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Analgesia.

Critical to reducing patient morbidity as well as heightened ethical awareness, alleviation of pain in animals has become integral to medical case management and surgical procedures. Pharmacotherapy is directed at peripheral nociceptors, primary and secondary spinal neurons, and pain-processing areas in the CNS. Accordingly, three primary pharmacologic strategies have evolved: drugs that bind to and activate opioid receptors, drugs that bind to and activate alpha 2 receptors, and drugs that reduce de novo prostaglandin synthesis. In horses, the two predominant types of pain encountered are musculoskeletal and visceral pain. Several factors must be considered when devising a therapeutic strategy, including the etiology of the painful event, desired duration of therapy (acute vs chronic), desire for sedation, and potential side effects and toxicity. Opioids and alpha 2 agonists are particularly effective for visceral pain associated with colic. Butorphanol remains the only commercially available opioid and provides superior visceral analgesia compared with pentazocine or flunixin meglumine but not compared with the alpha 2 agonists. The behavioral changes such the sedative effects of alpha 2 agonists and the increased locomotion and CNS excitability seen with some opioids are important considerations when these agents are used as analgesics. NSAIDs may be considered for visceral pain therapy also, especially pain associated with an inflammatory component or endotoxemia. In particular, flunixin meglumine and ketoprofen provide prolonged analgesia and suppress the effects of endotoxin. Long-term therapy of musculoskeletal diseases usually necessitates chronic NSAID use. Although many NSAIDs are now available in approved equine formulations, there remain some important differences among NSAIDs for the practitioner to consider when choosing an analgesic. NSAIDs differ in their ability to ameliorate pyrexia, affect platelet function, alleviate pain, and reduce inflammation. For ease of administration, those available for oral use include phenylbutazone, meclofenamic acid, flunixin meglumine, and naproxen. All are potentially ulcerogenic, and poor tolerance to one may necessitate switching to another with a better toleration profile or to drug from a different analgesic class.

Adrenergic alpha-Agonists↗

Comparison of peptidic and nonpeptidic delta-opioid agonists on guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding in brain slices from Sprague-Dawley rats.

Previous studies have demonstrated that peptidic and nonpeptidic delta-opioid receptor agonists have different effects depending on the measure. For example, nonpeptidic delta-opioid agonists, but not peptidic agonists, produce convulsions in rats, and in vitro studies suggested that peptidic and nonpeptidic delta-opioid agonists might have differential mechanisms of receptor downregulation. The present study evaluated potential differences between peptidic and nonpeptidic delta-opioid agonists in their ability to activate G proteins using guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) autoradiography experiments in rat brain slices. The peptidic agonist [d-Pen(2),d-Pen(5)]-enkephalin and the nonpeptidic agonist (+)BW373U86 [(+)-4-[alpha(R)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide] demonstrated concentration-dependent increases in [(35)S]GTPgammaS binding that were attenuated by the delta-opioid antagonist naltrindole. (+)BW373U86 was more potent and efficacious than the peptidic agonist, and this difference remained consistent across brain regions where significant stimulation was observed. In addition, multiple delta-opioid compounds were evaluated for their agonist activity in this assay. These data suggested that differences between peptidic and nonpeptidic delta-opioid agonists in behavioral studies were most likely caused by differences in agonist efficacy. Finally, these data also revealed that [(35)S]GTPgammaS autoradiography could be used to compare efficacy differences among agonists across various brain regions in rat brain slices.

Animals↗

Social organization in a group of free-ranging patas monkeys.

A free-ranging group of patas monkeys (Erythrocebus patas) was studied at the Caribbean Primate Research Center through parts of a complete seasonal cycle. Analysis of the data revealed that dispersal was the major strategy utilized by individuals in the performance of intragroup social behavior. Dominance phenomena were not found to be of major importance in the organization of intragroup social behavior despite the presence of a linear, stable dominance hierarchy among the adult females. The data further suggested that genealogical relationships were relatively insignificant in their effect on the patterning of intragroup behavior.

Agonistic Behavior↗

The behavioral effects of the calcium agonist Bay K 8644 in the mouse: antagonism by the calcium antagonist nifedipine.

