Study of µ- and δ-Opioid Activities in Agents with Various κ-Receptor Selectivity.

A putative opioid agonist RU-1205 was ineffective within in vitro model of electrically induced contractions of rat ileum assessing the µ- and δ-opioid receptor pathways, while morphine inhibited these contractions in a dose-dependent and naloxone-reversible manners with EC50=2.6×10-7 M. In vivo experiments revealed no significant effects of RU-1205 on respiration and gastrointestinal tract contractile activity. In contrast, butorphanol decreased respiration rate by 25% (25-100 mg/kg) and slowed down the transit of labeled particles along the small intestine by 77.1% (1 mg/kg) and by 45.5% (10 mg/kg). Morphine-induced inhibition of peristalsis was dose-dependent with maximum effect (by 68.6%) observed in the dose of 10 mg/kg. It was concluded that the effects of RU-1205 are not related to activation µ- and δ-opioid receptors known to mediate the effects of non-selective opioid agonist morphine and agonist-antagonist butorphanol.

Transcranial flavoprotein-autofluorescence imaging of sound-evoked responses in the mouse auditory cortex under three types of anesthesia.

The effects of anesthesia on the functional auditory characteristics of cortical neurons, such as spatial and temporal response properties, vary between an anesthetized and an awake subject. However, studies have shown that an appropriate anesthetic method that approaches the awake condition is still useful because of its greater stability and controllability. The present study compared neural response properties from two core fields of the mouse auditory cortex under three anesthetic conditions: urethane; ketamine and xylazine hydrochloride (KX) mixture; and a combination of medetomidine, midazolam, and butorphanol (MMB). To measure sound stimulation in vivo, we recorded flavoprotein-autofluorescent images of endogenous green fluorescence. Under all conditions, fluorescence changes in auditory core subfields in response to tones were observed, and response properties, such as peak intensity, latency, duration, and activated areas were analyzed. Results showed larger response peak intensity, latency, and duration in the core subfields under urethane compared with KX and MMB, with no significant differences between KX and MMB. Conversely, under KX anesthesia the activated areas showed characteristic response properties in a subfield-dependent manner. These results demonstrated the varied effects of anesthesia on response properties in the core subfields of the auditory cortex.

Blood biochemical changes in mice after administration of a mixture of three anesthetic agents.

Currently, from the viewpoint of animal welfare, anesthesia or analgesia is required during experimental procedures in animals that are likely to cause pain. A part of these anesthetics have been reported to influence a blood biochemical level. It is important for us to understand the effect of the anesthetic on blood biochemistry when we choose the anesthetic agent to be used in experiments. In this study, we examined the blood biochemical changes in mice after administration of a new mixture of three anesthetic agents -medetomidine / midazolam / butorphanol (MMB). We subcutaneously administered two dose combinations of MMB (0.45 / 6 / 7.5 and 0.9 / 12 / 15 mg/kg) in mice, followed by administration of atipamezole, for reversal of anesthetic effects, after 1 hr. Thereafter, blood biochemistry was assessed at 1, 4 and 24 hr after MMB administration. We observed that MMB administration caused a transient increase in blood sugar, inorganic phosphorus, potassium and creatine kinase levels. These, however, returned to the reference range 24 hr after MMB administration. In conclusion, MMB changes the levels of some blood biochemical parameters, but not to an extent that would threaten health. However, when using laboratory animals, this effect of MMB may influence the experimental results, depending on the experimental content. Hence, the choice of anesthetic agents used in laboratory animals should be based on detailed knowledge of their pharmacological effects.

Evaluation of modified techniques for immobilization of wild ring-tailed lemurs (Lemur catta).

Wild ring-tailed lemurs (Lemur catta) can be anesthetized with Telazol via blow dart, but improved techniques are needed so that each lemur is reliably induced with a single dart. Medetomidine-butorphanol (MB) is a good supplemental protocol to be administered once the lemurs are captured, but other protocols may provide longer periods of sedation and immobility. One possible way of increasing the efficacy of each dart is to increase the time it is retained in the leg. In this investigation, a "double-sleeve" technique was used to try to increase the time of dart retention. This technique used a standard silicone sleeve on the needle, along with a second sleeve at the needle hub. Induction values were compared between lemurs darted with double-sleeve needles and those induced with needles that each had a single silicone sleeve. Once the lemurs were induced, supplementation with MB (0.04 mg/kg and 0.2 mg/kg) was compared with supplementation with ketamine-medetomidine (KM) (10 mg/ kg and 0.04 mg/kg). Twenty-three lemurs were darted with Telazol by using single-sleeve needles, and 24 were darted with double-sleeve needles. The number of darts per lemur and number of escapes were not different between animals darted with a single sleeve compared with a double-sleeve; thus, there were no significant improvements in induction success with the double-sleeve technique. Adequate sedation and muscle relaxation were achieved with both MB and KM; however, lemurs that received MB were more relaxed and needed fewer additional supplements that those that received KM. Single-sleeve dart needles are recommended for Telazol induction of ring-tailed lemurs via blow dart and MB is preferable to KM for supplemental sedation and muscle relaxation.

