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RATIONALE: Triazole 1.1 is a novel kappa-opioid receptor (KOR) agonist reported to produce antinociception without KOR-typical adverse effects. When combined with the mu-opioid receptor (MOR) agonist, oxycodone, triazole 1.1 blocks oxycodone-induced pruritis without producing sedation-like effects in nonhuman primates. However, it is unknown if triazole 1.1 can reduce the abuse-related effects or enhance the antinociceptive effects of oxycodone similarly to other KOR agonists. OBJECTIVES: The aim of the present study was to quantitatively compare the behavioral effects of triazole 1.1 to the KOR agonists, U50,488h and nalfurafine, on oxycodone self-administration and oxycodone-induced thermal antinociception when administered as mixtures with oxycodone. METHODS: In the self-administration study, male Sprague-Dawley (SD) rats (n=6) self-administered intravenous (i.v.) oxycodone alone (0.056 mg/kg/inj) or combined with U50,488h (0.032–0.32 mg/kg/inj), nalfurafine (0.00032–0.0032 mg/kg/inj), or triazole 1.1 (0.32–1.8 mg/kg/inj) under a progressive-ratio schedule of reinforcement. In a hot plate assay, male SD rats (n=6) received i.v. injections of oxycodone (1.0–5.6 mg/kg), U50,488h (1.0–18.0 mg/kg), nalfurafine (0.01–1.0 mg/kg), or triazole 1.1 (3.2–32.0 mg/kg) alone or in combinations of fixed proportion with oxycodone based on the relative potencies of the single drugs. Each study concluded with administration of the KOR antagonist nor-BNI and some degree of retesting of the previous conditions to verify that the behavioral effects were mediated by KOR activation. RESULTS: All KOR agonists reduced oxycodone self-administration in a dose-dependent manner. Moreover, all single drugs and drug combinations produced dose-dependent, fully efficacious thermal antinociception. All KOR agonist:oxycodone combinations produced either additive or super-additive thermal antinociception. Finally, each KOR agonist was blocked in effect by nor-BNI in both behavioral measures. CONCLUSION: This study demonstrates that triazole 1.1 reduces oxycodone’s reinforcing effects and enhances oxycodone-induced antinociception to degrees that are comparable to typical KOR agonists. Given triazole 1.1’s mild adverse-effect profile, developing MOR-KOR agonist combinations from the triazole 1.1 series may render new pain therapeutics with reduced abuse liability.

Objective: This research examined whether a cannabidiol (CBD)-opioid pharmacotherapy could attenuate cisplatin-induced tactile allodynia. Methods: Mice (C57BL/6) were given 6 doses of 2.3 mg/kg cisplatin intraperitoneally (IP) on alternating days to induce tactile allodynia as quantified using an electric von Frey (eVF). Test groups in Experiment 1 received either vehicle, 0.1 or 2.5 mg/kg morphine, 1.0 or 2.0 CBD, or the 2 drugs in combination. Test groups in Experiment 2 received either vehicle, 0.1 or 2.5 mg/kg morphine, 1.0, 2.0, 3.0, or 4.0 mg/kg NB2111 (a long-acting CBD analogue), or the 2 drugs in combination. Drugs were administered IP 45 min before eVF assessment. Results: Cisplatin produced tactile allodynia that was attenuated by 2.5 mg/kg morphine. Both CBD and NB2111 produced dose-dependent attenuation of tactile allodynia. CBD and NB2111, given in combination with sub-analgesic doses of morphine, produced attenuation of tactile allodynia equivalent to 2.5 mg/kg morphine. Conclusions: While both CBD and NB2111, either alone or in combination with sub-analgesic doses of opioids, exhibited analgesic effects, NB2111 could be capable of superior analgesia over time by virtue of enhanced pharmacokinetics.