Mice injected with the calcium agonist BAY K 8644 (2-4 mg/kg, i.p.) displayed profound behavioral changes including ataxia, decreased motor activity, Straub tail, arched back, limb clonus and tonus, and an increased sensitivity to auditory stimulation. BAY K 8644 significantly impaired rotorod performance in mice with an ED50 of 0.8 mg/kg. The behavioral effects of BAY K 8644 were antagonized by nifedipine, but not by the non-dihydropyridine calcium channel antagonist verapamil or the alpha-adrenoceptor antagonist prazosin. Further, the actions of BAY K 8644 were not mimicked by the alpha-adrenoceptor agonist methoxamine at doses up to 4.5 mg/kg. These observations, coupled with the findings that BAY K 8644 is a potent, competitive inhibitor of [3H]nitrendipine binding to the dihydropyridine binding site in mouse brain (Ki = 7.0 X 10(-9) M), suggests that BAY K 8644 may produce its behavioral actions via an interaction with the DHP binding site, which has been linked to the control of calcium flux across membranes in peripheral tissues.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

Selective breeding for diisopropyl fluorophosphate-sensitivity: behavioural effects of cholinergic agonists and antagonists.

The behavioral effects of cholinergic agonists and antagonists were examined in two lines of rats which have been developed through selective breeding techniques to be differentially sensitive to the anticholinesterase diisopropyl fluorophosphate (DFP). The line of rats which were determined to be more sensitive to DFP (Flinders S line) were also more sensitive to the depressant effects of the agonists pilocarpine and physostigmine on locomotor activity, water intake, and operant responding maintained by water reward. In contrast, the locomotor stimulant effects of scopolamine, a muscarinic antagonist, were less marked in the S-line rats, while the depressant effects of atropine and scopolamine on water intake and operant responding maintained by water reward were comparable in the two lines. The S-line rats were also significantly more sensitive to the hypothermic effects of pilocarpine and oxotremorine. These findings are consistent with the hypothesis that the S-line rats are more sensitive to the acute effects of DFP because they have a higher number of muscarinic-cholinergic receptors.

Animals↗

Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia.

OBJECTIVE: Although four meta-analytic reviews support the efficacy of pharmacotherapy and behavior therapy for the treatment of insomnia, no meta-analysis has evaluated whether these treatment modalities yield comparable outcomes during acute treatment. The authors conducted a quantitative review of the literature on the outcome of the two treatments to compare the short-term efficacy of pharmacotherapy and behavioral therapy in primary insomnia. METHOD: They identified studies from 1966 through 2000 using MEDLINE, psycINFO, and bibliographies. Investigations were limited to studies using prospective measures and within-subject designs to assess the efficacy of benzodiazepines or benzodiazepine receptor agonists or behavioral treatments for primary insomnia. Benzodiazepine receptor agonists included zolpidem, zopiclone, and zaleplon. Behavioral treatments included stimulus control and sleep restriction therapies. Twenty-one studies summarizing outcomes for 470 subjects met inclusion criteria. RESULTS: Weighted effect sizes for subjective measures of sleep latency, number of awakenings, wake time after sleep onset, total sleep time, and sleep quality before and after treatment were moderate to large. There were no differences in magnitude between pharmacological and behavioral treatments in any measures except latency to sleep onset. Behavior therapy resulted in a greater reduction in sleep latency than pharmacotherapy. CONCLUSIONS: Overall, behavior therapy and pharmacotherapy produce similar short-term treatment outcomes in primary insomnia.

Anti-Anxiety Agents↗

Blocking of enhanced sensitivity to behavioral effects of naloxone induced by narcotic agonists in rats.

The present experiment evaluated whether prior treatment with naloxone could block the sensitization to opiate antagonist induced by single dose administration of pure agonist (morphine) or mixed agonist (buprenorphine). Food deprived male Wistar rats were trained to respond for food on a multiple-trial, fixed-interval 3 min schedule. Reinforcement was contingent upon a response within a 10-s limited hold period following a fixed-interval of 3 min. A trial consisted of three fixed interval of 3 min separated by a 10 min timeout period during which responses were not reinforced. The rate decreasing effects of the opioid antagonist naloxone was determined by cumulative dosing. Pretreatment with morphine (0.3 mg/ kg, SC) and buprenorphine (0.03 mg/kg, SC) resulted in an increase sensitivity to the rate decreasing effect of naloxone compared to saline pretreatment. Administration of naloxone (0.3 mg/kg) 10 min prior to pretreatment doses of buprenorphine (0.03 mg/kg; 1.0 mg/kg) and morphine (0.3 mg/kg) increased sensitization to naloxone. However, greater sensitization was observed at low dose of buprenorphine. The increased sensitivity was partially blocked at high dose of buprenorphine (1.0 mg/ kg) by naloxone pretreatment. These results suggest that the doses of naloxone used to block opioid induced sensitization might be different from those required in animals with normal sensitivity to opioid antagonists. Further agonist-induced sensitization to behavioral effects of opioid antagonist appears to be opioid receptor specific.

