 healthy adult dogs. PROCEDURE: Minimal alveolar concentration of isoflurane was determined following administration of carprofen alone, butorphanol alone, carprofen and butorphanol, and neither drug (control). Anesthesia was induced with isoflurane in oxygen, and MAC was determined by use of a tail clamp method. Three hours prior to induction of anesthesia, dogs were fed a small amount of canned food without any drugs (control) or with carprofen (2.2 mg/kg of body weight [1 mg/lb]). Following initial determination of MAC, butorphanol (0.4 mg/kg [0.18 mg/lb], i.v.) was administered, and MAC was determined again. Heart rate, respiratory rate, indirect arterial blood pressure, endtidal partial pressure of CO2, and saturation of hemoglobin with oxygen were recorded at the time MAC was determined. RESULTS: Mean +/- SD MAC of isoflurane following administration of butorphanol alone (1.03 +/- 0.22%) or carprofen and butorphanol (0.90 +/- 0.21%) were significantly less than the control MAC (1.28 +/- 0.14%), but MAC after administration of carprofen alone (1.20 +/- 0.13%) was not significantly different from the control value. The effects of carprofen and butorphanol on the MAC of isoflurane were additive. There were not any significant differences among treatments in regard to cardiorespiratory data. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that administration of butorphanol alone or in combination with carprofen significantly reduces the MAC of isoflurane in dogs; however, the effects of butorphanol and carprofen are additive, not synergistic.

Animals↗

PubMed2002

Evaluation of sedative and cardiorespiratory effects of romifidine and romifidine-butorphanol in cats.

OBJECTIVE: To determine sedative and cardiorespiratory effects of romifidine alone and romifidine in combination with butorphanol and effects of preemptive atropine administration in cats sedated with romifidine-butorphanol. DESIGN: Randomized crossover study. ANIMALS: 6 healthy adult cats. PROCEDURES: Cats were given saline (0.9% NaCl) solution followed by romifidine alone (100 microg/kg [45.4 microg/lb], i.m.), saline solution followed by a combination of romifidine (40 microg/kg [18.1 microg/lb], i.m.) and butorphanol (0.2 mg/kg [0.09 mg/lb], i.m.), or atropine (0.04 mg/kg [0.02 mg/lb], s.c.) followed by romifidine (40 microg/kg, i.m.) and butorphanol (0.2 mg/kg, i.m.). Treatments were administered in random order, with > or = 1 week between treatments. Physiologic variables were determined before and after drug administration. Time to recumbency, duration of recumbency, time to recover from sedation, and subjective evaluation of sedation, muscle relaxation, and analgesia were assessed. RESULTS: Bradycardia developed in all cats that received saline solution and romifidine-butorphanol or romifidine alone. Preemptive administration of atropine prevented bradycardia for 50 minutes in cats given romifidine-butorphanol. Oxyhemoglobin saturation was significantly decreased 10 minutes after romifidine-butorphanol administration in atropine-treated cats. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that administration of romifidine alone or romifidine-butorphanol causes a significant decrease in heart rate and that preemptive administration of atropine in cats sedated with romifidine-butorphanol effectively prevents bradycardia for 50 minutes.

Adjuvants, Anesthesia↗

PubMed1994

Comparing the subjective, psychomotor and physiological effects of intravenous butorphanol and morphine in healthy volunteers.

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of butorphanol in healthy nondrug-abusing volunteers and to compare and contrast the effects of butorphanol to those of morphine. Into an antecubital vein, the subjects (seven men and five women), who had no history of opiate dependence, were injected with 0, 0.5, 1.0 or 2.0 mg/70 kg of butorphanol or 10 mg/70 kg of morphine; a randomized, double-blind, crossover design was used. The subjective effects of butorphanol included increased scores on the Pentobarbital-Chlorpromazine-Alcohol Group scale and Lysergic Acid Diethylamide scale of the Addiction Research Center inventory; increased visual analog scale ratings of "sedated," "coasting or spaced out" and "difficulty concentrating;" increased adjective checklist ratings of "sweating," "skin itchy" and "sleepy;" and increased "feel drug effect" and drug-liking ratings. Morphine had some subjective effects of a magnitude similar to those of an equianalgesic dose of butorphanol (2 mg) (e.g., "strength of drug effect," "sedated," "heavy or sluggish feeling" and "high"). However, other effects of morphine were lesser in magnitude (e.g., "coasting or spaced out," "drunken" and "lightheaded") than those of butorphanol. Also, morphine did not affect a number of ratings that were affected by butorphanol (e.g., "confused," "dreamy," "stimulated," "difficulty concentrating," "floating" or "sweating"). The psychomotor impairing effects of butorphanol, as measured by the Maddox Wing test, an eye-hand coordination test, and the Digit Symbol Substitution Test, were dose related; in contrast, morphine had no effect on psychomotor functioning. Both butorphanol and morphine induced miosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2003