This study sought to determine whether the cannabis constituent cannabidiol attenuates the development of morphine reward in the conditioned place preference paradigm. Separate groups of mice received either saline or morphine in combination with one of four doses of cannabidiol using three sets of drug/no-drug conditioning trials. After drug-place conditioning, morphine mice displayed robust place preference that was attenuated by 10 mg/kg cannabidiol. Further, when administered alone, this dose of cannabidiol was void of rewarding and aversive properties. The finding that cannabidiol blocks opioid reward suggests that this compound may be useful in addiction treatment settings.

Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats. To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 μg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 μg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared. Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression. These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone.

Introduction: Cannabis sativa has been used for centuries in treating pain. However, the analgesic role of many of its constituents including terpenes is unknown. This research examined the contributions of terpenes (volatile oil) and cannabinoids in cannabis-mediated analgesia in rats. Methods: Animals received intraperitoneal administration of either vehicle, 10.0 or 18.0 mg/kg morphine, or various doses of the extract without terpenes, isolated terpenes, Δ(9)-tetrahydrocannabinol (THC), or the full extract. Thirty minutes later animals were tested on hotplate and tail-flick tests of thermal nociception. One week later, rats received a second administration of test articles and were tested 30 min later in the abdominal writhing test of inflammatory nociception. Results: In the thermal assays, hotplate and tail-flick latencies for morphine-treated rats were dose dependent and significantly higher than vehicle-treated animals. All the cannabinoid compounds except for the isolated terpenes produced dose-dependent increases in hotplate and tail-flick latencies. In the inflammatory nociceptive assay, animals treated with vehicle and isolated terpenes demonstrated increased abdominal writhing, whereas all the cannabinoid compounds significantly decreased abdominal writhing responses. Conclusions: Overall, THC alone produced robust analgesia equivalent to the full cannabis extract, whereas terpenes alone did not produce analgesia. These data suggest the analgesic activity of cannabis is largely mediated by THC, whereas terpenes alone do not cause alterations in cannabis-mediated analgesia.

This study sought to compare the effects of Mitragyna speciosa (Korth.) Havil. extract, alkaloids fraction, and mitragynine, a μ-opioid receptor agonist, to that of morphine and oxycodone in a test of thermal nociception. In Experiment 1, male Sprague-Dawley rats were administered test articles intraperitoneally (IP) 30 min prior to testing to compare the effects of M. speciosa articles to opioid reference compounds on the hotplate assay. Test articles were vehicle, 10 mg/kg morphine, 3 mg/kg oxycodone, 300 mg/kg M. speciosa extract, 75 mg/kg M. speciosa alkaloids fraction, or 30 mg/kg mitragynine. To mirror consumer usage, Experiment 2 sought to determine whether M. speciosa articles retained their biological activity when given orally (PO). Test articles were vehicle, 6 mg/kg oxycodone, 300 mg/kg M. speciosa extract, or 100mg/kg mitragynine with hotplate tests conducted 30 and 60 min after administration. Mitragynine produced antinociceptive effects similar to the reference opioid agonists when administered IP and PO routes. These data suggest that M. speciosa extracts containing significant quantities of mitragynine may warrant consideration for further studies in primate self-administration models to yield insight into the abuse liability of this commercially available product.

Ethnopharmacological relevance Consumer use of botanicals has increased despite, in many instances, the paucity of research demonstrating efficacy or identifying liabilities. This research employed the place preference/aversion paradigm to characterize the psychoactive properties of Salvia divinorum extract (10, 30, 100 mg/kg), salvinorin A (0.1, 0.3, 1.0 mg/kg), Mitragyna speciosa MeOH extract (50, 100, 300 mg/kg), Mitragyna speciosa alkaloid-enriched fraction (12.5, 25, 75 mg/kg) and mitragynine (5, 10, 30 mg/kg) in rats. Material and methods Following apparatus habituation and baseline preference scores, male Sprague-Dawley rats were given eight counter-balanced drug versus vehicle conditioning trials followed by a preference test conducted under drug-free states. S ( + )-amphetamine (1 mg/kg) served as the positive control (in Exp. 2) and haloperidol (0.8, 1.0 mg/kg) served as the negative control in both studies. Results Rats displayed place aversion to both Salvia divinorum and salvinorin A that exceeded that of haloperidol. Rats showed place preference to mitragynine that was similar to that of S ( + ) - amphetamine. This CPP effect was much less pronounced with the Mitragyna speciosa extract and its fraction. Conclusions These findings suggest that both botanicals possess liabilities, albeit somewhat different, that warrant caution in their use.

