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PubMed2004

Nociceptive sensitivity and opioid antinociception and antihyperalgesia in Freund's adjuvant-induced arthritic male and female rats.

The present study was designed to examine sex differences in complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia and sex differences in opioid antinociception and anti-hyperalgesia. Female rats developed inflammation and hyperalgesia faster and exhibited greater peak hyperalgesia than male rats. In arthritic (CFA-treated) rats, lower thresholds were observed during estrus and proestrus, and in nonarthritic (vehicle-treated) rats, lower thresholds were observed during proestrus. Morphine and oxycodone were more potent in male than female arthritic rats, and butorphanol was more potent and effective in male than female arthritic rats. The potency of morphine was increased in arthritic rats, although to a greater magnitude in males. The potency of oxycodone was increased in male but not female arthritic rats. The potency of butorphanol was increased in arthritic male rats and the maximal antinociceptive effect of butorphanol was increased in arthritic female rats, but it did not result in greater than 20% antinociception. Morphine, oxycodone, and butorphanol all produced antihyperalgesic effects (returning thresholds of arthritic rats to the thresholds of nonarthritic rats) with greater potency in males than females. The peripherally acting opioid agonist loperamide produced intermediate levels of antinociception in male and female arthritic rats and no antinociception in nonarthritic rats. Loperamide was more potent in male than female arthritic rats at producing antihyperalgesia. These data demonstrate sex differences in arthritis-induced hyperalgesia and responsiveness to opioid analgesics. In arthritic rats, the antinociceptive effects of opioid agonists are most probably mediated by both central and peripheral opioid receptors, whereas their antihyperalgesic effects are mediated primarily by actions at peripheral opioid receptors.

Analgesics, Opioid↗
PubMed2002

Effects of mu-opioid agonists on cocaine- and food-maintained responding and cocaine discrimination in rhesus monkeys: role of mu-agonist efficacy.

Mu-opioid agonists decrease cocaine self-administration in laboratory studies and cocaine use by many cocaine- and opioid-dependent polydrug abusers. To assess the role of mu-agonist efficacy as a determinant of these effects, this study evaluated cocaine- and food-maintained responding by rhesus monkeys (Macaca mulatta) during chronic treatment with saline or the high-efficacy mu-agonist fentanyl (0.001-0.01 mg/kg/h), the intermediate-efficacy mu-agonist morphine (0.032-0.32 mg/kg/h), or the low-efficacy mu-agonists nalbuphine (0.1-1.0 mg/kg/h) and butorphanol (0.0032-0.032 mg/kg/h). Responding was maintained by cocaine and food under a second order schedule of reinforcement during multiple daily sessions of cocaine and food availability. Saline and each opioid dose were administered continuously for 7 consecutive days during availability of each cocaine dose. All four mu-agonists produced dose-dependent and sustained decreases in cocaine self-administration across a range of cocaine doses (0.0032-0.1 mg/kg/injection). Nalbuphine and butorphanol produced the greatest decreases in cocaine self-administration and the smallest effects on food-maintained responding. Morphine and fentanyl produced smaller decreases in cocaine self-administration, and undesirable effects precluded evaluation of higher fentanyl and morphine doses. Decreases in cocaine self-administration produced by nalbuphine and butorphanol probably did not reflect a general blockade of cocaine's abuse-related effects, because nalbuphine and butorphanol did not block the discriminative stimulus effects of cocaine in monkeys trained to discriminate 0.4 mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. These results suggest that low-efficacy mu-agonists may decrease cocaine self-administration to a greater degree and with fewer undesirable effects than high-efficacy mu-agonists.

Analgesics, Opioid↗
PubMed1989

Thiopental-sparing properties of butorphanol/diazepam for induction of anesthesia in ambulatory gynecologic surgery.