Comparison of electroacupuncture and butorphanol on respiratory and cardiovascular effects and rectal pain threshold after controlled rectal distention in mares.

OBJECTIVE: To compare effects of electroacupuncture and butorphanol on hemodynamic and respiratory variables and rectal analgesia in mares after controlled rectal distention. ANIMALS: 8 healthy mares. PROCEDURE: Each horse received saline (0.9% NaCl) solution (0.01 mL/kg, IV; control treatment), butorphanol tartrate (0.1 mg/kg, IV), or 2 hours of electroacupuncture (EA) at acupoints Bladder 21, 25, and 27 on both sides of the vertebral column, Bai hui, and Stomach 36 (right side only). Order of treatments in each mare was randomized. At least 7 days elapsed between treatments. A balloon was inserted in the rectum of each mare, and controlled distention of the balloon (pressures of < or = 220 mm Hg) was used to measure nociceptive rectal pain threshold. Rectal temperature and cardiovascular and respiratory variables were measured before (baseline) and 5,15, 30, 60, 90, and 120 minutes after onset of each treatment. RESULTS: Butorphanol produced greater increases in rectal pain threshold, compared with EA (mean +/- SD, 214 +/- 24 vs 174 +/- 35 mm Hg of balloon pressure). Electroacupuncture produced minimal cardiovascular and respiratory changes. Although clinically not important, butorphanol produced moderate significant increases in heart and respiratory rates, arterial blood pressure, and rectal temperature and decreases in arterial oxygen tension. Arterial pH, carbon dioxide tension, bicarbonate concentrations, base excess, Hct, and concentration of total solids were not significantly different from baseline values after EA, butorphanol, and control treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Electroacupuncture and butorphanol (0.1 mg/kg, IV) may provide useful rectal analgesia in horses.

Effects of treatment with oxytocin, xylazine butorphanol, guaifenesin, acepromazine, and detomidine on esophageal manometric pressure in conscious horses.

OBJECTIVE: To compare effects of oxytocin, acepromazine maleate, xylazine hydrochloride-butorphanol tartrate, guaifenesin, and detomidine hydrochloride on esophageal manometric pressure in horses. ANIMALS: 8 healthy adult horses. PROCEDURE: A nasogastric tube, modified with 3 polyethylene tubes that exited at the postpharyngeal area, thoracic inlet, and distal portion of the esophagus, was fitted for each horse. Amplitude, duration, and rate of propagation of pressure waveforms induced by swallows were measured at 5, 10, 20, 30, and 40 minutes after administration of oxytocin, detomidine, acepromazine, xylazine-butorphanol, guaifenesin, or saline (0.9% NaCI) solution. Number of spontaneous swallows, spontaneous events (contractions that occurred in the absence of a swallow stimulus), and high-pressure events (sustained increases in baseline pressure of > 10 mm Hg) were compared before and after drug adminision. RESULTS: At 5 minutes after administration, detomidine increased waveform amplitude and decreased waveform duration at the thoracic inlet. At 10 minutes after administration, detomidine increased waveform duration at the thoracic inlet. Acepromazine administration increased the number of spontaneous events at the thoracic inlet and distal portion of the esophagus. Acepromazine and detomidine administration increased the number of high-pressure events at the thoracic inlet. Guaifenesin administration increased the number of spontaneous events at the thoracic inlet. Xylazine-butorphanol, detomidine, acepromazine, and guaifenesin administration decreased the number of spontaneous swallows. CONCLUSIONS AND CLINICAL RELEVANCE: Detomidine, acepromazine, and a combination of xylazine butorphanol had the greatest effect on esophageal motility when evaluated manometrically. Reduction in spontaneous swallowing and changes in normal, coordinated peristaltic activity are the most clinically relevant effects.

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.

Site of opioid action in the human brain: mu and kappa agonists' subjective and cerebral blood flow effects.

OBJECTIVE: Humans experience the subjective effects of mu and kappa opioid agonists differently: mu agonists produce mainly euphoria, while kappa agonists are more likely to produce dysphoria. This study tested the hypothesis that these subjective effects would be associated with anatomically distinct changes in regional cerebral blood flow (CBF) relative to baseline as assessed with single photon emission computed tomography (SPECT). METHOD: Nine nondependent opioid abusers participated in the study. In the first phase of the study, the participants were acclimated to effects of the study drugs. In the second phase they underwent repeat challenges with the study drugs followed by an assessment of CBF with use of the SPECT tracer [99mTc]HMPAO. Medications tested were the prototypic mu agonist hydromorphone, the mixed agonist/antagonist butorphanol (which has a kappa agonist component of activity), and saline placebo. RESULTS: Subjective effects of the drugs were distinctly different. Hydromorphone produced increased ratings of "good effects," while butorphanol led to more "bad effects." Hydromorphone significantly increased regional CBF in the anterior cingulate cortex, both amygdalae, and the thalamus--all structures belonging to the limbic system. Butorphanol caused a less distinct picture of regional CBF increases, mainly in the area of both temporal lobes. CONCLUSIONS: This study demonstrates that opioids with different subjective effects also produce statistically significant patterns of change in regional CBF from baseline, and the regions of statistical significance appear in different brain regions. In addition, these results demonstrate the applicability of SPECT functional neuroimaging in the study of medications with potential abuse liability.

