Vocalization Test Research Articles

The anxiolytic-like profile of the nociceptin receptor agonist, endo-8-[bis(2-chlorophenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octane-3-carboxamide (SCH 655842): Comparison of efficacy and side effects across rodent species

The endogenous opioid-like peptide, nociceptin, produces anxiolytic-like effects that are mediated via the nociceptin (NOP) receptor. Similarly, synthetic, non-peptide NOP agonists produce robust anxiolytic-like effects although these effects are limited by marked side effects. In the present studies, the effects of a novel NOP receptor agonist, SCH 655842, were examined in rodent models sensitive to anxiolytic drugs and tests measuring potential adverse affects. Oral administration of SCH 655842 produced robust, anxiolytic-like effects in three species, i.e., rat, guinea pig, and mouse. Specifically, SCH 655842 was effective in rat conditioned lick suppression (3–10 mg/kg) and fear-potentiated startle (3–10 mg/kg) tests, a guinea pig pup vocalization test (1–3 mg/kg), as well as in mouse Geller–Seifter (30 mg/kg) and marble burying (30 mg/kg) tests. The anxiolytic-like effect of SCH 655842 in the conditioned lick suppression test was attenuated by the NOP antagonist, J-113397. In mice, SCH 655842 reduced locomotor activity and body temperature at doses similar to the anxiolytic-like dose and these effects were absent in NOP receptor knockout mice. In rats, SCH 655842 did not produce adverse behavioral effects up to doses of 70–100 mg/kg. Pharmacokinetic studies in the rat confirmed dose-related increases in plasma and brain levels of SCH 655842 across a wide oral dose range. Taken together, SCH 655842 may represent a NOP receptor agonist with improved tolerability compared to other members of this class although further studies are necessary to establish whether this extends to higher species.

SSR181507, a dopamine D2 receptor and 5-HT1A receptor ligand: Evidence for mixed anxiolytic- and antidepressant-like activities

SSR181507, a dopamine D2 receptor antagonist/partial agonist and 5-HT1A receptor agonist, is active in animal models of schizophrenia. Furthermore, it shows activity in several anxiety and/or depression models (Depoortere et al. 2003). Presently, we sought to further characterize the latter two activities in rats, using a step-down passive avoidance procedure, a shock-induced ultrasonic vocalization (UV) test in adult subjects and a social interaction test.SSR181507 (0.3 & 1mg/kg ip), but not the atypical antipsychotics clozapine and olanzapine, decreased the latency time to step-down from a “safety” platform. Effects of SSR181507 were reversed by the selective 5-HT1A receptor antagonist SL88.0338. SSR181507 also reduced UV (0.3 & 1mg/kg ip), an effect not reversed by SL88.0338, and observed with olanzapine, haloperidol, fluoxetine and the 5-HT1A receptor agonists 8-OH-DPAT and buspirone, but not diazepam. Furthermore, SSR181507 remained active following 3weeks of administration (1mg/kg ip, once daily) in the UV test. Lastly, SSR181507 (3mg/kg ip) potentiated social interaction, an effect shared by diazepam and buspirone, but not by olanzapine, clozapine, haloperidol and 8-OH-DPAT.These data further strengthen previous findings that the putative atypical antipsychotic SSR181507 has mixed antidepressant and anxiolytic activities.

A Single Nitrous Oxide (N2O) Exposure Leads to Persistent Alleviation of Neuropathic Pain in Rats

Using the rat chronic constriction injury (CCI) pain model, we evaluated whether nitrous oxide (N2O), a gas shown to have potent anti-hyperalgesic properties, may alleviate neuropathic pain. Mechanical nociceptive threshold was estimated using the paw pressure vocalization test. Thermal allodynia was challenged by measuring the struggle latency by immersion of the hind paw in a 10 degrees C water bath. A single 50% N2O exposure for 1 hour, 15 minutes not only induced potent anti-nociception during N2O exposure but also provoked a delayed and sustained reduction (37% to 46%) of pain hypersensitivity of the injured hind paw and abolished pain hypersensitivity of the contralateral uninjured hind paw for at least 1 month. Thermal allodynia was completely prevented by a single N2O exposure. A preadministration of naltrexone, which markedly reduced acute N2O-induced anti-nociception, did not affect the persistent reduction of hyperalgesia. The administration of naltrexone in N2O-treated rats, 1 week after the gas exposure, did not induce any effect. This suggests that the long-lasting effect of N2O was not due to its prior acute analgesic effect and was independent of endogenous opioid systems. These data suggest that 50% N2O exposure could be an efficient and safe strategy for alleviating neuropathic pain in a persistent manner. Because a single 50% N2O exposure induced a persistent reduction of hyperalgesia-allodynia in a rat neuropathic pain model, clinical trials must be developed for evaluating the N2O effects in patients with neuropathic pain. The ability of N2O to potentiate analgesic effects of other drugs also must be evaluated.

