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PubMed1999

Development of a scale to evaluate postoperative pain in dogs.

OBJECTIVE: To design and evaluate a scale for measurement of postoperative pain in dogs. DESIGN: Randomized, blinded, prospective study, with positive- and negative-control groups. ANIMALS: 36 dogs undergoing general anesthesia for ovariohysterectomy and 12 dogs undergoing general anesthesia without surgery. PROCEDURE: A pain assessment scale was developed for dogs, which incorporated physiologic data (heart and respiratory rates) and behavioral responses (response to palpation, activity, mental status, posture, and vocalization). This pain scale was then applied to a study in which dogs were allocated to 2 groups, depending on the type of medication administered (acepromazine maleate only or acepromazine and butorphanol) before induction of general anesthesia. The 36 dogs that had ovariohysterectomy were allocated to 3 groups, members of which received butorphanol, carprofen, or no analgesic after surgery. Dogs were scored for signs of pain and videotaped at 0, 1, 2, 4, 6, 8, 12, and 18 hours after surgery by an assessor who was blinded to the groups. Results were analyzed for significant differences in pain scores for single categories and total pain scores among groups. Video segments were scrambled and then scored by a second external assessor to test the repeatability of the results, using the pain assessment scale. RESULTS: Mean total pain scores were significantly different between the group of dogs that underwent general anesthesia only and each group of dogs that underwent general anesthesia and surgery. Pain scores for the analgesic-treatment groups reflected the known onset and duration of action of the analgesic used. Agreement between the internal and external assessors was excellent and indicated high precision between the 2 assessors for the population of dogs as a whole. CLINICAL IMPLICATIONS: Behavioral and physiologic measurements can be used reliably to evaluate degree of pain in dogs during the postoperative period and their response to analgesics.

Acepromazine↗
PubMed2003

Recovery of male rats from major abdominal surgery after treatment with various analgesics.

The objective of this study was to compare the recovery of male rats after a major abdominal surgical procedure (the implantation of a radiotelemetry transmitter) when treated with buprenorphine, butorphanol, or ketoprofen and subcutaneous fluids (5% dextrose) or with subcutaneous fluids only. The parameters for assessing recovery were heart rate (HR), mean arterial blood pressure (MAP), home cage activity, food and water consumption, and body weight. HR, MAP, and activity were continuously monitored by radiotelemetry methods, food and water intakes were determined daily, and body weights were measured once or three times a week. In light of HR, nocturnal home cage activity, water consumption, and body weight gain, animals were recovered by about 7 days after surgery. MAP normalized by 1 to 2 days postsurgery, and food consumption returned to presurgical levels 5 to 12 days after surgery, depending on the analgesic treatment. On the basis of nocturnal activity, HR, and food and water intakes, buprenorphine-treated animals recovered more slowly than did the other two analgesic-treated groups. By the other parameters, all three analgesic-treated groups showed very similar responses across time. Surprisingly, when compared with the groups receiving only subcutaneous fluids, buprenorphine and butorphanol delayed or did not advance recovery, whereas ketoprofen neither retarded nor advanced recovery. Explanations for these results include: (a) the analgesics were effective in relieving pain but had pharmacological side effects that altered the measured parameters, making it difficult to determine recovery; (b) the level of pain experienced did not notably affect recovery; (c) the analgesics, at the doses and/or dosing schedules used, were not effective in the relief of pain, thereby causing both groups of animals to recover at the same rate; and (d) the analgesics interfered with recovery. Final resolution of these issues awaits further investigation.

Abdomen↗
PubMed2004

[Comparison of analgesics used during balanced anesthesia on the incidence of PONV].

BACKGROUND: When we make reference to the quality of anesthesia, we consider three points, early emergence, postoperative pain relief, and postoperative nausea and vomiting (PONV). Among these, PONV is comparatively neglected. Many analgesics used during anesthesia may cause PONV. METHODS: The incidence of PONV was assessed in 100 surgical patients who had received balanced anesthesia. Anesthesia was induced with propofol, ketamine, midazolam and buprenorphine (Group P), or butorphanol (Group T), and vecuronium was given to facilitate tracheal intubation. The patients received balanced anesthesia with infusion of propofol, ketamine, vecuronium, and either buprenorphine (Group P) or butorphanol (Group T), with nitrous oxide. PONV was recorded for 24 hours postoperatively. RESULTS: Incidences of nausea were 27.1% in Group P and 15.8% in Group T (NS). Incidences of vomiting were 12.5% in Group P and 5.3% in Group T (NS). However, a high incidence of PONV was found in female (42.2%) vs. male (6.2%) (P < 0.01) and in over 25 BMI group (34.5%) vs. under 25 BMI group (15.5%) (P < 0.05). CONCLUSIONS: The type of analgesics used during balanced anesthesia is not important for development of PONV, but patient's factors, such as gender and BMI, are more closely associated with PONV.