Butorphanol/diazepam was compared with thiopental for induction of anesthesia, and the thiopental-sparing effects of butorphanol/diazepam determined. One hundred women, American Society of Anesthesiology physical status class I, undergoing ambulatory, elective termination of pregnancy were randomized to receive either butorphanol 2 mg plus diazepam 10 mg, or thiopental, until loss of the lid reflex occurred. The butorphanol/diazepam group received supplemental thiopental as necessary to attain adequate induction of anesthesia. The combination of butorphanol and diazepam significantly reduced the thiopental dose required to produce loss of the lid reflex, from 4.2 +/- 0.8 to 0.8 +/- 0.6 mg/kg (p less than 0.005), with 22 percent of the patients not requiring supplemental thiopental. The intraoperative course and anesthetic requirements were similar between the two groups. Lower recovery room rating scale values upon arrival at the recovery room were attributed to significantly higher weight-normalized doses of butorphanol (p = 0.004) and diazepam (p = 0.005). The duration of the recovery room stay was 68.8 +/- 24.9 min for the control group, and 80.8 +/- 29.0 min for the butorphanol/diazepam-treated patients (p = 0.026). There were no clinically significant differences in anesthesia or postanesthesia recovery. The combination of butorphanol and diazepam has a significant thiopental-sparing effect, and is a useful induction technique for short, ambulatory surgical procedures.

Abortion, Induced↗
PubMed2003

Comparison of the efficacy and cardiorespiratory effects of medetomidine-based anesthetic protocols in ring-tailed lemurs (Lemur catta).

The relative efficacies and cardiorespiratory effects of three injectable anesthetic combinations containing medetomidine were evaluated in ring-tailed lemurs (Lemur catta). In addition, the direct effects of medetomidine on heart rate and blood pressure were evaluated in lemurs anesthetized with isoflurane. For injectable anesthesia, captive adult ring-tailed lemurs were anesthetized with medetomidine and ketamine (0.04-0.06 mg/kg, i.m. and 3 mg/kg, i.m., respectively), medetomidine, butorphanol, and ketamine (0.04 mg/kg, i.m., 0.4 mg/kg, i.m., and 3 mg/kg, i.m., respectively), or medetomidine, butorphanol, and midazolam (0.04 mg/kg, i.m., 0.4 mg/kg, i.m., and 0.3 mg/kg, i.m., respectively). For inhalation anesthesia, lemurs were mask-induced and maintained with isoflurane for 30 min before receiving medetomidine (0.04 mg/kg, i.m.). Sedation produced by medetomidine-ketamine was unpredictable and of short duration. Both medetomidine-butorphanol-ketamine (MBK) and medetomidine-butorphanol-midazolam (MBMz) provided adequate anesthesia for routine physical exams; however, the effects of MBMz lasted longer than those of MBK. Heart rates and respiratory rates were within clinically normal ranges for all groups, and lemurs remained normotensive throughout the study. Common side effects such as hypertension and bradycardia associated with the use of alpha2-adrenergic receptor agonist combinations in other species were not observed. Likewise, medetomidine administration had no effect on HR in lemurs receiving isoflurane. Lemurs in all groups were well ventilated and remained well oxygenated throughout the procedures, though arterial partial pressure of O2 was lowest in the MBMz group. All three injectable medetomidine combinations were effective in ring-tailed lemurs but only MBK and MBMz provided adequate depth and duration of anesthesia for use as sole regimes. For many clinical procedures in lemurs, MBMz offers advantages over MBK because of its longer duration of action and its rapid and more complete reversibility with specific antagonists.

Anesthetics, Combined↗
PubMed2003

The cardiac anesthetic index of isoflurane in green iguanas.