Analgesics, Opioid↗

Behavioral effects of delta-opioid receptor agonists: potential antidepressants?

The development of selective delta-opioid receptor agonists has revealed some very intriguing behavioral properties. delta-Opioid agonists have antinociceptive, seizuregenic and convulsive properties. A number of studies have identified a novel behavioral effect of delta-opioid-receptor agonists, implicating a role for the delta-opioid receptor in depression. Early clinical experiments demonstrated that exogenously administered opioid peptides had antidepressant activity in human patients. Also, enkephalinase inhibitors, which prevent the degradation of endogenous enkephalins, produced antidepressant-like effects mediated through the delta-opioid receptor in animal models of depression. More recently, the selective non-peptidic delta-opioid agonists SNC80 and (+)BW373U86 demonstrated antidepressant-like activity in the forced swim assay in rats. These studies propose that the delta-opioid receptor may provide a new therapeutic target for treating human depression.

Animals↗

SCH 23390 and its S-enantiomer stereoselectively prevent EEG and behavioral activation induced by dopamine agonists in the rabbit.

The selective D-1 dopamine antagonist SCH 23390 (R-enantiomer) and its unselective S-enantiomer (SCH 23388) were compared for their ability to prevent EEG and behavioral activation induced by the dopamine receptor agonists SKF 38393, apomorphine and LY 171555 in the rabbit. SCH 23390, at very low doses (0.003 mg/kg IV), inhibited EEG responses elicited by SKF 38393 and apomorphine, while the S-enantiomer displayed similar effects at doses at least 300-fold higher (1-3 mg/kg IV). Both isomers were approximately equipotent in preventing behavioral excitation caused by the D-2 agonist LY 171555. The dose of SCH 23390 interacting with LY 171555 was at least 100-fold higher than that effective for D-1 mediated responses. Conversely, the doses of S-enantiomer which prevented the stimulating effects induced by the different dopamine agonists were similar. The data demonstrate the stereoselectivity of the R-isomer SCH 23390 for blockade of D-1 receptors in vivo and provide evidence for the sensitivity of the EEG models in studying D-1 mediated responses.

Animals↗

Effects of kappa receptor agonists on D1 and D2 dopamine agonist and antagonist-induced behaviors.

Striatal dynorphin-containing neurons receive dopaminergic inputs from the substantia nigra pars compacta and project primarily to the substantia nigra pars reticulata and entopeduncular nucleus. These neurons mainly express dopamine (DA) D1 receptors and thus dynorphin system stimulation might be expected largely to influence D1 receptor agonist or antagonist effects on motor function. It is well known the interaction existing between DA D1 and D2 drugs in the induction of behavioral effects. However, the effects of dynorphin on selective D1 and D2 DA agonist and antagonist-induced behaviors have not yet been investigated. Administration of the kappa agonists spiradoline (0.5, 1 and 5 mg/kg) or U50,488H (1, 10 and 25 mg/kg) decreased non-stereotyped grooming induced by the selective D1 agonist SKF38393. This effect was inhibited by the non-selective opioid receptor antagonist naloxone (20 mg/kg) and by the selective kappa antagonist nor-binaltorphimine (nor-BNI, 20 mg/kg). Stereotypies induced by the selective D2 agonist quinpirole were decreased by spiradoline (1 and 5 mg/kg) and by U50,488H (1, 10 and 25 mg/kg), while jerking movements of a type associated with increased D2 receptor and decreased D1 receptor stimulation emerged. Kappa agonist effects were inhibited by the prior administration of SKF38393 (10 mg/kg); these inhibitory effects were blocked by prior administration of the D1 antagonist SCH23390 (5 mg/kg). Naloxone reversed the effects of both kappa agonists on quinpirole-induced stereotypies. Kappa agonists increased D1 antagonist-induced catalepsy, but had no effect on D2 antagonist-induced catalepsy. Naloxone and nor-BNI inhibited this effect. These results suggest that the motoric effects of D1 receptor antagonists in part reflect stimulation of striatal dynorphin containing efferents.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