Ethnopharmacological relevance Sceletium tortuosum (L.) N.E. Br. has been reported to elevate mood, reduce anxiety and stress and alleviate pain. Aim of study This study sought to examine the effects of an S. tortuosum alkaloid enriched fraction in the chick anxiety-depression model, a model that shows high predictive validity as a pharmacological screening assay. Material and methods Socially-raised male Silver Laced Wyandotte chicks (4–6 days old) were given IP vehicle, imipramine (10 mg/kg), or S. tortuosum fraction (10, 20, 30 mg/kg in Exp. 1 or 50, 75, 100 mg/kg in Exp. 2) 15 min prior to a 60 min isolation test period in which distress vocalizations (DVoc) were continuously recorded. Results Vehicle chicks displayed high DVoc rates in the anxiety phase (first 3 min). DVoc rates declined about 50% (i.e., behavioral despair) in the depression phase (30–60 min). S. tortuosum fraction at 75 and 100 mg/kg decreased DVoc rates during the anxiety phase indicative of an anxiolytic effect. Imipramine, but not S. tortuosum groups, increased DVoc rates in the depression phase indicative of an antidepressant effect. Conclusions The findings suggest that an alkaloid enriched S. tortuosum fraction may benefit some forms of stress-related disorders.

Background This research sought to further validate the rat nitroglycerin (NTG) migraine model by comparing the effects of single versus recurrent NTG episodes on behavioral endpoints that mirror ICHD-3 diagnostic criteria for migraine, and to determine if the altered behavioral endpoints are reduced after administration of sumatriptan. Methods Separate cohorts of rats were administered NTG (10 mg/kg/2 ml) or saline (Experiment 1: single injection; Experiment 2: repeated injections; Experiment 3: repeated injections with sumatriptan [0.0, 0.3 and 1.0 mg/kg/ml] rescue. Behavioral endpoints were assessed 2 h after final NTG administration and included time in light/dark chambers for photophobia and activity, pain facial ratings, and cool (5 °C) and warm (46 °C) tail dip. Results The first two experiments demonstrated that repeated (n = 5) but not single NTG injections produced photophobia, decreased activity, and yielded less weight gain than saline injections. Experiment 3 showed that sumatriptan attenuated hypoactivity, reduced facial expressions of pain, and reversed weight alterations in a dose-dependent manner. Conclusions These findings identify numerous clinical homologies of a recurrent NTG rat migraine model that may be useful for screening novel pharmacotherapies.

Ethnopharmacological relevance Broad historical and current uses in addition to diverse activity on CNS targets may make Sceletium tortuosum a useful therapeutic in a variety of clinical settings. This study sought to more broadly characterize activity of Sceletium tortuosum and mesembrine in a number of common, rodent-based assays that model nociception, depression, anxiety, ataxia, and abuse liability. Materials and methods Male Sprague-Dawley were administered Sceletium tortuosum extract products and behavioral responses were evaluated in the conditioned place preference (CPP), hot plate, forced swim, elevated plus, and rotarod tests. Results and conclusions Sceletium tortuosum does not cause preference or aversion in CPP. Mesembrine appears to have analgesic properties without abuse liabilities or ataxia. The Sceletium tortuosum fraction has antidepressant properties but does produce ataxia. The ataxia may limit its usefulness as an antidepressant unless the antidepressant activity is associated with one constituent and the ataxia is associated with a separate constituent.