Aged↗
PubMed1988

Clinical pharmacology of antagonists of narcotic-induced respiratory depression. A brief review.

A variety of drugs have been used to antagonize the respiratory depression caused by narcotics. Some of these drugs, such as nalorphine, naloxone, butorphanol, and nalbuphine, are opiates, which interact directly with opiate receptors. Others, such as physostigmine, doxapram, and aminophylline, probably act indirectly by stimulating neuronal pathways involved in the regulation of ventilation. None of these drugs is ideal, and all have adverse side effects. Cardiovascular instability and eradication of analgesia have been troublesome, especially with the use of naloxone. The newer mixed agonist-antagonist agents, butorphanol and nalbuphine, may have significant advantages compared with naloxone. The purpose of this review is to summarize the pharmacology of the common narcotic antagonists, with an emphasis on obtaining acceptable results while avoiding adverse side effects.

Animals↗
PubMed1986

Opiates and the anorexia of uremia.

Uremia results in a decrease in food intake. In the present study we investigated whether opiates known to stimulate feeding would alter food intake in rats made uremic by 1 and 5/6 nephrectomy. Morphine increased food intake in sham nephrectomized rats, but failed to alter food intake in uremic animals and depressed the ingestion of rat chow in a group of weight restricted rats. Butorphanol tartrate increased feeding in sham and uremic animals but did not alter intake in the weight restricted group. Higher doses of butorphanol were needed to stimulate feeding in the uremic rats compared to the sham group, suggesting a relative resistance to opioid-induced feeding in the uremic rats. The opiate antagonist, naloxone, suppressed food intake in the uremic and sham groups more effectively than in the weight restricted rats. These data suggest that the opioid feeding system functions in a reduced fashion in uremic rats, but probably is not the sole factor involved in producing the anorexia associated with uremia.

Animals↗
PubMed1983

A new analgesic drug combination in the horse.

A xylazine and butorphanol drug combination produced minimal and transient hemodynamic effects and no significant respiratory depression when administered to 6 healthy horses. Combining xylazine and butorphanol produced a synergistic analgesic effect and provided good chemical restraint for a standing surgical procedure.

Analgesia↗
PubMed1995

[Postoperative management following open heart surgery by thoracic epidural anesthesia].

The significance of thoracic epidural anesthesia as a postoperative analgesic-sedative was evaluated. Ninety-seven open heart surgery patients with average age of 64 years, were classified into: Non-Epidural (N) group, Epidural with butorphanol (B) group and Epidural with morphine (M) group, in each of which the pulmonary, circulatory and sedative states were studied. Anesthesia was induced with low-dose fentanyl and isoflurane-nitrous oxide-oxygen, and epidural catheter was inserted through Th 7-10 on the day before the operation for Epidural groups. Butorphanol 0.5-1.0 mg was administrated in B group, and morphine 2-5 mg in M group. The Epidural groups required only small amount of fentanyl, 5 micrograms.kg-1, were extubated earlier compared to N group, and showed higher postoperative cardiac index. As for the respiratory state, although PaCO2 was slightly higher in the Epidural group, there was no difference in oxygenation. The incidence of administration of postoperative analgesic-sedative was extremely low in the Epidural especially in M group. As long as the indication is appropriately selected, the epidural anesthesia will not have negative effect on the postoperative pulmonary and circulatory state, allows for an earlier extubation and has excellent sedative effect. It is an effective method for patient management following open heart surgery.

Aged↗
PubMed1997

Effects of three sedative protocols on glomerular filtration rate in clinically normal dogs.