OBJECTIVE: To determine the cardiac anesthetic index (CAI) of isoflurane in green iguanas and whether butorphanol affected the CAI. DESIGN: Prospective randomized controlled trial. ANIMALS: 7 healthy mature iguanas. PROCEDURE: In 5 iguanas, CAI was determined after induction of anesthesia with isoflurane alone, and in 5 iguanas, CAI was determined after induction of anesthesia with isoflurane and IM administration of butorphanol (1 mg/kg [0.45 mg/lb]). Three iguanas underwent both treatments. Animals were equilibrated for 20 minutes at 1.5 times the minimum alveolar concentration (MAC) of isoflurane and observed for evidence of cardiovascular arrest. If there was no evidence of cardiovascular arrest, end-tidal isoflurane concentration was increased by 20%, and animals were allowed to equilibrate for another 20 minutes. This process was repeated until cardiovascular arrest occurred or vaporizer output could no longer be consistently increased. The CAI was calculated by dividing the highest end-tidal isoflurane concentration by the MAC. RESULTS: None of the iguanas developed cardiovascular arrest and all survived. Mean +/- SD highest end-tidal isoflurane concentration during anesthesia with isoflurane alone (9.2 +/- 0.60%) was not significantly different from mean concentration during anesthesia with isoflurane and butorphanol (9.0 +/- 0.43%). The CAI was > 4.32. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that the CAI of isoflurane in green iguanas is > 4.32 and not affected by administration of butorphanol. Isoflurane appears to be a safe anesthetic in green iguanas.

Analgesics, Opioid↗
PubMed1992

Ketamine/xylazine/butorphanol: a new anesthetic combination for rabbits.

Ketamine is often used in combination with tranquilizers to produce surgical anesthesia in rabbits. While generally effective, there is considerable variation in the depth and duration of anesthesia achieved with ketamine combinations. Butorphanol is a mixed agonist-antagonist opioid that is widely used in a variety of other species. In this study, the commonly used ketamine (35 mg/kg)/xylazine (5 mg/kg) combination is compared with ketamine (35 mg/kg)/xylazine (5 mg/kg)/butorphanol (0.1 mg/kg). Rabbits were anesthetized on consecutive weeks with one of the two regimens. Physiologic parameters including heart rate, respiratory rate, blood pressure and arterial blood gases (pH, PO2, PCO2) were measured throughout anesthesia. Loss of palpebral, pedal and righting reflexes were recorded and reflexes were subsequently evaluated. The addition of butorphanol prolonged reflex loss to 140% (X = 68 min +/- 20 SEM) of control for palpebral reflex; 506% (X = 52 min +/- 18 SEM) of control for pedal reflex; and 159% (X = 128 min +/- 21 SEM) of control for righting reflex. Addition of butorphanol to ketamine/xylazine resulted in mild alterations in the physiologic changes traditionally associated with this combination. Butorphanol can be safely added to the ketamine/xylazine combination in rabbits and results in moderate increases in the duration of reflex loss.

Anesthesia↗
PubMed2005

Behavioral and clinical pathology changes in koi carp (Cyprinus carpio) subjected to anesthesia and surgery with and without intra-operative analgesics.

Fish surgery is becoming increasingly common in laboratory and clinical settings. Behavioral and physiologic consequences of surgical procedures may affect experimental results, so these effects should be defined and, if possible, ameliorated. We document behavioral and clinical pathology changes in koi carp (Cyprinus carpio) undergoing surgery with tricaine methanesulphonate (MS-222) anesthesia, with and without intraoperative administration of the opiate butorphanol (0.4 mg/kg intramuscularly) or the nonsteroidal antiinflammatory analgesic ketoprofen (2 mg/kg intramuscularly). For all fish combined, surgery resulted in reduced activity, lower position in the water column, and decreased feeding intensity at multiple time points after surgery. The butorphanol-treated group was the only one not to experience significant (P < 0.05) alterations from presurgical behaviors. Clinical pathology changes at 48 h after anesthesia and surgery included decreased hematocrit, total solids, phosphorus, total protein, albumin, globulin, potassium, and chloride and increased plasma glucose, aspartate aminotransferase, creatine kinase, and bicarbonate. The only clinical pathology difference between treatment groups was a lower increase in creatine kinase in the ketoprofen-treated group. No adverse effects of butorphanol or ketoprofen at these doses were identified. These results suggest a mild behavioral sparing effect of butorphanol and reduced muscle damage from the antiinflammatory activity of ketoprofen.

