OBJECTIVE: To determine which class of opioid alone or in conjunction with other anesthetic drugs causes post-anesthetic hyperthermia in cats. STUDY DESIGN: Prospective, randomized, crossover study. ANIMALS: Eight adult, healthy, cats (four spayed females and four castrated males weighing 3.8 +/- 0.6 kg). METHODS: Each cat was instrumented with a wireless thermistor in the abdominal cavity. Temperature in all phases was recorded every 5 minutes for 5 hours. Population body temperature (PBT) was recorded for approximately 8 days. Baseline body temperature is the final 24 hours of the PBT. All injectable drugs were given intramuscularly. The cats were administered drugs in four phases: 1) hydromorphone (H) 0.05, 0.1, or 0.2 mg kg(-1); 2) morphine (M)(0.5 mg kg(-1)), buprenorphine (BUP)(0.02 mg kg(-1)), or butorphanol (BUT)(0.2 mg kg(-1)); 3) ketamine (K)(5 mg kg(-1)) or ketamine (5 mg kg(-1)) plus hydromorphone (0.1 mg kg(-1))(KH); 4) isoflurane in oxygen for 1 hour. Fifteen minutes prior to inhalant anesthetic, cats received either no premed (I), hydromorphone (0.1 mg kg(-1))(IH), or hydromorphone (0.1 mg kg(-1)) plus ketamine (5 mg kg(-1))(IHK). RESULTS: Mean PBT for all unmedicated cats was 38.9 +/- 0.6 degrees C (102.0 +/- 1 degrees F). The temperature of cats administered all doses of hydromorphone increased from baseline (p < 0.03) All four opioids (H, M, BUP and BUT) studied increased body temperature compared with baseline (p < 0.005). A significant difference was observed between baseline temperature values and those in treatment KH (p < 0.03). Following recovery from anesthesia, temperature in treatments IH and IHK was different from baseline (p < 0.002). CONCLUSIONS AND CLINICAL RELEVANCE: All of the opioids tested, alone or in combination with ketamine or isoflurane, caused an increase in body temperature. The increase seen was mild to moderate (<40.1 degrees C (104.2 degrees F) and self limiting.

The function of the central cannabinoid receptor (CB1) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB1 and opiate receptors in the brain areas mediating addictive behavior.

The nucleus accumbens is considered a critical target of the action of drugs of abuse. In this nucleus a "shell" and a "core" have been distinguished on the basis of anatomical and histochemical criteria. The present study investigated the effect in freely moving rats of intravenous cocaine, amphetamine, and morphine on extracellular dopamine concentrations in the nucleus accumbens shell and core by means of microdialysis with vertically implanted concentric probes. Doses selected were in the range of those known to sustain drug self-administration in rats. Morphine, at 0.2 and 0.4 mg/kg, and cocaine, at 0.5 mg/kg, increased extracellular dopamine selectivity in the shell. Higher doses of cocaine (1.0 mg/kg) and the lowest dose of amphetamine tested (0.125 mg/kg) increased extracellular dopamine both in the shell and in the core, but the effect was significantly more pronounced in the shell compared with the core. Only the highest dose of amphetamine (0.250 mg/kg) increased extracellular dopamine in the shell and in the core to a similar extent. The present results provide in vivo neurochemical evidence for a functional compartmentation within the nucleus accumbens and for a preferential effect of psychostimulants and morphine in the shell of the nucleus accumbens at doses known to sustain intravenous drug self-administration.

Narcotics affect adenylate cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] in two opposing ways, both mediated by the opiate receptor. The first process is the readily reversible inhibition of the enzyme by narcotics; the second is a compensatory increase in enzyme activity which is delayed in onset and relatively stable. Late positive regulation of the enzyme counteracts the inhibitory influence of morphine and is responsible for narcotic dependence and tolerance. The coupled inhibitory and positive regulatory mechanisms for adenylate cyclase provide a means of activating and deactivating neural circuits hours after the initial event and thus may play a role in a memory process.

The social interaction test in rats provides a method for detecting anxiolytic activity that does not use food or water deprivation, or electric shock, and therefore obviates difficulties of interpretation that might arise from drug-induced changes in motivation. Since social interaction is measured under more than one test condition any overall increase or decrease in social behaviour can be detected independently from the drug x test condition interaction that characterizes an anxiolytic drug. The Geller-Seifter conflict test was designed with two schedules of reinforcement for the same reasons. Any candidate test for anxiolytic action that examines drug effects under only one experimental condition is open to misinterpretation and may also prove unreliable if the critical experimental factors ( e.g. the level of food deprivation or the shock intensity) are changed. The testing procedure in the social interaction test is relatively time consuming in terms of observer-hours, but no lengthy pretraining of the animals is required. There is no way of fully automating the scoring and therefore it is important that the observers do not know the experimental group of the rats that they are scoring, and that tape recordings are made so that the scores can be checked. It has not so far been fruitful to analyze drug effects on every individual social behaviour, but this method does allow changes in individual behaviours to be detected. By entering the data directly into a computer we are now able to store the frequency and duration of each behaviour as well as the sequence of behaviours. It will then be possible to determine whether a detailed analysis of drug effects on the patterning of social behaviours will prove a useful addition to the social interaction test