OBJECTIVE: To determine the effects of 3 sedative protocols (butorphanol and diazepam [BD] IV; acepromazine and butorphanol [AB] IV; diazepam and ketamine [DK] IV) on glomerular filtration rate (GFR) as measured by 99mTc DTPA nuclear scintigraphy and to compare them with GFR measured without sedation. Cardiovascular, respiratory, and sedative effects of each protocol also were measured. ANIMALS: 12 adult male Walker Hounds. PROCEDURE: Systolic, diastolic, and mean arterial blood pressures and heart and respiratory rates were measured before, during, and after scintigraphic measurement of GFR. RESULTS: Difference in GFR was not significant between any of the sedative regimens and the control. The DK protocol caused significant increases in systolic, diastolic, and mean arterial blood pressure; compared with the AB and BD protocols, it caused significant increases in heart rate versus all protocols, and was associated with the lowest mean GFR (2.80 ml/min/kg of body weight). The AB protocol caused significant decreases in systolic, diastolic, and mean arterial blood pressures, compared with DK and the nonsedation protocols. Mean GFR for the BD protocol was 2.94 ml/min/kg, and was 3.13 ml/min/kg for the AB and the nonsedation protocols. The AB protocol provided the best sedation with minimal additional restraint required. The BD and nonsedation protocols often were associated with substantial dog movement. The DK protocol induced inadequate duration of immobilization (< 10 minutes) in some dogs and excitement in others. CONCLUSION: GFR measurements obtained with any of the sedative protocols were not significantly different, compared with measurements in awake dogs. The AB protocol provides the best sedative effects and was associated with GFR values identical to those in awake dogs. Systemic hypotension caused by acepromazine did not decrease GFR in clinically normal dogs.

Acepromazine↗
PubMed2003

Interactions between opioids and cocaine on locomotor activity in rats: influence of an opioid's relative efficacy at the mu receptor.

RATIONALE: Cocaine and mu opioid agonists increase central dopamine concentrations and produce robust interactions at both neurochemical and behavioral levels. Although the interactions between cocaine and high-efficacy mu opioids have been well characterized, the interactions between cocaine and lower efficacy opioids have not been as extensively examined. OBJECTIVE: The purpose of this study was to examine the interactions between cocaine and opioids possessing a range of relative efficacy at the mu receptor. METHODS: Male, Long-Evans rats were habituated to an open-field, locomotor activity chamber, and the effects of cocaine and various opioids were tested under a cumulative dosing procedure. In this procedure, a selected dose of an opioid was administered during the first component of a session, with increasing doses of cocaine administered during subsequent components. RESULTS: When administered alone, cocaine produced dose-dependent increases in locomotor activity that was stable across 5 weeks of behavioral testing. The high-efficacy mu opioid levorphanol, and the low-efficacy opioids buprenorphine, butorphanol, nalbuphine and (-)-pentazocine, dose-dependently enhanced the effects of cocaine at doses that did not alter locomotor activity when administered alone. In contrast, the opioid antagonist naloxone, and to a lesser extent, the kappa opioid spiradoline attenuated the effects of cocaine at doses that did not alter locomotor activity when administered alone. Across an extensive dose range, the low-efficacy opioid nalorphine failed to alter cocaine's locomotor-activating effects. CONCLUSIONS: These data suggest that low-efficacy opioids possessing significant mu-agonist activity (e.g. buprenorphine, butorphanol, nalbuphine, (-)-pentazocine) may potentiate the effects of cocaine in a manner similar to that typically observed with high-efficacy mu opioids.

Analgesics↗
PubMed2003

Sensitivity to the effects of opioids in rats with free access to exercise wheels: mu-opioid tolerance and physical dependence.

RATIONALE: Exercise stimulates the release of endogenous opioid peptides and increases nociceptive (i.e. pain) thresholds in both human and animal subjects. During chronic, long-term exercise, sensitivity to the effects of morphine and other mu opioids decreases, leading some investigators to propose that exercise may lead to the development of cross tolerance to exogenously administered opioid agonists. OBJECTIVE: The purpose of the present investigation was to examine the effects of chronic exercise on sensitivity to mu opioids, and to determine whether these effects can be attributed to the development of opioid tolerance and dependence. METHODS: Rats were obtained at weaning and housed singly in standard polycarbonate cages (sedentary) or modified cages equipped with exercise wheels (exercise). After 6 weeks under these conditions, opioids possessing a range of relative efficacy at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine) were examined in a warm-water tail-withdrawal procedure. RESULTS: Morphine, levorphanol and buprenorphine produced maximal levels of antinociception in both groups of rats, but all were more potent in sedentary rats than in exercising rats. Butorphanol and nalbuphine produced maximal levels of antinociception in sedentary rats under some conditions in which they failed to produce antinociception in exercising rats. Sensitivity to the effects of buprenorphine was decreased in sedentary rats that were transferred to cages equipped with exercise wheels, and increased in exercising rats that were transferred to sedentary housing conditions. In the latter group, exercise output prior to housing reassignment was positively correlated with increases in sensitivity to buprenorphine following housing reassignment. Naloxone administration precipitated a mild withdrawal syndrome in exercising rats that was not readily apparent in sedentary rats. CONCLUSIONS: These data suggest that chronic exercise leads to the development of mu-opioid tolerance and physical dependence, and that these effects are similar to those produced by chronic opioid administration.