Aminobenzoates↗
PubMed2001

Subjective, psychomotor, and physiological effects of cumulative doses of mixed-action opioids in healthy volunteers.

RATIONALE: Conducting complete dose-response evaluations of multiple drugs in a single within-subjects experiment is very time-consuming when a complete session is required for evaluation of each dose. OBJECTIVE: To evaluate a within-session cumulative-dosing procedure as a potentially efficient method for conducting dose-response evaluations of mixed-action opioids. METHODS: Fifteen healthy volunteers received intravenous injections of saline, butorphanol, nalbuphine, pentazocine, or morphine in a randomized, double-blind, crossover design. Subjects received one injection per hour for the first 4 h, and a 3-h recovery period followed. Saline was injected first, then saline or increasing doses of each drug (except pentazocine, see below) were administered every hour for the next 3 h. The absolute doses per injection were morphine and nalbuphine 2.5, 5, and 10 mg/70 kg, butorphanol 0.5, 1, and 2 mg/70 kg, and pentazocine 7.5, 15, and 0 mg/70 kg. (The highest dose of pentazocine was omitted because of the risk of dysphoria and psychotomimesis). These injections resulted in cumulative doses of morphine or nalbuphine 2.5, 7.5, and 17.5 mg/70 kg, butorphanol 0.5, 1.5, and 3.5 mg/70 kg, and pentazocine 7.5 and 22.5 mg/70 kg. Mood, psychomotor performance, and vital signs were assessed. RESULTS: Effects of all opioids were similar, with some exceptions. Butorphanol had the strongest effects on psychomotor performance and some subjective effects. Morphine was associated with delayed or prolonged side effects. CONCLUSIONS: Orderly dose-response functions and replication of results of single-dosing studies confirmed that the cumulative-dosing procedure is an efficient way of determining dose-response functions for multiple opioids within the same subjects.

Adult↗
PubMed2006

A comparison of four methods of analgesia in cats following ovariohysterectomy.

OBJECTIVE: To evaluate the effectiveness of preoperative administration of oral carprofen, subcutaneous ketoprofen, and local nerve block with bupivacaine in preventing postoperative pain-associated behavior in cats after ovariohysterectomy. ANIMALS: Fifty-two female intact cats. Materials and methods Cats received butorphanol (0.44 mg kg(-1) IM), carprofen (2.2 mg kg(-1) PO), ketoprofen (2.2 mg kg(-1) SQ), or bupivacaine infiltration block (1.1 mg kg(-1) SQ) before surgery. Cortisol and drug concentrations and visual analog scale (VAS) and interactive visual analog scale (IVAS) pain-associated behavior scores were measured 2 hours before and 0, 1, 2, 4, 8, 12, and 24 hours after ovariohysterectomy. RESULTS: Cats receiving butorphanol had significantly increased IVAS scores 2 hours after surgery compared with baseline measurements. Cats receiving carprofen, ketoprofen, and bupivacaine had significant increases from baseline in VAS and IVAS scores 1 and 2 hours after surgery. VAS and IVAS scores for cats receiving bupivacaine were significantly greater 1 and 2 hours after surgery than for cats that received butorphanol. Cats receiving carprofen had significant increases in cortisol 1 hour after surgery and significant decreases 24 hours after surgery compared with baseline measurements. CONCLUSIONS AND CLINICAL RELEVANCE: Preoperative carprofen and ketoprofen have effects on pain-associated behavior similar to butorphanol in cats undergoing ovariohysterectomy. Cats receiving bupivacaine blocks may require additional analgesics immediately after surgery.

Administration, Oral↗
PubMed1975

Inhibition of ADH release in the rat by narcotic antagonists.

The diuretic action of two new narcotic antagonists, oxilorphan and butorphanol, was studied in rats heterozygous for hereditary hypothalmic diabetes insipidus. Both drugs caused a prompt increase in urine volume and a decrease in urine osmolality with an associated decrease in urinary ADH excretion. The effects appeared to be dose related and of short duration. Tolerance to butorphanol administration was evident on repeated daily injections. The diuretic effect was not associated with alternation in creatinine excretion, but butorphanol resulted in decreased osmolal, sodium and potassium excretion. Butorphanol prevented the expected rise in urine osmolality and ADH excretion due to 31 h of dehydration. Oxilorphan did not interfere with the ability of administered ADH to cause an antidiuresis. The data indicate that these narcotic antagonists cause a diuresis by inhibiting ADH release from the neurohypophysis.

Animals↗
PubMed1999

Opioid antinociception in ovariectomized monkeys: comparison with antinociception in males and effects of estradiol replacement.

Baseline nociception and opioid antinociception were compared in male and ovariectomized female rhesus monkeys. Females were studied without estradiol replacement or during treatment with estradiol benzoate at doses (0.002 and 0.01 mg/kg/day) designed to mimic 17beta-estradiol blood levels observed during different phases of the menstrual cycle and during pregnancy. Baseline sensitivity to thermal stimuli (42-54 degrees C) was similar in male and ovariectomized female monkeys. The antinociceptive effects of the mu-opioid agonists fentanyl, morphine, butorphanol, and nalbuphine were examined at 50 and 54 degrees C. There were no sex-related differences in the antinociceptive effects of the high-efficacy mu agonist fentanyl; however, the lower-efficacy mu agonists morphine, butorphanol, and nalbuphine produced greater antinociceptive effects in males than in untreated ovariectomized females. Because butorphanol and nalbuphine have low selectivity for mu versus kappa receptors and may produce kappa-agonist effects under some conditions, the high-efficacy, kappa-selective agonist U50,488 was also studied. U50,488 also produced greater antinociceptive effects in males. Treatment with estradiol benzoate tended to enhance opioid antinociception in the ovariectomized females; however, this effect was significant only for butorphanol and U50,488 during treatment with the highest dose of estradiol benzoate. These findings suggest that opioid agonists usually produce greater antinociception in male monkeys than in females, and the magnitude of these sex-related differences may be inversely related to efficacy at mu receptors or selectivity for mu versus kappa receptors. Estradiol appears to have little effect on mu-agonist antinociception in primates but may enhance the antinociceptive effects of kappa agonists.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1992

Assessment of buprenorphine in a drug discrimination procedure in humans.

These studies indicate that buprenorphine shares stimulus effects with other opioid drugs and that in overall profile of effects buprenorphine is more similar to hydromorphone than are the other opioid mixed agonist-antagonists tested-pentazocine, butorphanol, and nalbuphine. This characterization is supported by the behavioral drug discrimination results and by the subjective effect self-report results. In the drug discrimination assessments buprenorphine showed a pattern of generalization that was different from that of the other opioid-mixed agonist-antagonists. It did not generalize completely to either pentazocine or butorphanol, but it did generalize to hydromorphone in two studies and partially in a third. Both nalbuphine and pentazocine showed at least partial generalization to butorphanol, but buprenorphine did not. Butorphanol showed little generalization to hydromorphone except in the two-choice hydromorphone vs. saline discrimination in which all the tested mixed agonist-antagonists generalized to hydromorphone. The subjective effect self-report data also revealed a pattern of response to buprenorphine that was different from that to the other mixed agonist-antagonists. In particular, buprenorphine's profile of acute subjective effects was similar to that of hydromorphone. There were dose-related increases on various scales reflecting positive subjective effects, with little evidence of the dysphoric effects that are characteristic of high doses of the other mixed agonist-antagonists. These data are compatible with the view that buprenorphine is a partial agonist at the mu-receptor. Although they do not demonstrate the ceiling on magnitude of pharmacological effects that would be characteristic of a partial agonist, they do demonstrate that buprenorphine's profile of activity--both stimulus effects and subjective effects--is similar to that of the pure mu-agonist hydromorphone.

Buprenorphine↗
PubMed1996

Respiratory effects of opioid full and partial agonists in rhesus monkeys.

Respiratory and behavioral effects of the mu selective opioids levorphanol (0.01-3.0 mg/kg), methadone (0.03-5.6 mg/kg) and codeine (0.3-30.0 mg/kg) and the mixed-action opioids buprenorphine (0.003-10.0 mg/kg), butorphanol (0.003-0.3 mg/ kg) and nalbuphine (0.03-30.0 mg/kg) were studied in rhesus monkeys. In respiratory experiments, awake, seated monkeys wore plastic masks through which they breathed air or differing concentrations of CO2 mixed in air. Exposure to CO2 in air stimulated ventilation in a concentration-dependent manner. All opioids produced dose-dependent decreases in ventilation that were more pronounced as the concentration of CO2 increased. The highest doses of levorphanol, methadone, and butorphanol reduced the ventilatory stimulant effects of 5% CO2 in air by 85 to 90%, whereas the highest doses of nalbuphine, buprenorphine and codeine reduced the effects of 5% CO2 in air by only 50 to 75%. After presession butorphanol (0.01-0.1 mg/kg) or nalbuphine (1.0-3.0 mg/kg), levorphanol further reduced the ventilatory stimulant effects of 5% CO2 mixed in air, with some evidence of dose-effect flattening. However, pretreatment with buprenorphine (1.0-10.0 mg/kg) and the highest dose of nalbuphine (10.0 mg/kg) attenuated the effects of 10.0 mg/kg levorphanol, indicative of antagonism. In behavioral experiments, all drugs produced dose-related decreases in responding under a 30-response fixed-ratio schedule. The highest doses of levorphanol, methadone, codeine, and butorphanol nearly abolished responding in all subjects, whereas buprenorphine and nalbuphine most often reduced response rates by no more than 50%. Except for codeine, rank orders of potency were the same in behavioral and respiratory experiments. The lesser effects of nalbuphine and buprenorphine on ventilation, in conjunction with their levorphanol-antagonist effects, suggest their limited mu agonist efficacy at sites mediating the respiratory-depressant effects of opioids.

Animals↗
PubMed1996

Effects of diltiazem, a Ca2+ channel blocker, on naloxone-precipitated changes in dopamine and its metabolites in the brains of opioid-dependent rats.

The effects of diltiazem, an L-type Ca2+ channel blocker, on naloxone (an opioid receptor antagonist)-precipitated withdrawal signs and changes in extracellular levels of dopamine (DA) and its metabolites in various brain regions of morphine (a mu-opioid receptor agonist) or butorphanol (a mu/delta/kappa mixed opioid receptor agonist) dependent rats were investigated using high performance liquid chromatography fitted with an electrochemical detector (HPLC-ED). Rats were rendered opioid-dependent by continuous intracerebroventricular (i.c.v.) infusion with morphine (26 nmol/microliters per h) or butorphanol (26 nmol/microliters per h) for 3 days. The expression of physical dependence produced by these opioids, as evaluated by naloxone (5 mg/kg. i.p.)-precipitated withdrawal signs, was reduced by concomitant infusion of diltiazem (10 and 100 nmol/microliters per h). Under the same condition, naloxone decreased the levels of: DA in the cortex, striatum, and midbrain; 3,4-dihydroxyphenylacetic acid (DOPAC) in the cortex, striatum, limbic areas, and midbrain: and homovanilic acid (HVA) in the striatum, limbic areas, and midbrain regions. In animals rendered dependent on butorphanol, the results obtained were similar to those of morphine-dependent rats except for the changes in DOPAC levels. Furthermore, concomitant infusion of diltiazem and opioids blocked the decreases in levels of DA, DOPAC, and HVA in a dose-dependent manner. These results suggest that the augmentation of intracellular Ca2+ mediated through L-type Ca2+ channels during continuous opioid infusion results in a decrease in extracellular levels of DA and its metabolites in some specific regions, which are intimately involved in the expression of withdrawal syndrome precipitated by naloxone.

Animals↗
PubMed1998

The role of glutamate in the locus coeruleus during opioid withdrawal and effects of H-7, a protein kinase inhibitor, on the action of glutamate in rats.

