Yohimbine Pretreatment Research Articles

Effect of Moxonidine on the Uveoscleral Outflow: Role of α2-Adrenoceptors or I1 Imidazoline Receptors

Purpose: The purpose of this study is to assess the change of uveoscleral outflow induced by moxonidine and to investigate whether the increase of uveoscleral outflow induced by moxonidine is mediated by α1, α2, or I1 receptors. Methods: 0.05% moxonidine was topically and unilaterally administered in rabbit eyes with or without pretreatment of prazosin, yohimbine, efaroxan, or AGN 192403, as indicated. We injected fluorescein isothiocyanate-bovine serum albumin (FITC-BSA) into the anterior chamber and observed the fluorescence intensity of the uveoscleral outflow. Finally, the volume of uveoscleral outflow was calculated based on the fluorescence intensities captured. Results: A bilateral increase of fluorescence intensity was observed along the uveoscleral outflow pathway following moxonidine administration, especially in the ciliary body and supraciliochoroidal space. Pretreatment with prazosin further enhanced the bilateral increase of fluorescence intensity at between 2 and 4 hours after moxonidine administration. The response of moxonidine was antagonized by either yohimbine, an α2 receptor antagonist, or efaroxan, an I1/α2 receptor antagonist. The antagonizing effect of yohimbine was more potent than that of efaroxan. The moxonidne-induced response was not antagonized by AGN 192403, an I1 receptor antagonist. The bilateral volumes of aqueous humor within the uveoscleral pathway increased significantly induced by moxonidine (p < 0.01 versus control). The increased bilateral volumes of uveoscleral outflow were 0.381 ± 0.073 and 0.376 ± 0.095 μ l/min, respectively. Conclusion: These results suggest that topical, unilateral administration of moxonidine causes a bilateral increase of aqueous humor via the uveoscleral outflow pathway. The moxonidine-induced increase of uveoscleral outflow is mediated by α2 adrenergic receptors, not by I1 imidazoline receptors.

Preoptic norepinephrine mediates the febrile response of guinea pigs to lipopolysaccharide

Norepinephrine (NE) microdialyzed in the preoptic area (POA) raises core temperature (T(c)) via 1) alpha(1)-adrenoceptors (AR), quickly and independently of POA PGE(2), and 2) alpha(2)-AR, after a delay and PGE(2) dependently. Since systemic lipopolysaccharide (LPS) activates the central noradrenergic system, we investigated whether preoptic NE mediates LPS fever. We injected LPS (2 microg/kg iv) in guinea pigs prepared with intra-POA microdialysis probes and determined POA cerebrospinal (CSF) NE levels. We similarly microdialyzed prazosin (alpha(1) blocker, 1 microg/microl), yohimbine (alpha(2) blocker, 1 microg/microl), SC-560 [cyclooxygenase (COX)-1 blocker, 5 microg/microl], acetaminophen (presumptive COX-1v blocker, 5 microg/microl), or MK-0663 (COX-2 blocker, 0.5 microg/microl) in other animals before intravenous LPS and measured CSF PGE(2). All of the agents were perfused at 2 microg/min for 6 h. T(c) was monitored constantly. POA NE peaked within 30 min after LPS and then returned to baseline over the next 90 min. T(c) increased within 12 min to a first peak at approximately 60 min and to a second at approximately 150 min and then declined over the following 2.5 h. POA PGE(2) followed a concurrent course. Prazosin pretreatment eliminated the first T(c) rise but not the second; PGE(2) rose normally. Yohimbine pretreatment did not affect the first T(c) rise, which continued unchanged for 6 h; the second rise, however, was absent, and PGE(2) levels did not increase. SC-560 and acetaminophen did not alter the LPS-induced PGE(2) and T(c) rises; MK-0663 prevented both the late PGE(2) and T(c) rises. These results confirm that POA NE is pivotal in the development of LPS fever.