Animals↗
PubMed2001

Age-related differences in sensitivity to the antinociceptive effects of opioids in male rats. Influence of nociceptive intensity and intrinsic efficacy at the mu receptor.

RATIONALE: Despite the widespread popularity of opioid analgesics, significant differences in the potency and effectiveness of these drugs are often observed across age groups. OBJECTIVES: The purpose of this investigation was to examine age-related differences in sensitivity to the antinociceptive effects of mu opioids and to identify the conditions under which these differences are most apparent. METHODS: In a warm-water tail-withdrawal procedure, young (3 months) and aged (24 months) male rats were habituated to restraint and the latencies to remove their tails from 50 degrees C (low nociceptive intensity) and 55 degrees C (high nociceptive intensity) water were measured. Opioids possessing a range of intrinsic efficacy at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine, nalorphine) were examined. RESULTS: Young and aged rats were equally sensitive to the antinociceptive effects of morphine, levorphanol, and buprenorphine when tested at the low nociceptive intensity. When these drugs were tested at the high nociceptive intensity, differences between the two age groups became apparent, such that aged rats were significantly more sensitive to the antinociceptive effects of these drugs than young rats. Differences between age groups were most apparent when butorphanol, nalbuphine, and nalorphine were tested, in that each of these drugs produced maximal levels of antinociception in aged rats under conditions in which they failed to produce antinociceptive activity in young rats. Under conditions in which lower efficacy opioids failed to produce antinociceptive activity in young rats, they antagonized the effects of morphine in drug combination tests. CONCLUSIONS: These data may be taken as evidence that aged male rats are more sensitive to the antinociceptive effects of mu opioids than young male rats, and that age-related differences in opioid sensitivity are most apparent when lower efficacy opioids and higher nociceptive intensities are employed during behavioral testing.

Aging↗
PubMed2004

Treatment of the Pruritus of Cholestasis.

The etiology of the pruritus of cholestasis is unknown. It is inferred that the pruritogen(s) is produced in the liver, excreted in bile, and as a result of cholestasis it accumulates in plasma. It may follow, logically, that the removal of the substance(s) that mediate pruritus leads to its resolution. The problem with this approach, however, is that the substance(s) is unknown; thus, it is not possible to reduce its serum levels specifically. Oral cholestyramine, a resin that is not absorbed, is associated with increased fecal excretion of certain substances, including cholesterol and bile acids. Many patients respond to treatment with cholestyramine with a relief of pruritus, which unfortunately may be temporary, but is well tolerated in general and it seems reasonable to prescribe it as an initial therapy. When pruritus is not relieved by resins, the use of opiate antagonists (eg, naloxone and naltrexone) is supported by data from controlled clinical trials. Butorphanol is an agonist at the kappa opioid receptor and an antagonist at the mu opioid receptor with minimal or absent abuse potential. The use of butorphanol spray in selective patients may be a therapeutic alternative. In uncontrolled observations dronabinol, an agonist at the cannabinoid B1 receptor, and sertraline, a serotonin reuptake inhibitor, have been reported to be associated with the relief of pruritus. The cannabinoidergic and serotoninergic systems participate in the mediation of nociception; therefore, there appears to be a rationale for the use of these drugs to treat pruritus. Data from controlled clinical trials on the use of dronabinol and sertraline, however, are not available at present.

Journal Article↗
PubMed1996

Direct evidence for a role of glutamate in the expression of the opioid withdrawal syndrome.