Long-Term Pain Vulnerability After Surgery in Rats: Prevention by Nefopam, an Analgesic with Antihyperalgesic Properties

Tissue damage associated with surgery often produces peripheral and central sensitization that may outlast the stimuli, leading to exaggerated postoperative pain. Paradoxically, the use of opioid analgesia, which is essential for surgical pain management may induce pain sensitization leading to enhanced postoperative pain and an increased risk of developing chronic pain. We studied whether a surgical incision in the rat hindpaw may favor the development of long-term pain vulnerability by estimating hyperalgesia induced by an inflammatory stimulation of the unlesioned contralateral hindpaw 3 wk later. We also evaluated the ability of nefopam, an analgesic drug commonly used in postoperative pain management, to prevent not only exaggerated postoperative pain but also long-term pain vulnerability. The efficacy of morphine was assessed 1 day after surgical incision. On Day 0, a surgical plantar incision was performed in one hindpaw of rats treated or untreated with fentanyl (4 x 100 microg/kg, one injection every 15 min). Nefopam (10 mg/kg) or saline was subcutaneously injected 30 min before injury. Three weeks later, once pain measures had returned to basal values, a subsequent nociceptive stimulus, specifically intraplantar carrageenan injection, was performed to evaluate pain sensitivity in incision- and fentanyl-experienced rats. Pain was measured by the paw-pressure vocalization test and the weight bearing test. Surgical incision in rats induced latent and long-term pain hypersensitivity, which was manifested by exaggerated hyperalgesia on carrageenan injection. Administering fentanyl in association with the surgical incision induced exaggerated postoperative pain. When injected before incision, nefopam reduced the exaggerated postoperative pain induced by perioperative fentanyl treatment and prevented the development of long-term pain hypersensitivity. Preoperative nefopam administration also improved morphine analgesic efficacy in the context of fentanyl-induced postoperative hyperalgesia. Given preemptively, nefopam may be effective at improving postoperative pain management and at reducing the risk of developing postoperative chronic pain, because the drug has both analgesic and antihyperalgesic properties.

Effect of acute administration of selective serotonin reuptake inhibitors (SSRIs) in different ultrasonic vocalization test paradigms

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Models of Anxiety: Ultrasonic Vocalizations of Isolated Rat Pups

Described in this unit is the ultrasonic distress vocalization test in rat pups. This test is a reliable method for detecting anxiolytic properties of test compounds. In this test, ultrasonic vocalizations (30 to 50 kHz) are elicited by separating rat pups of 9 to 11 days of age from their mother and littermates for a brief period of time. The test can be performed under two different stress conditions. Pups are placed in isolation in either a warm (37°C) or cold (18°C) environment for 5 min. The total number and duration of ultrasonic calls emitted by the pups during this period is used as an index of anxiety. Established anxiolytic compounds, including benzodiazepines, serotonin(1A) receptor agonists, and selective serotonin reuptake inhibitors (SSRIs), consistently reduce the number and cumulative duration of these ultrasonic distress vocalizations.