Influence of acute and chronic morphine or stadol on the secretion of adrenocorticotrophin and its hypothalamic releasing hormone in the rat.

The effects of acute and chronic treatment with morphine and stadol on the functional activity of the hypothalamo-pituitary-adrenocortical (HPA) system in the rat were studied by investigating their effects on the secretion of adrenocorticotrophin (ACTH) by the pituitary gland and corticotrophin-releasing hormone (CRH) by the hypothalamus. The acute injection of morphine or stadol (3.5 mg/100 g body weight i.p.) caused a rise at 5 and 25 min followed by a fall at 90 and 120 min in the concentrations of ACTH in the plasma and adenohypophysis and in hypothalamic CRH content. It appears that, in the rat, the response of HPA system to acute morphine or stadol administration could change depending upon the time of courses. In addition, chronic morphine or stadol (0.5 mg/100 g body weight i.p. daily) administration for a period of 7 days have little effect on plasma and adenohypophysis ACTH concentrations and hypothalamic CRH content. This may indicate that drug tolerance might have developed. Conversely, repeated daily doses of morphine or stadol (2 mg/ 100 g body weight i.p.) for 7 days cause a significant lowering of plasma and pituitary ACTH concentrations and hypothalamic CRH content. These data suggest that the effect of both drugs is dose related. Overall, the present results are consistent with an increased release of pro-opiomelanocortin-derived peptides after acute morphine or stadol treatment for a short-term, and with a decreased release of these peptides in chronic treatment. However, the results indicate that morphine and stadol change HPA activity by acting on specific receptors in the hypothalamus and raise the possibility that opioid peptides and their receptors are physiologically important in the control of the secretion of CRH.

[The characteristics of the opioid regulation of the afferent reactions of the stomach and duodenum to the early stages of their acute damage]. / Osobennosti opioidnykh reguliatsii afferentnykh reaktsii zheludka i dvenadtsatiperstnoi kishki na rannikh étapakh ikh ostrogo povrezhdeniia.

Acute cat experiments were conducted to study the effect of naloxone, moradol and dalargin on the formation of afferent reactions of gastroduodenal complex components by registration of cortical and subcortical evoked potentials during electrostimulation of the stomach and duodenum at an early stage of their acute lesion. It is found that agonists and antagonists of opiate receptors prevent the depression of afferentation of gastroduodenal complex components early after acute lesion. It is suggested that the main mechanism underlying the depression of gastric and duodenal afferent reactions at early post-alteration period may be related to activation of intraorganic opioid systems.

Comparison of detomidine, butorphanol, flunixin meglumine and xylazine in clinical cases of equine colic.

Detomidine hydrochloride, butorphanol tartrate, flunixin meglumine and xylazine hydrochloride were evaluated in a blind multi-centre clinical trial in 152 horses with abdominal pain. The drugs were administered as follows: detomidine 20 or 40 micrograms/kg bodyweight (bwt); butorphanol 0.1 mg/kg bwt; flunixin meglumine 1.0 mg/kg bwt; xylazine hydrochloride 0.5 mg/kg bwt. Each centre compared responses to the two doses of detomidine with those to one of the other analgesics. The drugs were administered intravenously (i.v.) after clinical assessment of the degree of sweating, kicking, pawing, head and body movement, attitude, lip curling, stretching to urinate, pulse rate, respiratory rate and rectal temperature. Similar assessments were repeated at 15 min intervals for at least 1 h. The investigators ranked the response to treatment from 'not satisfactory' to 'highly satisfactory'. Significant differences in sweating, kicking, pawing, head and body movement, attitude, pulse rate and respiratory rate were noted between the horses receiving butorphanol and either dose of detomidine. The investigators' subjective evaluation of the analgesic and sedative effects of either dose of detomidine were significantly better than for butorphanol. Analgesia was rated as highly satisfactory or satisfactory in 93.3 per cent and 6.7 per cent of the horses receiving 40 micrograms/kg bwt of detomidine, 73.3 per cent and 26.7 per cent of the horses receiving 20 micrograms/kg bwt of detomidine, and none of the horses receiving butorphanol. There were no differences in the incidence of side effects with the two compounds. Significant differences were noted in kicking, pawing, head and body movement and attitude between the horses receiving flunixin meglumine and either dose of detomidine. Flunixin meglumine provided significantly less analgesia than either dose of detomidine. Analgesia was rated as highly satisfactory or satisfactory in 73.7 per cent and 21.0 per cent of the horses receiving 40 micrograms/kg bwt of detomidine, 42.9 per cent and 21.4 per cent of the horses receiving 20 micrograms/kg bwt of detomidine, and 6.3 per cent and 37.5 per cent of the horses receiving xylazine. Sedation was considered to be at least satisfactory in 84.2 per cent of the horses receiving 40 micrograms/kg of detomidine, 71.5 per cent of the horses receiving 20 micrograms/kg of detomidine and 53.3 per cent of the horses receiving xylazine.