Muscarinic receptors and alpha2-adrenoceptors interact to modulate the respiratory rhythm in mouse neonates

The respiratory rhythm generator (RRG) is modulated by several endogenous substances, including acetylcholine (ACh) and noradrenaline (NA) that interact in several modulatory processes. To know whether ACh and NA interacted to modulate the RRG activity, we used medullary "en bloc" and slice preparations from neonatal mice where the RRG has been shown to receive a facilitatory modulation from A1/C1 neurons, via a continuous release of endogenous NA and activation of alpha2 adrenoceptors. Applying ACh at 25 microM activated the RRG but ACh had no effects at 50 microM. Applying the ACh receptor agonists nicotine and muscarine facilitated and depressed the RRG, respectively. After yohimbine pre-treatment that blocked the alpha2 facilitation, the nicotinic facilitation was not altered, the muscarinic depression was reversed and ACh 50 microM significantly facilitated the RRG. After L-tyrosine pre-treatment that potentiated the alpha2 facilitation, the muscarinic depression was enhanced. Thus, ACh regulates the RRG activity via nicotinic and muscarinic receptors, the muscarinic receptors interacting with alpha2 adrenoceptors.

Potentiation of cue-induced reinstatement of cocaine-seeking in rats by the anxiogenic drug yohimbine

Stress and drug-associated cues can trigger drug desire and relapse in abstinent cocaine users. Although the role of these two factors in relapse is well documented, it remains unclear as to whether an interaction between stress and drug-associated cues can lead to an enhancement in cocaine-seeking behavior. Here, we assessed the effects of the anxiogenic α 2-noradrenergic receptor antagonist, yohimbine, on reinstatement of cocaine-seeking in rats either in the presence or absence of cocaine-associated cues. Yohimbine pretreatment in the absence of cocaine-associated cues or cues by themselves reliably reinstated responding on the previously cocaine-paired lever (3–4 times higher than extinction levels). However, animals showed greatly potentiated responding if yohimbine preceded cue-induced reinstatement (10–13 times higher than extinction levels, or 3–5 times over cues or yohimbine alone). While cocaine self-administration produced a significant increase in plasma corticosterone, plasma corticosterone levels did not show a clear relationship to cocaine-paired lever responding during cue and/or yohimbine-induced reinstatement. These results demonstrate that exposure to drug-paired cues during a stressful state can greatly potentiate cocaine-seeking and suggest that future treatment interventions should target multiple modalities.

Antinociceptive effect and the mechanism of bee venom acupuncture (Apipuncture) on inflammatory pain in the rat model of collagen-induced arthritis: Mediation by α 2-Adrenoceptors

The antinociceptive effect and the mechanism of bee venom acupuncture (BVA) on inflammatory pain, especially in the rat model of collagen-induced arthritis (CIA), have not yet been fully studied. This study was designed to investigate the antinociceptive effect and its μ-opioid and α 2-adrenergic mechanism of BVA in the CIA rat model. To induce CIA, male Sprague–Dawley rats were immunized with bovine type II collagen emulsified in Freund's incomplete adjuvant followed by a booster injection 14 days later. The antinociceptive effect was evaluated by tail flick latency (TFL). After induction of arthritis, the inflammatory pain threshold decreased as time passed, and there was no big change of the pain threshold after 3 weeks. Three weeks after the first immunization, BVA (0.25 mg/kg) injected into the Zusanli acupoint (ST 36) showed the antinociceptive effect. Furthermore, the antinociceptive effect of BVA was blocked by yohimbine (α 2-adrenergic receptor antagonist, 2 mg/kg, i.p) pretreatment, but not by naloxone (μ-opioid receptor antagonist, 2 mg/kg, i.p.) pretreatment. These results suggest that BVA can relieve inflammatory pain in CIA and the antinociceptive effect of BVA can be mediated by α 2-adrenergic receptor.

A pharmacological modulation of opiate withdrawal using an up-/down-regulation of the noradrenergic system in opiate-dependent rats

Chronic opioid exposure induces neuroadaptative changes in several brain systems. Amongst others the alpha adrenergic system appears to be extremely sensitive to opioid exposure and has, therefore, been proposed to play a key role in opiate withdrawal symptoms. In order to better understand the influence of the noradrenergic system in opioid withdrawal and be able to develop new therapeutic strategies, we studied the effect of pre-treatment with the alpha2 agonist (clonidine) and alpha2 antagonist (yohimbine) on naloxone-precipitated withdrawal in opiate-dependent rats. As is already known clonidine pre-treatment significantly enhances autonomic and behavioural signs of opioid withdrawal whereas yohimbine significantly attenuates them with dose-related effect. We also tested the effect of clonidine (0.1 mg/kg) during naloxone-precipitated opiate withdrawal in rats pre-treated with yohimbine (5 mg/kg) and we observed that yohimbine pre-treatment potentiates clonidine efficiency in decreasing opiate withdrawal signs. This study supports the possibility of using a noradrenergic antagonist in order to regulate adrenoreceptors chronically exposed to opioids, therefore interfering with the intensity of naloxone-precipitated opiate withdrawal and potentiating later effectiveness of noradrenergic agonists like clonidine. These results may have various applications in clinical opiate detoxification protocols and are discussed through an up-/down- regulation of adrenoreceptors.