Role of cholinergic, opioidergic and GABAergic neurotransmission of the dorsal hippocampus in the modulation of nociception in guinea pigs

Aims: Several physiological, pharmacological and behavioral lines of evidence suggest that the hippocampal formation is involved in nociception. The hippocampus is also believed to play an important role in the affective and motivational components of pain perception. Thus, our aim was to investigate the participation of cholinergic, opioidergic and GABAergic systems of the dorsal hippocampus (DH) in the modulation of nociception in guinea pigs. Main methods: The test used consisted of the application of a peripheral noxious stimulus (electric shock) that provokes the emission of a vocalization response by the animal. Key findings: Our results showed that, in guinea pigs, microinjection of carbachol, morphine and bicuculline into the DH promoted antinociception, while muscimol promoted pronociception. These results were verified by a decrease and an increase, respectively, in the vocalization index in the vocalization test. This antinociceptive effect of carbachol (2.7 nmol) was blocked by previous administration of atropine (0.7 nmol) or naloxone (1.3 nmol) into the same site. In addition, the decrease in the vocalization index induced by the microinjection of morphine (2.2 nmol) into the DH was prevented by pretreatment with naloxone (1.3 nmol) or muscimol (0.5 nmol). At doses of 1.0 nmol, muscimol microinjection caused pronociception, while bicuculline promoted antinociception. Significance: These results indicate the involvement of the cholinergic, opioidergic and GABAergic systems of the DH in the modulation of antinociception in guinea pigs. In addition, the present study suggests that cholinergic transmission may activate the release of endorphins/enkephalin from interneurons of the DH, which would inhibit GABAergic neurons, resulting in antinociception.

The melanin-concentrating hormone1 receptor antagonists, SNAP-7941 and GW3430, enhance social recognition and dialysate levels of acetylcholine in the frontal cortex of rats

Melanin-concentrating hormone (MCH)1 receptors are widely expressed in limbic structures and cortex. Their inactivation is associated with anxiolytic and antidepressive properties but little information is available concerning cognition. This issue was addressed using the selective antagonists, SNAP-7941 and GW3430, in a social recognition paradigm in rats. The muscarinic blocker, scopolamine (1.25 mg/kg s.c.), reduced social recognition, an action dose-dependently blocked by SNAP-7941 and GW3430 (0.63-10.0 and 20.0-80.0 mg/kg i.p., respectively) which did not themselves display amnesic properties. Further, in a protocol where a spontaneous deficit was induced by a prolonged inter-session delay, SNAP-7941 and GW3430 dose-dependently enhanced social recognition. In dialysis studies, SNAP-7941 (0.63-40.0 mg/kg i.p.) and GW3430 (10.0-40.0 mg/kg i.p.) elevated extracellular levels of acetylcholine (ACh) in the frontal cortex (FCX) of freely moving rats. The SNAP-7941 effect was specific, as it did not increase levels of ACh in ventral and dorsal hippocampus: moreover, it did not modify levels of noradrenaline, dopamine, serotonin and glutamate in FCX. Active doses of SNAP-7941 and GW3430 corresponded to doses (2.5-40.0 and 10.0-80.0 mg/kg i.p., respectively) exerting anxiolytic properties in Vogel conflict and ultrasonic vocalization tests, and antidepressant actions in forced swim, isolation-induced aggression and marble-burying procedures. In contrast to SNAP-7941 and GW3430, the benzodiazepine, diazepam, decreased social recognition and dialysate levels of ACh, while the tricyclic, imipramine, reduced social recognition and failed to enhance cholinergic transmission. In conclusion, at anxiolytic and antidepressant doses, SNAP-7941 and GW3430 improve social recognition and elevate extracellular ACh levels in FCX. This profile differentiates MCH1 receptor antagonists from conventional anxiolytic and antidepressant agents.

Olanzapine counteracts stress-induced anxiety-like behavior in rats

Atypical antipsychotics, such as olanzapine, have been reported to display anxiolytic properties as shown in several preclinical and clinical studies. Furthermore, several experimental evidences have shown that olanzapine reduces fear and anxiety in activated anxiety-like behavior test such as Geller-Seifter test, ultrasonic vocalization test and stress-induced EtOH consumption. Here, we hypothesized that the anxiolytic action of olanzapine might be due to via an indirect activation of the gamma-amino butyric acid (GABA)-ergic system through 3alpha-hydroxy-5alpha-pregnan-20-one [allopregnanolone (ALLO)], a potent neuroactive steroid that positively modulates the benzodiazepine-gamma-aminobutyric acid type A (GABA(A))/benzodiazepine receptors complex. To address this question, we used a preclinical animal test to screen for novel anxiolytic compounds - the elevated plus-maze (EPM) - in basal condition and after 45 min restrain stress after acute or repeated (21 days) administration of olanzapine (0.5mg/kg, i.p.). In this condition, we therefore study the effect of the 5-alpha-reductase inhibitor finasteride (FIN) (50mg/kg) after co-administration with olanzapine. FIN is an inhibitor of steroidogenic enzymes which acts by inhibiting type II 5-alpha reductase, the enzyme that converts into 5-alpha-reduced metabolites like the GABA(A) positive neuroactive steroid ALLO. Results showed an anxiolytic effect of the acute, but not of the chronic, treatment with olanzapine only in stressed rats. This anxiolytic effect was counteracted by the co-administration with FIN. These evidences suggest that the anxiolytic effects of olanzapine might be due to possible action of olanzapine on steroid function via activation of GABA system.