Enhanced binding of nor-binaltorphimine to kappa-opioid receptors in rats dependent on butorphanol.

Autoradiographic characterization of binding for brain kappa(1) ([(3)H]CI-977) and kappa(2) ([(3)H]bremazocine) in the presence of DAMGO ([D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin), DPDPE ([D-Pen(2), D-Pen(5)]-enkephalin), and U-69,593 opioid receptors, in the presence of different concentrations of a selective unlabeled kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI), was performed in rats in which dependence on or withdrawal from butorphanol had been established. Dependence was induced by a 72 hr intracerebroventricular (i.c.v.) infusion with butorphanol (26 nmol/microl/hr; butorphanol dependent). Butorphanol withdrawal was produced by terminating the infusion of butorphanol in dependent animals. Responses were studied 7 hr following termination (butorphanol withdrawal). IC(50) values from competition studies were estimated by fitting inhibition curves for both kappa(1)- and kappa(2)-opioid receptor assays. In both dependent and withdrawal groups, the IC(50) values obtained against [(3)H]CI-977 or [(3)H]bremazocine with nor-BNI were decreased (ratios of approximately 0.03-0.21 and approximately 0.05-0.42 vs. control, respectively) in brain regions, including frontal cortex, nucleus accumbens, claustrum, dorsal endopiriform nucleus, caudate putamen, parietal cortex, posterior basolateral amygdaloid nucleus, dorsomedial hypothalamus, hippocampus, posterior paraventricular thalamic nucleus, periaqueductal gray, substantia nigra, superficial gray layer of the superior colliculus, ventral tegmental area, and locus coeruleus, compared with control. These results indicate that, in butorphanol-dependent and butorphanol-withdrawal rats, the brain kappa(1)- and kappa(2)-opioid receptors developed a supersensitivity to antagonist binding.

Animals↗

PubMed1980

Serum levels of butorphanol by radioimmunoassay.

A radioimmunassay was developed for the analysis of butorphanol in human serum. The procedure involves extraction of serum with hexane containing 2% isoamyl alcohol, followed by evaporative solvent removal and radioimmunoassay of the reconstituted residue. The antibody significantly cross-reacts with unidentified butorphanol metabolites but not with two known metabolites, hydroxybutorphanol and norbutorphanol. Extraction eliminated interference from the butorphanol metabolites normally present in serum. The antibody also cross-reacts with pentazocine and cyclazocine but not with morphine, hydromorphone, oxymorphine, codeine, methadone, and meperidine. Butorphanol tartrate was administered intravenously (2 mg) to normal male volunteers. Serum butorphanol levels declined biexponentially with an average terminal half-life of 2.7 hr. Enzymatic serum hydrolysis prior to extraction yielded additional butorphanol, indicating the presence of butorphanol conjugates. The specificity of the assay for butorphanol was confirmed by GLC--mass fragmentography.

Adult↗

PubMed1993

Effects of nor-binaltorphimine on butorphanol dependence.