Attenuation of capsaicin-induced acute and visceral nociceptive pain by α- and β-amyrin, a triterpene mixture isolated from Protium heptaphyllum resin in mice

The triterpene mixture, α- and β-amyrin, isolated from Protium heptaphyllum resin was evaluated on capsaicin-evoked nociception in mice. Orally administered α- and β-amyrin (3 to 100 mg/kg) significantly suppressed the nociceptive behaviors—evoked by either subplantar (1.6 μg) or intracolonic (149 μg) application of capsaicin. The antinociception produced by α- and β-amyrin against subplantar capsaicin-induced paw-licking behavior was neither potentiated nor attenuated by ruthenium red (1.5 mg/kg, s.c.), a non-specific antagonist of vanilloid receptor (TRPV1), but was greatly abolished in animals pretreated with naloxone (2 mg/kg, s.c.), suggesting an opioid mechanism. However, participation of α 2-adrenoceptor involvement was unlikely since yohimbine (2 mg/kg, i.p.) pretreatment failed to block the antinociceptive effect of α- and β-amyrin in the experimental model of visceral nociception evoked by intracolonic capsaicin. The triterpene mixture (3 to 30 mg/kg, p.o.) neither altered significantly the pentobarbital sleeping time, nor impaired the ambulation or motor coordination in open-field and rota-rod tests, respectively, indicating the absence of sedative or motor abnormality that could account for its antinociception. Nevertheless, α- and β-amyrin could significantly block the capsaicin (10 mg/kg, s.c.)-induced hyperthermic response but not the initial hypothermia. These results suggest that the triterpene mixture, α- and β-amyrin has an analgesia inducing effect, possibly involving vanilloid receptor (TRPV1) and an opioid mechanism.

The α 2-adrenoceptor antagonist yohimbine reduces glial fibrillary acidic protein upregulation induced by chronic morphine administration

Previous literature data show prominent interactions between α 2-adrenoceptor ligands and opioid drugs, however, the nature of such interactions is still largely unknown. In the present study, we aimed to examine the potential protective effect of yohimbine, a α 2-adrenoceptor antagonist, against glial fibrillary acidic protein (GFAP) alterations elicited by chronic morphine treatment. Increased astrogliosis, as indicated by increased GFAP immunohistochemical staining, was observed in the ventral tegmental area, nucleus accumbens shell, and frontal cortex of chronic morphine-treated (10 mg kg −1, i.p., every 12 h for 13 days) rats compared with those treated with saline. Pretreatment with yohimbine (2 mg kg −1, i.p., 30 min before each morphine injection) provided protection against morphine-induced GFAP upregulation. The present study demonstrates that yohimbine pretreatment reduces long-term morphine exposure-induced alterations in the astroglial reaction, suggesting that α 2-adrenergic mechanisms may play an important role in mediating morphine-induced pathological effects in the brain.

One for all or one for one: does co-transmission unify the concept of a brain galanin “system” or clarify any consistent role in anxiety?

Galanin (GAL) is a potential target for novel antidepressant or anti-anxiety drug development. However, no integrated role for a "brain galanin system" in anxiety has yet emerged. It is possible that such a function may be revealed by examining the interaction of GAL with norepinephrine (NE), with which it is prominently co-localized. We showed previously that enhancing stress-activation of the NE system by yohimbine (YOH) pretreatment induced the release of GAL in central amygdala (CeA) to exert an anxiolytic effect on the elevated plus-maze. However, it remained to be demonstrated conclusively that GAL was co-released from NE terminals in CeA in this context, or if a multi-synaptic circuit activated GAL release from another afferent to CeA, or from local GAL neurons in the vicinity of CeA. In studies presented at the Third International Symposium on Galanin and Its Receptors, we utilized a combination of behavioral pharmacological approaches, testing the effects of YOH on the behavioral response to stress on the plus-maze after lesioning NE afferents to CeA with 6-OHDA, and anatomical approaches to identify GAL afferents to CeA that are activated in the context of stress with yohimbine pretreatment, to address these alternatives. Our results suggest that GAL was not co-released from noradrenergic terminals innervating CeA to exert an anxiolytic influence when noradrenergic activation was amplified by yohimbine pretreatment. Rather, it most likely originated from GAL neurons immediately adjacent to CeA that were activated by a non-noradrenergic afferent arising from elsewhere in the brain, itself activated by increasing NE activity. Thus, any role for brain GAL in anxiety remains region-specific, pathway specific, response specific and context-specific, which is likely to continue to present challenges to the development of novel agents targeting brain GAL for treatment of depression or anxiety.