Nitrous oxide (N 2O) prevents latent pain sensitization and long-term anxiety-like behavior in pain and opioid-experienced rats

Improving rehabilitation after a severe tissue injury does not only require a reduction in pain, but also requires alleviation of negative affects, particularly anxiety. Although opioids remain unsurpassed analgesics to relieve moderate to severe pain, it has been shown that they also induce latent pain sensitization leading to long-lasting hyperalgesia via N-methyl- d-aspartate-(NMDA)-dependent pronociceptive systems. The present study evaluated the ability of nitrous oxide (N 2O), a gas with NMDA antagonist properties, to prevent latent pain sensitization and long-term anxiety-like behavior (ALB) in rats with pain and opioid experiences. On D 0, the pro-inflammatory drug carrageenan was injected in one hind paw of rats treated with fentanyl (4 × 100 μg/kg subcutaneously). Nociceptive threshold was evaluated with the paw pressure vocalization test. Rats were re-exposed to carrageenan or exposed to repeated non-nociceptive environmental stress (NNES) 2–3 weeks later. Rats were also challenged in the elevated plus-maze 2 weeks after fentanyl administration for evaluating ALB. The preventive effects of a single 4 h 50/50% N 2O-O 2 exposure performed on D 0 was evaluated. Fifty percent N 2O strongly reduced hyperalgesia induced by a first inflammation and its enhancement by fentanyl, and prevented exaggerated hyperalgesia induced by second inflammatory pain or NNES. Moreover, we provide first evidence that a high fentanyl dose induces long-term ALB 2 weeks after its administration. When associated with fentanyl, 50% N 2O prevented such long-term ALB. These results suggest that a single exposure to N 2O could improve post-injury pain management and facilitate rehabilitation especially when potent analgesics as opioids have to be used.

Male parenting and response to infant stimuli in the common marmoset (Callithrix jacchus)

Callithrix jacchus infants are raised in complex family environments where most members participate in rearing the young. Many studies examining male parental behavior have focused on the carrying of infants with observations made within the family context. However, interference from family members can make it difficult to assess the father's motivation to care for infants. Our goals were to develop a testing paradigm for determining an individual's response to infant stimuli separate from family influences, compare a male's motivation to respond to an infant stimulus outside the family with his paternal behavior within the family, to compare responses to infant stimuli of parentally experienced versus inexperienced males and finally to develop a reproducible and standardized method of testing male responsiveness to infant stimulus that could serve to evaluate hormonal manipulations. Fifteen experienced common marmoset fathers were evaluated using three different measures of parental behavior: (1) instantaneous scan sampling, (2) continuous focal sampling in the family, and (3) continuous focal sampling of males presented with four infant stimuli: familiar and unfamiliar infants, familiar and unfamiliar infant vocalizations. Six parentally inexperienced males (non-fathers) served as controls. Males that carried the most in the family were typically the same males that responded most to the infant vocalization tests. Experienced fathers did not differ in their latency to enter the stimulus cage for any of the four infant stimuli response tests while inexperienced males took significantly longer to enter the stimulus cage. In addition, fathers expressed a greater frequency of infant-directed behavior than did the inexperienced males during the unfamiliar infant and unfamiliar vocalization tests. These studies show that experienced male marmosets are highly motivated to interact with infant stimuli and that there is interindividual variability in response to infant vocalizations. Testing males outside of the family allows for a clear assessment of male's interest in infant stimuli in both parentally experienced fathers and inexperienced males.