Most pre-clinical analgesic efficacy assays still involve nociceptive testing in rodents. This is despite concerns as to the relevance of these tests for evaluating the pain-preventative properties of drugs. More appropriate methods would target pain rather than nociception, but these are currently not available, so it remains unknown whether animal pain equates to the negatively affective and subjective/emotional state it causes in humans. Mouse cancer models are common despite the likelihood of substantial pain. We used Conditioned Place Preference (CPP) testing, assessments of thermal hyperalgesia and behaviour to determine the likelihood that MBT-2 bladder cancer impacts negatively on mouse welfare, such as by causing pain. There was no CPP to saline, but morphine preference in tumour bearing mice exceeded that seen in tumour-free controls. This occurred up to 10 days before the study end-point alongside reduced body weight, development of hyperalgesia and behaviour changes. These effects indicated mice experienced a negative welfare state caused by malaise (if not pain) before euthanasia. Due to the complexity of the assessments needed to demonstrate this, it is unlikely that this approach could be used for routine welfare assessment on a study-by-study basis. However, our results show mice in sufficiently similar studies are likely to benefit from more intensive severity assessment and re-evaluation of end-points with a view to implementing appropriate refinements. In this particular case, a refinement would have been to have euthanased mice at least 7 days earlier or possibly by provision of end-stage pain relief. CPP testing was found to be a helpful method to investigate the responses of mice to analgesics, possibly on a subjective level. These findings and those of other recent studies show it could be a valuable method of screening candidate analgesics for efficacy against cancer pain and possibly other pain or disease models.

The use of ?9-THC hemisuccinate (HS) in a suppository formulation is an attempt to develop a cannabinoid possessing possible therapeutic effects with a minimal side effect profile. The purpose of this study was to investigate the antinociceptive and reinforcing effects of rectally administered ?9-THC-HS in rats. Tests were conducted in two groups of animals: Complete Freund's adjuvant-inflamed animals (CFA) and non-inflamed controls. A hotplate test was administered to index hyperalgesia and possible analgesic effects of ?9-THC-HS on thermal nociception. CFA animals demonstrated shorter latencies than non-inflamed animals. The highest dose of ?9-THC-HS produced longer hotplate latencies. Additionally, the reinforcing properties of ?9-THC-HS were evaluated using the Conditioned Place Preference (CPP) paradigm. ?9-THC-HS produced an increase in preference scores in non-inflamed animals (positive reinforcement), but did not affect preference scores in CFA animals. These data suggest that ?9-THC-HS h...

Rationale: The recent growth in sales of natural products labeled as dietary supplements in the United States has renewed scientific interest in the study of the therapeutic effects of multi-component botanical products. Objectives: This study sought to determine whether botanical extracts derived from the Rutaceae family, Acori graminei, the Magnoliaceae family, Alchemilla vulgaris and Primula veris, which had previously been identified in bioassays as having potential anxiolytic activity, were active in the chick social separation-stress procedure. Methods: Eight-day-old chicks received IP injections of test articles 30 min before being tested in the presence of two social companions or in isolation for a 3-min observation period. Dependent measures were: a) latency to adopt a ventral recumbent posture to index sedation, b) number of vocalizations to index separation-distress and c) a composite pain score (comprised of footlift frequency and footlift duration in response to 50 µl of 0.10% formalin injected into the plantar surface of the foot) to index stress-induced analgesia. Results: Proprietal extracts NPS00033 from the Rutaceae plant family and NPS00039 (Relora™) from the Magnoliaceae plant family screened positive in this chick model without causing sedation. Conclusions: These results suggest that botanical extracts Relora™ and NPS00033 may be useful in modulating anxiety states.