Galanin-mediated anxiolytic effect in rat central amygdala is not a result of corelease from noradrenergic terminals

Galanin is colocalized extensively with norepinephrine in brain. Although this suggests possible activity-dependent neurotransmitter interactions, the functional significance of such colocalization remains elusive. Previously, we showed that enhancing stress-activation of the noradrenergic system by yohimbine pretreatment released galanin in central amygdala, attenuating the anxiety-like behavioral response to stress on the elevated plus-maze. The present study was conducted to determine, in this context, whether galanin was indeed coreleased from noradrenergic terminals, or instead from another galanin afferent or local stress-responsive galanin neurons in the amygdala. In experiment 1, galanin-mediated anxiolytic effects on the plus-maze following yohimbine + stress were unaltered by lesioning the noradrenergic innervation of central amygdala. In experiment 2, combining immunohistochemistry and in situ hybridization, galanin neurons specifically activated by yohimbine + stress treatment were found only in the locus coeruleus and intraamygdalar bed nucleus of the stria terminalis, adjacent to central amygdala. In experiment 3, retrograde tracing combined with in situ hybridization revealed few if any galanin cells projecting to central amygdala in locus coeruleus or nucleus tractus solitarius, sources of noradrenergic innervation. Indeed, few retrogradely-labeled galanin neurons were observed anywhere in the brain, including a small number in the intraamygdalar bed nucleus. Together, these results suggest that stress following yohimbine may have induced galanin release from an afferent to central amygdala originating in the bed nucleus, or from local neurons in the intraamygdalar bed nucleus, but that anxiolytic effects exerted by galanin in this context of elevated noradrenergic activity were not the result of corelease from noradrenergic terminals innervating central amygdala.

Role of alpha-2 adrenoceptors in stress-induced reinstatement of alcohol seeking and alcohol self-administration in rats

Alpha-2 adrenoceptors are known to be involved in stress-induced reinstatement of heroin and cocaine seeking in laboratory animals. Here, we studied the involvement of these receptors in stress-induced reinstatement of alcohol seeking by using an agonist (lofexidine) and an antagonist (yohimbine) of these receptors, which inhibit and activate, respectively, noradrenaline transmission. We also tested the effect of lofexidine and yohimbine on alcohol self-administration. Lofexidine is used clinically for treating opiate withdrawal symptoms and yohimbine induces stress-like responses in humans and non-humans. Rats were trained to self-administer alcohol (12% w/v, 1 h/day) and after extinction of the alcohol-reinforced behavior, they were tested for the effect of lofexidine (0, 0.05 and 0.1 mg/kg, IP) on reinstatement of alcohol seeking induced by intermittent footshock stress (10 min, 0.8 mA) or for the effect of yohimbine (0, 1.25 and 2.5 mg/kg, IP) on reinstatement of alcohol seeking. Other rats were trained to self-administer alcohol, and after stable responding, the effects of lofexidine and yohimbine on alcohol self-administration were determined. Pretreatment with lofexidine (0.05 mg/kg and 0.1 mg/kg) attenuated stress-induced reinstatement of alcohol seeking and also decreased alcohol self-administration. In contrast, yohimbine pretreatment potently reinstated alcohol seeking after extinction and also induced a profound increase in alcohol self-administration. Results indicate that activation of alpha-2 adrencoceptors is involved in both stress-induced reinstatement of alcohol seeking and alcohol self-administration. To the degree that the present results are relevant to human alcoholism, alpha-2 adrencoceptor agonists should be considered in the treatment of alcohol dependence.