To investigate the role of glutamate in the locus coeruleus (LC) during opioid withdrawal, rats were continuously infused with morphine (a mu-opioid receptor agonist, 26 nmol/microl/h) or butorphanol (a mu/delta/kappa-mixed opioid receptor agonist, 26 nmol/microl/h) intracerebroventricularly (i.c.v.) via osmotic minipumps for 3 days. A direct LC injection of glutamate (1 or 10 nmol/5 microl) or naloxone (an opioid receptor antagonist, 24 nmol/5 microl) induced withdrawal signs in morphine- or butorphanol-dependent animals. However, these agents failed to precipitate any withdrawal signs in saline-treated control animals. On the other hand, the expression of withdrawal signs precipitated by the administration of glutamate or naloxone in opioid-dependent animals was completely blocked by concomitant infusion with 1 or 10 nmol/microl/h of an inhibitor of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase and protein kinase C, H-7 [1-(5-isoquinolinesulfonyl)-2-methylpiperazine]. In animals that had been infused with opioids in the same manner, i.c.v. injection of naloxone (48 nmol/5 microl) precipitated withdrawal signs and increased extracellular fluid levels of glutamate in the LC of morphine- or butorphanol-dependent rats measured by in vivo microdialysis method. However, concomitant infusion with H-7 inhibited the increases of glutamate levels in the LC. These results strongly suggest that an expeditious release of glutamate in the LC region plays an important role in the expression of physical dependence on opioids. Furthermore, the action on glutamate release might be increased by the enhancement of cAMP-dependent protein kinase and/or protein kinase C activity.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2002

Age-related differences in sensitivity to the antinociceptive effects of kappa opioids in adult male rats.

RATIONALE: Significant differences in the potency and effectiveness of opioid analgesics have been reported in subject populations differing in age. Although the relationship between aging and sensitivity to the antinociceptive effects of mu opioids has been examined extensively, relatively few studies have examined this relationship in kappa opioids. OBJECTIVES: The purpose of the present investigation was to examine the antinociceptive effects of selected kappa and mixed-action opioids in young (3 months) and aged (21 months) male rats. 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. Selected kappa (U69,593, U50,488) and mixed-action (butorphanol, nalbuphine) opioids were tested alone, and in combination with the high-efficacy, kappa-opioid spiradoline. RESULTS: All test drugs were more effective (i.e., produced a greater maximal effect) in aged rats than in young rats at both water temperatures. In drug combination tests, U69,593 and U50,488 enhanced the effects of spiradoline under conditions in which they failed to produce high levels of antinociception when administered alone. In contrast, butorphanol and nalbuphine antagonized the effects of spiradoline under conditions in which they failed to produce high levels of antinociception when administered alone. CONCLUSIONS: These data may be taken as evidence that: (1) aged male rats are more sensitive than young male rats to the antinociceptive effects of kappa opioids, (2) U69,593 and U50,488 display agonist activity in the warm-water, tail-withdrawal procedure under some conditions in which they fail to produce antinociceptive effects, and (3) butorphanol and nalbuphine possess only limited agonist activity at the kappa receptor.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1998

The mu opioid irreversible antagonist beta-funaltrexamine differentiates the discriminative stimulus effects of opioids with high and low efficacy at the mu opioid receptor.

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.

Animals↗
PubMed1994

A protein kinase inhibitor, H-7, inhibits the development of tolerance to opioid antinociception.

To investigate the effect of a protein kinase inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), on the development of tolerance to antinociception induced by morphine (mu-opioid receptor agonist) and butorphanol (mu/delta/kappa-mixed opioid receptor agonist), rats were infused i.c.v. with morphine, butorphanol and H-7 through osmotic minipumps for 3 days. Concomitant infusion of H-7 dose dependently inhibited the development of tolerance to i.c.v. morphine- and butorphanol-induced antinociception. These results suggest that protein kinases may play an important role in the development of opioid tolerance.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