The formalin test is a well-established model for assessing nociceptive processes and analgesic drug effects. Previous studies have provided statistical validation of optimal procedures for conducting and scoring the rat formalin test. In the mouse model, formalin concentration has been subjected to validation studies. The present research extended previous work by subjecting two additional parameters - the behaviors that should be scored and the optimal interval for second-phase formalin response - to empirical validation. Five behavioral (formalin-induced favoring, lifting, and biting/licking, rearing and locomotion) and two physiological measures (paw weight and paw thickness increases reflective of formalin-induced inflammation) were examined under four formalin concentrations (Exp. 1: 0.5, 1.0, 5.0, and 10.0%/25µl formalin) or under four morphine doses (Exp. 2: 0.0, 1.0, 5.0, and 10.0 mg/kg, s.c. with 5% formalin concentration). Multiple regression analyses defined the optimal second-phase formalin response in outbred, Swiss-Webster mice as 15-35 min post formalin injection, and revealed that the second-phase response is best characterized by the cumulative time spent biting/licking the injected paw. Finally, paw physiological measures provided convergent evidence of nociceptive and antinociceptive processes in the mouse formalin test. Copyright 1998European Federation of Chapters of the International Association for the Study of Pain.

1. Cocaine and anabolic-androgenic steroids are among the more commonly abused substances in selected populations. These agents, when used alone or in combination, have been reported to cause aggressive tendencies in both laboratory-based animal models and in human clinical situations. This project, using a resident-intruder paradigm, examined the effects of co-administration of cocaine and a typical anabolic-androgenic steroid, nandrolone decanoate, on the development of aggression in male Sprague-Dawley rats. 2. Dose response studies demonstrated that low dose cocaine (1 mg/kg) produced more aggression in a greater percentage of animals than for either the controls or groups receiving higher doses (up to 20 mg/kg). Initially, high intermittent doses of nandrolone (20 mg twice weekly) produced more aggression; however, low daily doses of nandrolone (2 mg) produced greater levels of aggression following 4 weeks of treatment. 3. Optimal doses of cocaine and nandrolone, when administered together, resulted in aggression scores that were not significantly different from controls or either drug singly. However, a greater percentage of animals receiving both drugs exhibited aggression than did rats receiving either drug alone. 4. These results support the interpretation that the drugs interact to produce unique effects in the development of aggression. However, the complexity and extent of the interactions is great and remains to be fully elucidated.

Research has documented the differential role of bradykinin (BK) B1 and B2 receptors in the mediation of inflammatory nociception and this research suggests that selective B1 antagonists may have therapeutic potential against chronic inflammatory pain. The present study sought to further define the stimulus properties (reinforcing and aversive effects) of the selective B1 antagonist des-Arg9,(Leu8)-BK (0.0, 0.03, 0.1, and 0.3 mg/kg) and the selective B2 antagonist HOE 140 (0.0, 0.1, 0.5, and 1.0 mumol/kg) in the Freund's adjuvant (100 microliters, i.p.) model of chronic inflammatory nociception using the place preference paradigm. In addition, this research examined the differential antinociceptive effects of these antagonists on the formalin test (2.5%). Des-Arg9,(Leu8)-BK exhibited antinociceptive effects against both the first and second phases of the formalin response; HOE 140 tended to increase nociceptive responding on both phases of the formalin response. In the place preference paradigm, des-Arg9,(Leu8)-BK, but not HOE 140, exhibited negatively reinforcing effects (i.e. analgesia) in adjuvant-inflamed animals and aversive effects in noninflamed control animals. Neither compound exhibited positively reinforcing effects (i.e. abuse potential). These results further define the stimulus properties of these selective BK antagonists and provide additional evidence to support the notion that B1 antagonists may possess therapeutic potential for conditions of chronic inflammatory pain.

The discovery of novel therapeutics for the treatment of chronic pain depends largely upon the development of clinically-relevant animal models and quantitative methods for evaluation of drug efficacy. This paper describes our use of the place preference paradigm and the operant response paradigm to provide unique and clinically-relevant measures of analgesic drug effects against chronic inflammatory pain in rats. The data presented demonstrate that the place preference paradigm can assess the affective properties of analgesic drugs under conditions of chronic pain, and that the operant response paradigm can quantify both the functional motor deficits that accompany chronic inflammatory pain and the recovery of function afforded by analgesic drugs. These data suggest that both place preference and operant response paradigms may serve as useful assays for evaluating unique and clinically-relevant aspects of analgesic drug effects in animal models of chronic inflammatory pain.