Central α-adrenergic receptors and corticotropin releasing factor mediate hemodynamic responses to acute cold stress

Behavioral stress is likely to contribute to the development of hypertension in susceptible individuals. We reported that hemodynamic response patterns to acute startle vary and that those patterns predict the predisposition of rats to sustained stress-induced elevations in arterial pressure. Since considerable evidence suggests that central catecholamines and corticotropin releasing factor (CRF) contribute to the regulation of arterial pressure and the development of hypertension, we investigated the role of central α-adrenergic receptors and CRF in mediating different hemodynamic response patterns to acute cold water stress in conscious rats. Rats were instrumented for arterial pressure, heart rate and cardiac output determination and for intracerebroventricular (icv) administration of selective antagonists. After acclimation to a water tight cage, ice water (1 cm deep) was rapidly added then drained 1 min later. Although the early startle response to cold water stress elicited a pressor response in all rats, the hemodynamic response pattern varied between rats. Vascular responders ( n=19) had an initial considerable increase in systemic vascular resistance and a decrease in cardiac output. In contrast, mixed responders ( n=11) had a smaller increase in vascular resistance and an increase in cardiac output. Pretreatment with phentolamine (30 μg/5 μl, icv, n=8), prazosin (10 μg/5 μl, icv, n=12) or α-helical CRF 9–41 (10 μg/5 μl, icv, n=9) prevented the decrease in cardiac output elicited by acute cold water stress in vascular responders without affecting mixed responders. Yohimbine (3 μg/5 μl, icv, n=8) pretreatment did not alter hemodynamic responses. Therefore, we conclude that central α 1-adrenoceptors and CRF mediate the specific hemodynamic response patterns to acute startle and may be responsible for the predisposition to develop hypertension in vascular responders.

Adrenoceptor mechanisms underlying imipramine-induced memory deficits in rats

The post-training administration of tricyclic antidepressant imipramine impairs memory consolidation in the passive avoidance task. The present study investigated the effects of intrahippocampal (i.h.) injection of adrenoceptor agents on imipramine-induced (2-8 microg/rat) amnesia. The administration of the alpha1-adrenoceptor agonist phenylephrine (0.05 microg/rat) and the alpha1-adrenceptor antagonist prazosin (0.5 microg/rat) did not alter the effect of imipramine. The lower doses of phenylephrine (0.005 and 0.015 microg/rat) impaired, while the higher dose of the drug (0.025 and 0.05 microg/rat) improved retention. The effect of phenylephrine was not altered by prazosin (0.5 and 1 microg/rat) pretreatment, although prazosin alone decreased retention latencies. The alpha2-adrenoceptor antagonist yohimbine (0.5 and 1 microg/rat) decreased the response induced by imipramine. However, the alpha2-adrenoceptor agonist clonidine (0.08 microg/rat) did not alter the effect of the drug. Clonidine (0.15 and 0.3 microg/rat) by itself decreased, while yohimbine (1 and 2 microg/rat) increased retention latencies. Yohimbine pretreatment attenuated the effect of clonidine. It is concluded that alpha2-adrenoceptor mechanism(s) may be involved in imipramine-induced impairment of memory.

THE ROLE OF α-ADRENOCEPTORS IN THE AMNESTIC EFFECT OF INTRACEREBROVENTRICULAR DEXAMETHASONE

Corticosteroids exert dual enhancing or impairing effects on cognitive functions. While their memory-enhancing effects have been well investigated, the mechanisms involved in their amnestic effects are not completely understood. Thus, we examined the role of α-adrenoceptors on dexamethasone-induced amnesia using step-through passive avoidance test in rat. Intracerebroventricular (i.c.v.) injection of dexamethasone (5 and 10 μg per rat) decreased the retention latencies. Likewise, intraperitoneal administration of α 2-adrenoceptor agonist clonidine (0.1–0.3 mg kg −1) but not α 2-adrenoceptor antagonist yohimbine (0.5–2 mg kg −1) decreased the retention latency. Yohimbine pre-treatment decreased the amnestic effects of dexamethasone or dexamethasone plus clonidine. On the other hand, intraperitoneal administration of α 1-adrenoceptor agonist phenylephrine (0.5–2 mg kg −1) per se increased, while prazosin at 2 mg kg −1 decreased the retention latency. Administration of phenylephrine before dexamethasone completely reversed the amnestic effect of the latter, while prozosin did not affect dexamethasone-induced amnesia. These data suggest that dexamethasone may induce its amnestic effect through activation of α 2-adrenoceptors, leading to decreased α 1-adrenergic activity.