To investigate the role of glutamate in the expression of the withdrawal signs from opioids, rats were intracerebroventricularly (i.c.v.) infused continuously with morphine (a mu-opioid receptor agonist, 26 nmol/microliters per h) or butorphanol (a mixed mu/delta/kappa-opioid receptor agonist, 26 nmol/microliters per h) through osmotic minipumps for 3 days. An i.c.v. injection of glutamate (5 and 50 nmol/5 microliters) dose dependently induced withdrawal signs in morphine- or butorphanol-dependent animals. The withdrawal signs precipitated by the glutamate injection were comparable to those precipitated by an opioid receptor antagonist, naloxone (48 nmol/5 microliters), except for the expression of some specific behaviors and the duration of withdrawal signs. Glutamate or naloxone challenge failed to precipitate any withdrawal signs in saline controlled animals. On the other hand, the expression of the withdrawal signs precipitated by glutamate or naloxone in opioid-dependent animals was completely blocked by pretreatment with MK-801 [a NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5,10-imine], 0.1 mg/kg, i.p. These unique actions of glutamate in continuously opioid-infused rats suggest that a rapid central release of glutamate may be a key factor in the expression of withdrawal signs from opioids. Furthermore, this effect may be mediated by the NMDA subtype of glutamate receptors.

Animals↗
PubMed2004

Standing sedation and pain management for ophthalmic patients.

Several ocular procedures, including examination, removal of corneal foreign bodies, nictitans surgery, eyelid repair, and tumor excision,can be successfully performed in the appropriately restrained and sedated standing horse. Sedation is best achieved with xylazine,with or without the addition of acepromazine. Additional analgesia can be provided with appropriate local anesthetic blocks. Surgical conditions are greatly improved by using an auriculopalpebral and supraorbital block and topical anesthetics. More elaborate standing sedation involving continuous rate infusions of lidocaine or detomidine combined with butorphanol may facilitate more involved surgery with appropriate support staff and equipment in animals that are at high risk for general anesthesia or when the latter is not an option. Short-term or long-term analgesia is most commonly provided with nonsteroidal anti-inflammatory drugs, but several newer techniques, including lidocaine and butorphanol infusions, may be effective. Topical treatment with opioids to provide analgesia and opioid antagonists to enhance corneal healing is an exciting new development that may revolutionize our approach to corneal ulcer therapy in the future if current research findings are supportive.

Anesthesia, Local↗
PubMed2003

Pharmacogenetic analysis of sex differences in opioid antinociception in rats.

Sex differences in opioid antinociception have been reported in rodents and monkeys, with opioids being more potent in males than females. In the present study, the influence of rat strain on sex differences in opioid antinociception was examined in a warm water tail-withdrawal procedure. Antinociceptive tests were conducted with the high-efficacy micro-opioid morphine, and the less efficacious opioids buprenorphine, butorphanol and nalbuphine. Baseline nociceptive latencies were consistently higher in males than their female counterparts. Sex differences in opioid antinociception were observed in all strains tested, with the opioids being more potent and/or effective in males. The magnitude of the sex differences was related to the relative efficacy of the opioid, with morphine, buprenorphine, butorphanol and nalbuphine being on average 2.2-, 2.6-, 15.9- and 11.9-fold more potent in males. Sex differences also varied markedly across strains, with large differences consistently obtained in the F344 and F344-Sasco strains, moderate differences in the ACI, DA, Lewis, Sprague Dawley, Wistar and Wistar-Kyoto strains, and small differences in the Long Evans-Blue Spruce, Long Evans, Brown Norway and Holtzman strains. When compared across strains, there was no relationship between sex differences in nociceptive sensitivity and opioid sensitivity. These findings provide strong support for the role of genetic factors in determining sex differences in opioid antinociception, and suggest that the use of low-efficacy opioids, coupled with the use of rat strains that display small and large sex differences in opioid antinociception, may provide a sensitive tool to investigate the mechanisms underlying sex differences in opioid antinociception.

Analgesics↗
PubMed2006

Chronic exercise decreases sensitivity to mu opioids in female rats: correlation with exercise output.