The present study examined the effects of systematically administered calcitonin (CT, 10 IU/0.25 ml, SC) on changes in CNS monoamines (MAs) following unilateral carrageenan (CARRA)-induced inflammation in the rat hindpaw. High-performance liquid chromatography with electrochemical detection (HPLC-EC) for MAs was performed on the whole brain and rostral spinal cord. Carrageenan-evoked inflammation significantly increased brain serotonin [5-hydroxytryptamine (5-HT)], norepinephrine (NE), and dopamine (DA) levels. CT significantly reduced these CARRA-induced elevations in brain MAs. Elevated spinal cord 5-HT and NE levels were observed in CARRA-treated animals. CT administration increased 5-HT and NE in both the CARRA-treated animals and their saline controls. Spinal cord DA levels were not affected by either CARRA or CT administration. These findings suggest the involvement of CNS monoaminergic substrates in CT-induced hypoalgesia in inflammatory nociception.

In light of evidence suggesting the proinflammatory and nociceptive action of peripheral serotonin (5-HT), the present study examined dose-dependent parameters of edema and algesia produced by intraplantar injections of 5-HT and the role of heterogeneous 5-HT receptors in these 5-HT-induced responses. Intraplantar 5-HT (0.05, 0.25, 0.5, or 1.0 mumols) produced paw edema at each 5-HT concentration and produced concentration-dependent increases in the nociceptive response as indexed by lifts of, and licks to the affected paw. Intraplantar pretreatment with the 5-HT1 receptor antagonist methysergide at concentrations greater than or equal to 3 nmol attenuated the 5-HT-induced (25 mumols) inflammatory and nociceptive responses. At concentrations greater than or equal to 300 nmol, both 5-HT2 receptor antagonist ketanserin and 5-HT3 receptor antagonist odansetron pretreatment blocked 5-HT-induced inflammatory and nociceptive responses. These results more completely define peripheral 5-HT-receptor-dependent systems of 5-HT-induced inflammation and nociception in rats.

The chick anxiety-depression model is a hybrid simulation, which may prove useful as an early preclinical dual pharmacological screen for novel therapeutics. Separate dose-response studies were conducted with seven test compounds that have screened positive for antidepressant effects in rodent depression models and included prasterone (5.0-40.0 mg/kg), memantine (2.5-20.0 mg/kg), ketamine (1.0-10.0 mg/kg), mifepristone (50.0-400.0 mg/kg), DOV216,303 (5.0-20.0 mg/kg), CGP36742 (2.5-15.0 mg/kg), and antalarmin (1.0-30.0 mg/kg). Chicks aged 4-6 days posthatch received test compounds intramuscularly 15 min before social separation, in which distress vocalization rates were recorded. High rates of vocalization in the first phase (0-5 min) of social separation seem to model an anxiety-like state and lower rates of vocalization in the second phase (30-60 min) seem to model a depression-like state. Prasterone, memantine, ketamine, and DOV216,303 attenuated and CPG36742 enhanced the pattern of vocalizations in the first phase. Prasterone, ketamine, mifepristone, DOV216,303, and CPG36742 attenuated and memantine and antalarmin enhanced the pattern of vocalizations in the second phase. This pattern of drug effects parallels what clinical data exist, and highlights two important characteristics of this dual-screening assay. For the compounds tested, this chick model identified phase II and III clinical failures (e.g. memantine and antalarmin) and has the potential to reveal possible contraindications of compounds (i.e. CPG36742) in cases where anxiety symptoms are concomitant with a depressive episode.