Noradrenaline release in rat locus coeruleus is regulated by both opioid andα2 -adrenoceptors

Extracellular fluid levels of noradrenaline (NA) in the locus coeruleus (LC) during naloxone-precipitated morphine withdrawal with pretreatment of yohimbine (1 mg kg −1, s.c.) or clonidine (1 mg kg −1, s.c.) were measured in rats. There was a significant increase in the NA level after the injection of naloxone (2 mg kg −1, i.p.) in the morphine-dependent rats. Moreover, the NA levels in the LC markedly increased during the 30–60 min following the naloxone (i.p.) challenge in the morphine-dependent rats pretreated with yohimbine. In contrast, the naloxone challenge in morphine-dependent rats pretreated with clonidine notably decreased the levels of NA in the LC. Behavioral signs of withdrawal were observed following the naloxone challenge in the morphine-dependent rats pretreated with yohimbine, with minimal signs in the morphine-infused rats pretreated with clonidine, and none in the saline-infused controls. These results directly suggest that NA increased within the LC after the naloxone challenge in morphine-dependent animals pretreated with yohimbine may be, at least in part, regulated byα2 -adrenoceptors in the LC.

Behavioral reactivity to stress: Amplification of stress-induced noradrenergic activation elicits a galanin-mediated anxiolytic effect in central amygdala

Brain norepinephrine (NE) modulates many aspects of the stress response. The interaction between NE and neuropeptides such as galanin, with which it is closely associated and which may be released from noradrenergic terminals under conditions of high activity, has not been well studied. We therefore investigated the modulatory effects of galanin in the central nucleus of the amygdala (CeA) on behavioral responsivity to stress when activation of the noradrenergic system was amplified using the adrenergic autoreceptor antagonist yohimbine (2.5 mg/kg ip). Either immobilization stress or yohimbine alone had anxiogenic effects on rat behavior in the elevated plus maze. However, yohimbine pretreatment before stress produced a paradoxical anxiolytic response, which we hypothesized was attributable to galanin release in CeA. Microdialysis verified that yohimbine amplified NE release in CeA during immobilization stress, and also showed that whereas there was no detectable change in galanin release in CeA during stress alone, there was an increase during immobilization stress after yohimbine pretreatment. Bilateral administration of the galanin antagonist M40 into CeA before stress blocked the anxiolytic influence of yohimbine pretreatment. Exogenous galanin mimicked the anxiolytic effect of yohimbine pretreatment, and this too was blocked by M40. These results suggest that amplifying the noradrenergic response to stress can recruit galanin release in CeA, which buffers the anxiety-like behavioral response to acute stress. The balance between noradrenergic and peptidergic neurotransmission may be modified by prior stress, drug treatment or genetic variability, and may represent a novel target for treatment of stress-related neuropsychiatric disorders.

A role for spinal, but not supraspinal, α 2 adrenergic receptors in the actions of improgan, a powerful, non-opioid analgesic

Improgan is a derivative of cimetidine that induces non-opioid antinociception after intracerebroventricular (i.c.v.) administration, but the mechanism of action of this compound remains unknown. Since activation of either supraspinal or spinal α 2 adrenergic receptors can induce antinociception, and since improgan showed affinity for these receptors in vitro, the effects of the α 2 antagonist yohimbine on improgan antinociception were presently studied in rats on the hot plate and tail flick tests. Systemic yohimbine pretreatment (4 mg/kg, i.p.) completely blocked improgan antinociception (80 μg, i.c.v.), suggesting a mediator role for α 2 receptors. However, i.c.v. pretreatment with yohimbine (30 μg) had no effect on improgan antinociception. Since this treatment completely antagonized clonidine antinociception (40 μg, i.c.v.), supraspinal α 2 receptors seem to mediate the antinociceptive effects of clonidine, but not that produced by improgan. In contrast, intrathecal (i.t.) yohimbine pretreatment (30 μg) completely blocked the antinociception elicited by i.c.v. improgan and i.c.v. morphine. These results suggest that spinal (but not supraspinal) α 2 adrenergic receptors play a significant role in the pain-relieving actions of improgan. Furthermore, although improgan shows some affinity at α 2 receptors, this drug does not act directly at these receptors to induce antinociceptive responses. Like several other classes of analgesics, improgan-like drugs seem to activate non-opioid, descending pain-relieving circuits.