Butorphanol has been shown to act on mu-, delta-, and kappa-opioid receptors. However, the relative involvement of different opioid receptor subtypes in butorphanol dependence is not known. In the present study, nor-binaltorphimine, a long-acting non-peptide kappa-opioid receptor antagonist, was employed to mask central kappa-opioid receptors before and during the induction of butorphanol dependence in rats, so that the involvement of kappa-opioid receptors could be elucidated. The results revealed that treatment with nor-binaltorphimine markedly blocked naloxone-precipitated withdrawal signs of escape behavior, teeth-chattering, wet shakes, ptosis, body weight loss, and hypothermia at all doses tested, and attenuated the withdrawal symptoms of forepaw tremors (24 nmol: P < 0.001) and diarrhea (12 nmol: P < 0.05; 24 nmol: P < 0.01). In contrast, nor-binaltorphimine had no effect on yawning, ejaculation, nor urination in butorphanol-infused rats undergoing withdrawal. Three days of butorphanol infusion significantly increased KD values (in the cortex and striatum), decreased Bmax (in the cortex only) of [3H]U-69,593 binding, and shifted Ki of nor-binaltorphimine against [3H]U-69,593 (4.5 nM) binding in the cortex by more than 10-fold. Treatment with nor-binaltorphimine blocked the effects of butorphanol on kappa-opioid receptors. It is therefore concluded that kappa-opioid receptors are involved in mediating escape behavior, teeth-chattering, wet shakes, forepaw tremors, ptosis, diarrhea, weight loss, and hypothermia in butorphanol-dependent rats undergoing withdrawal. Furthermore, kappa-opioid receptors become desensitized to agonists (in the cortex and striatum), down-regulated (in the cortex), and supersensitive to antagonists in butorphanol-dependent rats.

Animals↗

PubMed1990

Butorphanol's efficacy at mu and kappa opioid receptors: inferences based on the schedule-controlled behavior of nontolerant and morphine-tolerant rats and on the responding of rats under a drug discrimination procedure.

The purpose of the present investigation was to characterize the mu agonist and kappa antagonist effects of the mixed opioid agonist/antagonist butorphanol. To this end, the effects of butorphanol were examined: 1) alone and in combination with the kappa agonist bremazocine in nontolerant and morphine-tolerant rats responding under a fixed-ratio 30 (FR30) schedule of food presentation, and 2) in rats trained to discriminate 10 mg/kg morphine from saline. Prior to the induction of morphine tolerance, morphine, bremazocine and butorphanol produced dose-dependent decreases in rate of responding under the FR30. In these nontolerant rats, butorphanol failed to antagonize bremazocine's rate-decreasing effects. During the chronic morphine regimen, the dose-effect curve for morphine was shifted to the right of its prechronic position by approximately 0.9 log units, whereas the bremazocine curve was not altered substantially. The butorphanol dose-effect curve, in contrast, was shifted to the right and flattened such that doses which eliminated responding in nontolerant rats, as well as doses approximately 1.0 log unit higher, had no effect on responding. In these morphine-tolerant rats, butorphanol produced a dose-dependent antagonism of bremazocine's rate-decreasing effects. In rats trained to discriminate morphine from saline, butorphanol substituted completely for the morphine stimulus. Unlike morphine, which produced its stimulus effects only at doses that decreased rate of responding, butorphanol substituted for the morphine stimulus at doses that had little or no effect on rate of responding.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesics↗

PubMed1994

Crosstolerance between butorphanol and morphine in rats.

To investigate the antinociceptive effects of morphine and U-50,488 after continuous administration with butorphanol, rats were intracerebroventricularly (ICV) infused with butorphanol (26 nmol/microliters/h) through osmotic minipumps for 3 days. Six hours after termination of infusion, the rats were challenged with different doses of morphine or U-50,488. Antinociceptive effects, as assessed by tail-flick and acetic acid writing tests, were measured 15 min after challenge. Development of crosstolerance to morphine was evident in butorphanol-infused animals. The study also revealed that crosstolerance to butorphanol developed in continuously ICV morphine-infused animals. Continuous ICV infusion with butorphanol produced a marked rightward shift of the antinociceptive dose-response curve resulting from U-50,488 challenge. These results showed that there is an antinociceptive crosstolerance between butorphanol and morphine, and crosstolerance to U-50,488 developed in continuously butorphanol-infused animals. The present data suggested that chronic ICV treatment with high doses of butorphanol can lead to desensitization of the antinociceptive systems mediated through the central kappa as well as mu receptors in rats.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