Aerobic exercise stimulates the release of endogenous opioid peptides and increases nociceptive (i.e., pain) threshold in a naloxone-reversible manner. During chronic exercise, sensitivity to the antinociceptive effects of morphine and other mu opioids decreases, leading some investigators to propose that exercise may lead to the development of cross-tolerance to exogenously administered opioid agonists. The purpose of the present study was to examine the effects of chronic exercise on sensitivity to mu opioids, and to determine if changes in opioid sensitivity during chronic exercise are correlated with exercise output. Eight female rats were obtained at weaning and housed in standard laboratory cages that did not permit any exercise beyond normal cage ambulation. Following 6 weeks under these conditions, opioids possessing a range of relative efficacies at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol) were examined in a warm-water, tail-withdrawal procedure. Under sedentary conditions, all opioids produced dose-dependent increases in tail-withdrawal latencies, and high levels of antinociception were observed for all drugs. Following these tests, rats were reassigned to exercise conditions and transferred to cages equipped with running wheels. Under these conditions, rats ran an average of 7154 rev/day (7869 m/day), with a range across rats from 4501 to 10,164 rev/day (4951-11,180 m/day). Sensitivity to all four opioids decreased significantly during the exercise period, resulting in 2- to 5-fold decreases in the potency of morphine, levorphanol and buprenorphine, and decreases in the effectiveness of buprenorphine and butorphanol. When rats were returned to sedentary conditions, sensitivity to all four opioids increased significantly and returned to that observed prior to the exercise period. For all drugs, there was a positive correlation between exercise output and changes in opioid sensitivity between sedentary and exercise conditions. These data suggest that chronic exercise decreases sensitivity to mu opioids in female rats, and that these changes in sensitivity are positively correlated with exercise output.

Analgesics↗
PubMed1999

The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain.

Nalbuphine, pentazocine, and butorphanol, mixed agonist/antagonist opioids that induce analgesia by acting predominantly at kappa opioid receptors, have recently been shown in single-dose studies to have greater analgesic efficacy in women than in men. In the current experiments, the first placebo controlled dose response study of opioid analgesic efficacy that examines for gender differences, nalbuphine (5, 10, or 20 mg) and placebo were evaluated in 62 men and 69 women for the treatment of moderate to severe postoperative pain following extraction of impacted wisdom teeth. In a randomized, open injection, double blind experimental design, pain intensity was recorded on a 10 cm visual analog scale (VAS) immediately prior to drug administration (baseline) and at 20 min intervals thereafter. Although responses to placebo were similar in men and women, for all doses of nalbuphine women exhibited significantly greater analgesic response than men, compatible with our previous results. Unexpectedly, men receiving the 5 mg dose of nalbuphine experienced significantly greater pain than those receiving placebo; only the 20 mg dose of nalbuphine in men produced significant analgesia compared to placebo. While a similar antianalgesic effect was not observed in women, only the 10 mg dose of nalbuphine produced significant analgesia compared to placebo. These results suggest that the optimal analgesic dose of nalbuphine for women is lower than the highest dose that can be safely administered. In contrast, the antianalgesic effect of nalbuphine suggests avoidance of its routine use for postoperative analgesia in men until further studies clarify this issue. Because gender differences in other mixed kappa agonists/antagonists (i.e. pentazocine and butorphanol) have previously been shown, these results may generally apply to this class of opioid analgesics.

Adult↗
PubMed2001

Sex differences in opioid antinociception: kappa and 'mixed action' agonists.

A number of investigators have shown that male animals are more sensitive than females to the antinociceptive effects of mu-opioid agonists. The present study was conducted to examine sex differences in opioid antinociception in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu-receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine, (-)-bremazocine, (-)-pentazocine, butorphanol and nalbuphine on the 50 or 54 degrees C hotplate and warm water tail withdrawal assays; spontaneous locomotor activity was measured 32-52 min post-injection in the same rats. On the hotplate assay, only butorphanol (54 degrees C) and nalbuphine (50 degrees C) were significantly more potent in males than females. On the tail withdrawal assay, all agonists were significantly more potent or efficacious in males than females at one or both temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses to drug (50 degrees C experiment). These results suggest that (1) sex differences in antinociceptive effects of opioids are not mu-receptor-dependent, as they may occur with opioids known to have significant kappa-receptor-mediated activity; (2) the mechanisms underlying sex differences in kappa-opioid antinociception may be primarily spinal rather than supraspinal; (3) sex differences in antinociceptive effects of opioid agonists are not secondary to sex differences in their sedative effects.

Adaptation, Physiological↗