4-Phenyl-4-[1 H-imidazol-2-yl]-piperidine derivatives as non-peptidic selective δ-opioid agonists with potential anxiolytic/antidepressant properties. Part 2

Novel 4-phenyl-4-[1 H-imidazol-2-yl]-piperidine derivatives have been prepared and their synthesis described herein. In vitro affinities for δ-, μ-, and κ-opioid receptors are reported. Evaluation of some representative compounds from this series in the mouse neonatal ultrasonic vocalization test and the mouse tail suspension test revealed anxiolytic- and antidepressant-like effects, respectively, upon subcutaneous administration.

Locomotor response to novelty as a predictor of reactivity to aversive stimuli in the rat

In an animal model for vulnerability to drug abuse, animals that exhibit greater motor activity in a novel environment (high responders; HR) are more sensitive to drugs of abuse and are more likely to self-administer these drugs compared to less reactive animals (low responders; LR). In the light of clinical evidence on comorbidity between drug abuse and mood disorders, we used this model to investigate whether individual differences in locomotor reactivity to novelty are related to anxiety- and depression-like responsiveness using male Sprague–Dawley rats. Animals were categorized as HR and LR based on motor responses to novelty during a 30-min session. Anxiety-like reactivity was then measured using the elevated plus-maze, the defensive withdrawal test and acoustic startle-induced ultrasonic vocalization test. Depression-like reactivity was measured by the forced swim test. HR rats showed less anxiety-like behavior in the elevated plus-maze and defensive withdrawal tests than LR, but the opposite was true in the acoustic startle-induced vocalization test. In response to a series of loud acoustic stimuli, HR rats were faster to begin vocalizing and did so for a longer duration compared to LR. There were only minor differences between LR and HR rats in the forced swim test. These data suggest that an HR/LR model can be used to study a link between vulnerability to drug abuse and anxiety-like reactivity. The exact nature of this link depends upon the model of anxiety used and may reflect the heterogeneous nature of anxiety-like reactivity in the rat.

Non-Nociceptive Environmental Stress Induces Hyperalgesia, Not Analgesia, in Pain and Opioid-Experienced Rats

It is well admitted that stress induces analgesia (SIA) via endogenous opioid release. However, there is evidence that stressful events play a role in the pathogenesis of pain, but little is known about mechanisms underlying such pain vulnerability. Previous studies reported that a single opioid exposure activates NMDA-dependent pronociceptive systems leading to long-term pain vulnerability after analgesia. Here, we studied whether prior inflammatory pain or/and opioid experiences may favour the development of pain vulnerability after non-nociceptive environmental stress (NNES). Nociceptive threshold (NT) changes were evaluated by paw pressure vocalization test. By contrast to discrete SIA observed in naive rats, 1 h stress induced hyperalgesia (SIH) for several hours (15-65% NT decrease) in pain and opioid experienced rats. Repetition of NNES induced an 18- to 22-fold SIH enhancement (3-4 days), whereas SIA decreased. SIH was still observed 4 months after pain and opioid experiences. This phenomenon is referred to as latent pain sensitization. Furthermore, a fentanyl ultra-low dose (ULD, 50 ng/kg) administration, mimicking SIA in naive rats, induced hyperalgesia (65% NT decrease, 4 h), not analgesia, in pain and opioid-experienced rats. This indicates that low levels of opioids induce opposite effects, that is analgesia vs hyperalgesia dependent on prior life events. In pain and opioid-experienced rats, NMDA receptor antagonists, ketamine or BN2572, completely prevented hyperalgesia when injected just before NNES or fentanyl ULD. This latent pain sensitization model may be important for studying the transition from acute to chronic pain and individual differences in pain vulnerability associated with prior life events.

Acknowledgement of reviewers for Volume 17

The activity of the novel antidepressant agomelatine was evaluated in three models of anxiety and compared with that of melatonin and two anxiolytics, diazepam and buspirone. All drugs were tested 2 h before and 2 h after the dark phase of the diurnal cycle. Morning and evening agomelatine (10-75 mg/kg) administration increased animals' responses in the elevated plus maze and Vogel tests. Melatonin (10-75 mg/kg) enhanced open arms exploration in the evening experiment and was inactive in the Vogel test. In the conditioned ultrasonic vocalization test, agomelatine, but not melatonin, was active in the morning and evening experiment. Melatonin antagonist, S22153 (20 mg/kg), enhanced the action of morning and evening agomelatine administration in the Vogel and conditioned ultrasonic vocalization tests, while in the elevated plus maze test, S22153 inhibited effects of evening but not morning melatonin and agomelatine administration. These results indicate the involvement of both the melatonin and the 5-HT2C receptors in the mechanism of anxiolytic-like action of agomelatine.

Cholinergic modulation of tonic immobility and nociception in the NRM of guinea pig

Tonic immobility (TI) is an inborn defensive behavior characterized by a temporary state of profound and reversible motor inhibition elicited by some forms of physical restraint. It is known that endogenous antinociceptive systems are activated during the emission of defensive behaviors including TI. The nucleus raphe magnus (NRM) is related to the modulation of nociceptive and behavioral responses. In the present study, we investigated the role of the cholinergic system of the NRM in the modulation of TI and nociception in guinea pigs. Microinjection of the cholinergic agonist carbachol (0.5 μg/0.2 μl) into the NRM promoted a reduction in the duration of TI episodes and nociception, the latter measured by the vocalization test in guinea pigs. The effect of microinjection of carbachol on TI reduction and antinociception was blocked by the previous microinjection of the cholinergic antagonist atropine (0.5 μg/0.2 μl and 1 μg/0.2 μl, respectively), demonstrating the participation of muscarinic receptors in the modulation of these responses. Microinjection of atropine per se did not interfere with the duration of TI episodes. In summary, the present results demonstrate that cholinergic stimulation of the NRM promoted analgesia and a reduction in the duration of TI in guinea pigs. These data indicate that the NRM possibly contributes to the modulation of defensive and nociceptive behavioral responses, probably by modulating the activity of neurons in the ventral and dorsal horn of the spinal cord, respectively.

Behavioral, biochemical and histological studies in a model of pilocarpine-induced spontaneous recurrent seizures

Although the presence of profound cognitive disturbances in lithium–pilocarpine-induced spontaneous recurrent seizures (SRS) has been well documented, much less is known about changes in emotional behavior, in this model of temporal lobe epilepsy. To that end, a lithium–pilocarpine model of SRS was used to evaluate behavior of experimental animals (SRS, non-SRS and saline-treated rats) in different tests of anxiety (open field test, fear conditioning freezing and footshock-induced ultrasonic vocalization). Flinch-jump test, allowing determination of pain threshold, was employed to confirm specificity of data from anxiety tests. Moreover, neurotransmitters' (dopamine, serotonin and their metabolites) concentration was measured in selected brain structures involved in emotional and motor processing (hippocampus, frontal cortex and striatum). Finally, different brain structures were examined histologically in order to determine structures likely to be involved in behavioral changes. It was found that SRS rats, tested in a seizure free period, revealed an increase in motor activity, and a decrease in fear-related reactions (a freezing response to the aversively conditioned context, and a spontaneous, emotion-related ultrasonic vocalization). No changes in the pain threshold were present. The activity of dopamine and serotonin systems in examined brain structures remained unchanged. The neuropathological effects were widespread and involved a loss of neurons, proliferation of astroglial cells and the presence of activated ramified and ameboid microglial cells in the hippocampus proper, piriform cortex, amygdala and lateral posterior thalamic nuclei. The obtained results suggest a prevalence of disinhibitory effects on behavior in SRS rats, as shown by the results of contextual fear and aversive vocalization tests (i.e. a release of rat behavior controlled by fear). It is conceivable that the lesions to the limbic structures involved in the origin of emotions; the hippocampus, amygdala, and piriform cortex, may underlie changes in anxiety reactions in SRS rats. These results indicate that lithium–pilocarpine-induced SRS are also accompanied by profound alteration of animal emotional behavior.

Ketamine Improves the Management of Exaggerated Postoperative Pain Observed in Perioperative Fentanyl-treated Rats