Effects of intravenous cocaine administration on cerebellar Purkinje cell activity

The goal of the present study was to investigate the effects of intravenous cocaine administration on cerebellar Purkinje cell firing. Extracellular neuron activity was recorded and cells were locally excited with spaced microiontophoretic pulses of glutamate. Glutamate-evoked and spontaneous discharges were compared before and immediately following cocaine administration. Cocaine injections (1.0 and 0.25 mg/kg, i.v.) induced a reversible suppression of both spontaneous activity and glutamate-evoked excitation. Procaine was ineffective in producing similar actions. Cocaine only inhibited glutamate-induced excitation in animals pre-treated with reserpine (5 mg/kg, i.p.). Propranolol injections (10 mg/kg, i.p.) were ineffective in blocking cocaine-induced inhibitions. Yohimbine (5 mg/kg, i.p.) pre-treatment abolished cocaine-induced suppressions of either spontaneous or glutamate-evoked excitation. Therefore, cocaine administration decreases Purkinje cell spontaneous and glutamate-evoked discharges by a mechanism involving α 2-adrenoceptor activation. It is suggested that by changing the normal function of the cerebellum cocaine can produce drug-related alterations in overt behavior and cognition.

Pharmacological evidence for different alpha 2-adrenergic receptor sites mediating analgesia and sedation in the rat

Alpha2-adrenergic agonists given intrathecally result in antinociception and intracerebroventricularly (ICV) in sedation. To examine whether different alpha2-adrenergic receptor subtypes differentially mediate antinociception and sedation, we measured the relative potency of three alpha2-adrenergic agonists, dexmedetomidine (DMET), clonidine (CLON) and UK-14.304 (UK), after spinal and ICV administration. Each agonist was given either alone or in the presence of systemically administered yohimbine, which acts as a competitive alpha2-antagonist in unanaesthetized rats. Intrathecal delivery of the agonists alone resulted in a dose-dependent antinociceptive effect (ED50 (nmol): DMET = 1.2, UK = 1.7, CLON = 5.6) with little sedative effect at the lower doses. Yohimbine pretreatment resulted in a rightward shift of the dose-response curves (DMET > CLON > UK). ICV alpha2-adrenergic agonists produced a dose-dependent sedation (ED50 (nmol): DMET = 10.5; UK = 28.7; CLON = 126), with little antinociceptive action. Again, yohimbine pretreatment produced a right shift of the ICV sedation dose-response curves (UK > DMET > CLON). Thus, we conclude that the spinal analgesic effects of DMET, CLON and UK appear to be mediated by two sites. After ICV delivery, DMET, CLON and UK appear to act at a common supra-spinal site to produce sedation and this site resembles that acted upon by UK in the spinal cord.

Topical nicotine protects rat gastric mucosa against ASA-induced damage a role for mucosal fluid secretion in cytoprotection

Acute intragastric nicotine administration has previously been shown to protect against ethanol-induced gastric mucosal damage. The aim of this study was to examine the effects of acute nicotine exposure on ASA-induced gastric mucosal damage and to determine if nicotine's protective effect is secondary to an increase in mucosal blood flow or in mucosal fluid secretion, as reflected by changes in the juxtamucosal pH gradient and volume of intragastric fluid. Mucosal blood flow, using a laser Doppler flowmeter, juxtamucosal pH gradient (depth, magnitude, and surface pH), using antimony microelectrodes, and changes in volume of luminal bathing solutions were measured in rat ex vivo gastric chamber preparations prior to and after a 10-min exposure to topical nicotine (1 mg in 8 ml of 0.2 M mannitol in 50 mM HCl), or to mannitol-HCl solution (vehicle). This was followed by application of acidified ASA (80 mM in 160 mM HCl) to the chambered mucosae for 10 min. Lesion area, expressed as the percentage of total glandular mucosa which was damaged, was significantly (P < 0.05) reduced by nicotine pretreatment. Blood flow decreased with nicotine exposure by 18.4%, compared to 13.6% in the control group (NS). Both gradient depth and gastric fluid volume increased significantly in the nicotine group (P < 0.05) compared to controls. Yohimbine pretreatment prevented both the increase in juxtamucosal pH gradient depth and the protective effect of nicotine. These results suggest that acute intragastric nicotine exposure protects against ASA-induced gastric damage in rats.(ABSTRACT TRUNCATED AT 250 WORDS)