Piper methysticum extract (Kava kava) possesses anxiolytic properties. However, it is unknown whether these effects are best predicted by total kavalactone content or by one or more of its primary kavalactone constituents. Using the chick social separation-stress procedure as an anxiolytic bioassay, P. methysticum samples containing 12.8-100.0% total kavalactones (Exp. 1) and fractions containing 1-6 kavalactones of varying concentrations (0.1-67.5%; Exps. 2-3) were screened for activity and compared against a 5.0 mg/kg dose of chlordiazepoxide (CDP; Exp. 3). Eight-day-old chicks received IP injections of either vehicle or test compounds 30 min before being placed in the presence of two conspecifics or in isolation for a 3 min observation period. Dependent measures were ventral recumbency latency (sedation), distress vocalizations, and a measure of stress-induced analgesia (in Exps. 1 and 2 only). P. methysticum extract samples attenuated distress vocalizations in a concentration-dependent manner. The P. methysticum fraction that contained the highest concentration of dihydrokavain attenuated distress vocalizations in a manner equivalent to that of CDP. The extract samples and fractions that possessed anxiolytic properties did not possess the sedative properties found in CDP. Collectively, these findings suggest that dihydrokavain may be necessary and sufficient in mediating the anxiolytic properties of P. methysticum extract.

The present study examined analgesia produced by S and R isomers of the novel 5-HT 3 receptor antagonists, ADR-851 and ADR-882 (0.1–10 mg/kg s.c.) against acute thermal, mechanical and formalin-induced inflammatory pain in rats. Neither isomer of ADR-851 or ADR-882 was analgesic in the thermal or mechanical test. Similarly, neither S or R forms of ADR-882 produced significant anti-nociception in the formalin test. In contrast, ADR-851R produced significant analgesia at 3 and 10 mg/kg doses in this test, while ADR-851S produced significant analgesia only at 1 mg/kg.

Recent research in this laboratory has identified a biological model in which morphine produced a hyperalgesic response to a noxious thermal stimulus. Morphine effects, however, were examined at only one injection-to-test interval (10 min). Because a single injection-to-test interval is relatively uninformative, the present research was designed to more fully characterize this morphine hyperalgesic effect. In Experiment 1, 15-day-old White Leghorn cockerels were placed on a hot plate (59°C) in 10 min after injection of morphine (1.25, 2.5, 5.0, 10.0 mg/ml/kg) or the distilled water vehicle (1 ml/kg). Latency to perform a jump response or attainment of a 90-sec no-jump criterion were recorded. Experiment 2 examined morphine effects (2.5 mg/ml/kg) on hot plate jump latencies at various injection-to-test intervals (10, 30, 60, and 240 min). Morphine produced a dose-dependent hyperalgesic response. Temporal characteristics of morphine effects were evident as a U-shaped function. The dose and temporal characteristics of morphine-induced hyperalgesia in White Leghorn cockerels are similar to the dose and temporal characteristics of morphine-induced analgesia typically seen in other species.

Preliminary research demonstrated that formalin injected into the foot of leghorn cockerels elicited significantly more footlifts of longer duration than physiological saline. The formalin test was subsequently used to examine morphine effects in this species. Previous research demostrated strain-dependent naloxone-reversible morphine hyperalgesia against thermal nociception in cockerels. In Experiment 1 herein White Leghorn cockerels were given either 0.0, 0.5, 1.5, or 2.5% formalin SC into the foot 30 min after an IM injection of either physiological saline or 2.5 mg/kg morphine sulfate. The frequency and duration of formalin-elicited footlifts increased significantly as a function of formalin concentration. Morphine significantly increased footlift frequency and duration at all but the 0.0% formalin concentration. Morphine inhibited respiration in these animals. In Experiment 2, naloxone (5.0 mg/kg) significantly reversed both the hyperalgesia and the respiratory depression induced by morphine. These results demonstrate that morphine hyperlagesia in leghorn cockerels is neither unique to hot plate test procedures nor peculiar to thermal nociception. Atypical morphine effects in this model may specific to nociception, however, because hyperalgesia was not accompanied by atypical morphine effects on respiration.