Although opioids are unsurpassed analgesics, experimental and clinical studies suggest that opioids activate N-methyl-d-aspartate pronociceptive systems leading to pain hypersensitivity and short-term tolerance. Because it is difficult in humans to differentiate pain from hyperalgesia during the postoperative period, the authors performed experimental studies with fentanyl using the rat incisional pain model for evaluating relations between hyperalgesia and short-term tolerance. Because N-methyl-d-aspartate receptor antagonists oppose both pain hypersensitivity and tolerance induced by opioids, the authors examined the capability of ketamine for improving exaggerated postoperative pain management. During halothane anesthesia, a hind paw plantar incision was performed in rats receiving four fentanyl subcutaneous injections (100 microg/kg per injection, every 15 min). In some groups, three subcutaneous ketamine injections (10 mg/kg per injection, every 5 h) were performed in saline- or fentanyl-treated rats. One day after surgery, the analgesic effect of morphine (2 mg/kg subcutaneous) was tested. Analgesia, mechanical hyperalgesia, tactile allodynia, and pain score were assessed for several days using the paw pressure vocalization test, the von Frey application test, and the postural disequilibrium test. Fentanyl induced analgesia but also produced exaggerated postoperative pain as indicated by the enhancement of hyperalgesia, allodynia, and weight-bearing decrease after hind paw plantar incision. Ketamine pretreatment prevented such a fentanyl-induced enhancement of postoperative pain and improved its management by morphine. By opposing postoperative pain hypersensitivity and subsequent short-term tolerance induced by perioperative opioid use, ketamine not only improves exaggerated postoperative pain management but also provides better postoperative rehabilitation.

Cholinergic-opioidergic interaction in the central amygdala induces antinociception in the guinea pig.

Several studies have demonstrated the involvement of the central nucleus of the amygdala (CEA) in the modulation of defensive behavior and in antinociceptive regulation. In a previous study, we demonstrated the existence of a cholinergic-opioidergic interaction in the CEA, modulating the defensive response of tonic immobility in guinea pigs. In the present study, we investigated a similar interaction in the CEA, but now involved in the regulation of the nociceptive response. Microinjection of carbachol (2.7 nmol) and morphine (2.2 nmol) into the CEA promoted antinociception up to 45 min after microinjection in guinea pigs as determined by a decrease in the vocalization index in the vocalization test. This test consists of the application of a peripheral noxious stimulus (electric shock into the subcutaneous region of the thigh) that provokes the emission of a vocalization response by the animal. Furthermore, the present results demonstrated that the antinociceptive effect of carbachol (2.7 nmol; N = 10) was blocked by previous administration of atropine (0.7 nmol; N = 7) or naloxone (1.3 nmol; N = 7) into the same site. In addition, the decrease in the vocalization index induced by the microinjection of morphine (2.2 nmol; N = 9) into the CEA was prevented by pretreatment with naloxone (1.3 nmol; N = 11). All sites of injection were confirmed by histology. These results indicate the involvement of the cholinergic and opioidergic systems of the CEA in the modulation of antinociception in guinea pigs. In addition, the present study suggests that cholinergic transmission may activate the release of endorphins/enkephalins from interneurons of the CEA, resulting in antinociception.

Indolebutylamines as Selective 5-HT1A Agonists

A series of new 1-[4-(indol-3-yl)butyl]-4-arylpiperazines was prepared to identify highly selective and potent 5-HT(1A) agonists as potential pharmacological tools in studies of mood disorders. The combination of structural elements (indole-alkyl-amine and aryl-piperazine) known to introduce 5-HT(1A) receptor affinity and the proper selection of substituents (R on the indole moiety and R' on the aryl moiety) led to compounds with high receptor specificity and affinity. In particular, the introduction of the methyl ether or the unsubstituted carboxamide as substituents in position 5 of the indole (R) guaranteed serotonergic 5-HT(1A) affinity compared to the unsubstituted analogue. Para-substituted arylpiperazines (R') decreased dopaminergic D(2) binding and increased selectivity for the 5-HT(1A) receptor. Agonistic 5-HT(1A) receptor activity was confirmed in vivo in the ultrasonic vocalization test, and the results suggest that the introduction of the carboxamide residue leads to better bioavailability than the corresponding methyl ether. 3-[4-[4-(4-Carbamoylphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 54 was identified as a highly selective 5-HT(1A) receptor agonist [GTPgammaS, ED(50) = 4.7 nM] with nanomolar 5-HT(1A) affinity [IC(50) = 0.9 nM] and selectivity [D(2), IC(50) > 850 nM]. 3-[4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl]-1H-indole-5-carboxamide 45 is one of the most potent and selective 5-HT(1A) agonists known [5-HT(1A), IC(50) = 0.09 nM; D(2), IC(50) = 140 nM].