We studied the effect of opiates acting preferentially on mu receptors, like morphine, methadone and fentanyl (mu agonists) and on kappa receptors, like U50,488, bremazocine and tifluadom (kappa agonists) on the release of dopamine (DA) and of its metabolites, dihydroxyphenylacetic acid and homovanillic acid, from the nucleus accumbens and from the dorsal caudate of freely moving rats using brain dialysis coupled to high-performance liquid chromatography with electrochemical detection. Spontaneous behavior was videotaped and analyzed by estimating the percentage of time spent by the animals in performing certain specific behavioral items. Mu agonists stimulated DA-release and metabolism in the accumbens at lower doses than in the caudate. Maximal stimulation of DA release did not exceed 100% except after high doses of methadone (10 mg/kg) which stimulated DA release in the accumbens by more than 300%, possibly as a result of hypoxia. Stimulation of DA release was associated to stimulation of behavior at low doses and to a biphasic inhibitory-stimulatory syndrome after higher doses of the opiates. Pretreatment with low doses of naloxone (0.1 mg/kg s.c.) or with the irreversible mu antagonist beta-funaltrexamine (10 nmol i.c.v.) increased the ED50 for the stimulation of DA release by the three opiates. In contrast with mu agonists, agonists of kappa receptors like U50,488, bremazocine and tifluadom decreased DA release in the accumbens and in the caudate and reduced motor activity. These effects were antagonized only by rather high doses of naloxone (2.5 mg/kg s.c.) and were not affected by pretreatment with beta-funaltrexamine (10 nmol i.c.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Previous experiments have shown that noxious stimulation increases expression of the c-fos proto-oncogene in subpopulations of spinal cord neurons. c-fos expression was assessed by immunostaining for Fos, the nuclear phosphoprotein product of the c-fos gene. In this study, we examined the effect of systemic morphine on Fos-like immunoreactivity (FLI) evoked in the formalin test, a widely used model of persistent pain. Awake rats received a subcutaneous 150 microliters injection of 5% formalin into the plantar aspect of the right hindpaw. The pattern of nuclear FLI was consistent with the known nociceptive primary afferent input from the hindpaw. Dense labeling was recorded in the superficial dorsal horn (laminae I and IIo) and in the neck of the dorsal horn (laminae V and VI), areas that contain large populations of nociceptive neurons. Sparse labeling was noted in lamina IIi and in the nucleus proprius (laminae III and IV), generally considered to be nonnociceptive areas of the cord. Fos immunoreactivity was also evoked in the ventromedial gray, including laminae VII, VIII, and X. There was no labeling in lamina IX of the ventral horn. Since FLI was time dependent and distributed over several spinal segments, we focused our analysis where maximal staining was found (L3-L5) and at the earliest time point of the peak Fos immunoreactivity (2 hr). Twenty minutes prior to the formalin injection, the rats received morphine (1.0, 2.5, 5.0, or 10 mg/kg, s.c.) or saline vehicle. Two hours later, the rats were killed, their spinal cords removed, and 50 microns transverse sections of the lumbar enlargement were immunostained with a rabbit polyclonal antiserum directed against Fos. Prior treatment with morphine sulfate profoundly suppressed formalin-evoked FLI in a dose-dependent and naloxone-reversible manner. The dose-response relationship of morphine-induced suppression of FLI varied in different laminae. To quantify the effect of morphine on FLI, labeled neurons in sections taken from the L4/5 level of each rat were plotted with a camera lucida and counted. Staining in the neck of the dorsal horn (laminae V and VI) and in more ventral laminae VII, VIII, and X, was profoundly suppressed by doses of morphine which also suppress formalin-evoked behavior. Although the labeling was also significantly reduced in laminae I and II, at the highest doses of morphine there was substantial residual labeling in the superficial dorsal horn. These data indicate that analgesia from systemic opiates involves differential regulation of nociceptive processing in subpopulations of spinal nociceptive neurons.

The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system. Substance P is synthesized by small-diameter sensory 'pain' fibres, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation promotes central hyperexcitability and increased sensitivity to pain. However, despite the availability of specific NK-1 antagonists, the function of substance P in the perception of pain remains unclear. Here we investigate the effect of disrupting the gene encoding the NK-1 receptor in mice. We found that the mutant mice were healthy and fertile, but the characteristic amplification ('wind up') and intensity coding of nociceptive reflexes was absent. Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress.