Activation Of Endogenous Opioid System Research Articles

P-469 - Investigation of the functional activity of autonomic nervous system and endogenous opioid system in endogenomorphic depression

Introduction Investigation of the pathogenesis mechanisms in depression remains an actual task of modern psychiatry. Objectives The analysis of clinical-psychopathological characteristics, functional activity of autonomic nervous system and endogenous opioid system in endogenomorphic depression. The main group included 72 patients diagnosed with depressive episode. Methods Clinico- psychopathological, clinico-anamnestic, Hamilton Depression Rating Scale (HDRS-17), the analysis of heart rate variability (HRV) for evaluation of autonomic regulation. In 9 patients plasma levels of beta-endorphin were obtained. Patients were investigated 3 times - at baseline, and then during 2nd–3d and 4th–6th weeks of antidepressant therapy. Results The reduction of total HRV was observed at rest and in orthostatic test during evaluation of autonomic regulation in depressive patients. The hyperactivation of suprasegmental ergotropic systems was observed in depressive patients before treatment. In responders subgroup despite on positive dynamics of clinico-psychopathological and psychometric characteristics, in the 2nd–3d week of therapy increase in general HRV was observed, in the 4th–6th week parameters come back to baseline level. The balance of sympathetic, parasympathetic and suprasegmental parts of autonomic nervous system did not change. The plasma endorphin levels were rising to 2nd–3d treatment week, and come back to baseline level at the 4th–6th treatment week. Conclusion Obtained data confirm evidence that the therapeutic dynamics of depression is characterized by a faster reduction of clinical symptoms, whereas changes in functional activity of stress-realizing and stress-limiting mechanisms can be kept much longer. Acknowledgments This research is supported by grant provided by Russian Humanitarian Research Foundation project 11-06-00869а

Naloxone blocks ethanol-mediated appetitive conditioning and locomotor activation in adolescent rats

Age-related differences in ethanol sensitivity could put adolescents at risk for developing alcohol-related problems. Little information exists, however, about adolescent sensitivity to ethanol's appetitive effects and the neurobiological mechanisms underlying ethanol reinforcement during this developmental stage. The present study assessed the role of the opioid system in adolescent rats in an appetitive second-order schedule of ethanol reinforcement and ethanol-induced locomotor stimulation. On postnatal day 32 (PD32), animals were pretreated with the general opioid antagonist naloxone (0.0, 0.75, 1.50, or 2.5 mg/kg) and then given pairings of ethanol (0.0 or 2.0 g/kg, intragastrically) with intraoral pulses of water (conditioned stimulus 1 [CS 1], first-order conditioning phase). CS 1 delivery occurred 30–45 min after ethanol administration when the effect of ethanol was assumed to be appetitive. On PD33, adolescents were exposed to CS 1 (second-order conditioning phase) while in a chamber featuring distinctive exteroceptive cues (CS 2). Preference for CS 2 was then tested. Adolescents given CS 1–ethanol pairings exhibited greater preference for CS 2 than controls, indicating ethanol-mediated reinforcement, but only when not pretreated with naloxone. Blood alcohol levels during conditioning were not altered by naloxone. Experiment 2 revealed that ethanol-induced locomotor activation soon after administration, and naloxone dose-dependently suppressed this stimulating effect. The present study indicates that adolescent rats are sensitive to ethanol's reinforcing and locomotor-stimulating effects. Both effects of ethanol appear to be mediated by endogenous opioid system activation.

Region‐Specific Induction of FosB/ΔFosB by Voluntary Alcohol Intake: Effects of Naltrexone

ΔFosB is the best characterized transcription factor induced by chronic stimulation. Although previous studies have demonstrated that chronic passive ethanol exposure alters ΔFosB immunoreactivity (IR), the effect of chronic voluntary ethanol consumption on ΔFosB remains unknown. Furthermore, although previous studies have demonstrated that the opioid antagonist naltrexone reduces alcohol consumption in clinical and preclinical settings, the effect of naltrexone on FosB/ΔFosB has not been explored. Here, we examined the effects of chronic voluntary ethanol intake and naltrexone on FosB/ΔFosB IR in striatal region and prefrontal cortex, and the effect of naltrexone on voluntary ethanol intake. We utilized immunohistochemistry to define the changes in FosB/ΔFosB IR induced by chronic voluntary ethanol intake under a two-bottle intermittent access of 20% ethanol model and by systematic administration (intraperitoneal injection) of naltrexone in Sprague-Dawley rats. Chronic (15 drinking sessions in 35 days) voluntary ethanol intake robustly induces FosB/ΔFosB IR in nucleus accumbens core, dorsolateral striatum, and orbitofrontal cortex, but not in nucleus accumbens shell, dorsomedial striatum, and medial prefrontal cortex. Systemic administration of naltrexone for 6 days significantly reduced voluntary ethanol consumption and FosB/ΔFosB IR induced by chronic voluntary ethanol intake. Our results suggest that chronic voluntary ethanol intake induces FosB/ΔFosB IR in a subregion-specific manner which involves the activation of endogenous opioid system.

Effects of acute ethanol administration on methionine–enkephalin expression and release in regions of the rat brain

The dopaminergic mesolimbic system plays a key role in mediating the reinforcing properties of ethanol and other drugs of abuse. Ethanol reinforcement and high alcohol drinking behaviour have been suggested to involve the ethanol-induced activation of endogenous opioid systems. Ethanol may alter opioidergic transmission at different levels, including opioid peptide biosynthesis and release, as well as binding to opioid receptors. The aim of this work was to investigate the effects of different ethanol doses on methionine-enkephalin (Met-enk) release from the rat nucleus accumbens (NAcc). Ethanol effects were also studied on Met-enk content in the NAcc, prefrontal cortex (PFC) and caudate-putamen (CP). Met-enk release was studied by microdialysis in Wistar anesthetized rats and peptide concentrations were quantitated by radioimmunoassay. Ethanol was administered by intraperitoneal injection after a 2-h basal release period. Ethanol doses of 0.5, 1 and 2.5 g/kg induced a 2.7-, 4.9- and 3.4-fold increase in Met-enk release from the NAcc. However, ethanol responses followed different kinetics, with earliest effects observed with the highest ethanol dose. In comparison, a 2.5-fold increase in peptide release was produced by 100 mM KCl. Ethanol, at a dose of 2.5 g/kg, induced a significant 66.7% decrease in Met-enk content in the NAcc, as well as a 76.4% reduction in peptide levels in the CP. Lower ethanol doses did not alter Met-enk content in these regions. On the other hand, an ethanol dose of 0.5 g/kg produced a non-significant decrease in Met-enk levels in the PFC. Our results suggest that ethanol-induced changes in enkephalin expression and release in regions of the mesocorticolimbic and nigrostriatal pathways could be involved in ethanol central effects. Released enkephalins by ethanol may modulate the dopaminergic activity of mesolimbic neurons and play a critical role in ethanol reinforcement mechanisms.

Dysregulation of Regional Endogenous Opioid Function in Borderline Personality Disorder

Borderline personality disorder is characterized by a lack of effective regulation of emotional responses. The authors investigated the role of the endogenous opioid system and mu-opioid receptors in emotion regulation in borderline personality disorder. Mu-opioid receptor availability in vivo (nondisplaceable binding potential, or BP(ND)) was measured with positron emission tomography and the selective radiotracer [(11)C]carfentanil during neutral and sustained sadness states in 18 unmedicated female patients with borderline personality disorder and 14 healthy female comparison subjects. Patients showed greater regional mu-opioid BP(ND) than did comparison subjects at baseline (neutral state) bilaterally in the orbitofrontal cortex, caudate, and nucleus accumbens and in the left amygdala, but lower BP(ND) in the posterior thalamus. Sadness induction was associated with greater reductions in BP(ND) (endogenous opioid system activation) in the patient group than in the comparison group in the pregenual anterior cingulate, left orbitofrontal cortex, left ventral pallidum, left amygdala, and left inferior temporal cortex. Patients showed evidence of endogenous opioid system deactivation in the left nucleus accumbens, the hypothalamus, and the right hippocampus/parahippocampus relative to comparison subjects. Correlations of baseline measures with the Dissociative Experiences Scale and endogenous opioid system activation with the Barratt Impulsiveness Scale did not remain significant after correction for multiple comparisons. Differences exist between patients with borderline personality disorder and comparison subjects in baseline in vivo mu-opioid receptor concentrations and in the endogenous opioid system response to a negative emotional challenge that can be related to some of the clinical characteristics of patients with borderline personality disorder. The regional network involved is implicated in the representation and regulation of emotion and stress responses.

The Psychoanalysis of a Man with Heroin Dependence: Implications for Neurobiological Theories of Attachment and Drug Craving

Psychoanalytic treatment of a man with heroin dependence is described. The treatment had two phases. In the first, the patient’s experience that heroin use gave him pleasure was tempered by increasing awareness that using heroin was making him depressed, caused a panic attack, threatened his relationship with his girlfriend because she was becoming addicted, and undercut his ability to direct his company. He stopped using. The second phase of the treatment featured annihilation anxiety, which was experienced by the patient with the analyst. This transference was ameliorated by interpretation of early experiences of abandonment and then by an enactment where the patient insisted on controlling the degree of contact with the analyst. Having succeeded in regulating closeness to the analyst in this aggressive manner, the patient began to behave this way in other relationships. The use of opioids to regulate attachment, and the activation of endogenous opioid systems by human contact, is discussed as a likely factor underlying the outcome of the analysis. The fact that the patient craved opioids and had drug dreams for them, and yet was able to use alcohol and marijuana recreationally, is discussed with reference to the ventral tegmental dopaminergic SEEKING system.

Opioid receptor imaging in man

The existence of opioid receptors (OR) had long been suspected, but their demonstration in nervous tissue and the discovery of their natural ligands did not come until the 1970’s. By 1985, the study of brain OR was possible in vivo using Positron Emission Tomography (PET), thanks to technical advances in imaging and radiochemistry. Since then, multiple PET studies contributed to clarify the physiology and pathology of human endogenous opioid system in several conditions and pathologies. Thus, activation studies in tonic experimental pain have demonstrated opioid system activation in multiple opioid receptor bearing sites such as the amygdala, the ventrolateral thalamus, the insular cortex and hypothalamus, the anterior cingulate gyrus and the prefrontal cortex. Such activation is negatively correlated with the intensity of pain perception. Activation studies have also demonstrated sex-dependent and COMT (cathecol-O-methyltransferase)-dependent differences in the magnitude and direction of the activation of endogenous opioid systems. Endogenous opioid secretion is very likely to occur as a reaction to acute or chronic nociceptive pain, and PET studies have demonstrated a decrease in the binding of the exogenous ligand in patients suffering pain secondary to chronic inflammatory conditions like rheumatoid arthritis. In neuropathic pain (NP), endogenous reactive opioid secretion is also very likely as a global reaction to pain, but there are differences between central and peripheral causes of NP. Loss or inactivation of OR in the hemisphere containing the causal lesion (contralateral to clinical pain) has been demonstrated in central post-stroke pain, while no such lateralised loss seems to exists in peripheral NP. Difference in OR distribution abnormalities between peripheral and central types of NP might explain in part their differential response to exogenous opioids, which is better in peripheral NP. Motor Cortex Stimulation (MCS) for pain relief appears to induce endogenous opioid secretion in key areas of the endogenous opioid system, thus putatively explaining part of the mechanisms of action of this procedure. All these studies incite to the development of future investigations in order to clarify the role of the opioid system in various disorders of the nervous system, and, in chronic pain syndromes, to study the predictive potential of OR distribution abnormalities in the development of NP and in the clinical response of NP to aggressive therapeutic alternatives, like MCS.

Positron Emission Tomography Measures of Endogenous Opioid Neurotransmission and Impulsiveness Traits in Humans

The endogenous opioid system and opioid mu receptors (mu-receptors) are known to interface environmental events, positive (eg, relevant emotional stimuli) and negative (eg, stressors), with pertinent behavioral responses and to regulate motivated behavior. To examine the degree to which trait impulsiveness (the tendency to act on cravings and urges rather than to delay gratification) is predicted by baseline mu-receptor availability or the response of this system to a standardized, experientially matched stressor. Nineteen young healthy male volunteers completed a personality questionnaire (NEO Personality Inventory, Revised) and underwent positron emission tomography scans with the mu-receptor-selective radiotracer carfentanil labeled with carbon 11. Measures of receptor concentrations were obtained at rest and during receipt of an experimentally maintained pain stressor of matched intensity between subjects. Baseline receptor levels and stress-induced activation of mu-opioid system neurotransmission compared between subjects scoring above and below the population median on the NEO Personality Inventory, Revised, impulsiveness subscale and the orthogonal dimension (deliberation) expected to interact with it. High impulsiveness and low deliberation scores were associated with significantly higher regional mu-receptor concentrations and greater stress-induced endogenous opioid system activation. Effects were obtained in the prefrontal and orbitofrontal cortices, anterior cingulate, thalamus, nucleus accumbens, and basolateral amygdala-all regions involved in motivated behavior and the effects of drugs of abuse. Availability of the mu-receptor and the magnitude of stress-induced endogenous opioid activation in these regions accounted for 17% to 49% of the variance in these personality traits. Individual differences in the function of the endogenous mu-receptor system predict personality traits that confer vulnerability to or resiliency against risky behaviors such as the predisposition to develop substance use disorders. These personality traits are also implicated in psychopathological states (eg, personality disorders) in which variations in the function of this neurotransmitter system also may play a role.

Importance of Placebo Effect in Cough Clinical Trials

Cough is a unique symptom because, unlike sneeze and other symptoms, it can be under voluntary control and this complicates clinical trials on cough medicines. All over-the-counter cough medicines (OTC) are very effective treatments because of their placebo effect. The placebo effect is enhanced by expectancy related to advertising, brand, packaging, and formulation. This placebo effect creates a problem for the conduct of clinical trials on OTC cough medicines that attempt to demonstrate the efficacy of a pharmacological agent above that of any placebo effect. Up to 85% of the efficacy of some cough medicines can be attributed to a placebo effect. The placebo effect apparent in clinical trials consists of several components: natural recovery, regression of cough response toward mean, demulcent effect, effect of sweetness, voluntary control, and effects related to expectancy and meaning of the treatment. The placebo effect has been studied most in the pain model, and placebo analgesia is reported to depend on the activation of endogenous opioid systems in the brain; this model may be applicable to cough. A balanced placebo design may help to control for the placebo effect, but this trial design may not be acceptable due to deception of patients. The placebo effect in clinical trials may be controlled by use of a crossover design, where feasible, and the changes in the magnitude of the placebo effect in this study design are discussed.

Evidence of increased non-verbal behavioral signs of pain in adults with neurodevelopmental disorders and chronic self-injury

The role of pain in relation to self-injurious behavior (SIB) among individuals with intellectual disabilities is not well understood. Some models of SIB are based on altered endogenous opioid system activity which could result in elevated pain thresholds. In this study, non-verbal behavioral signs indicative of pain as measured by the Non-Communicating Children's Pain Checklist (NCCPC) were compared between matched individuals with ( N = 35) and without ( N = 35) chronic self-injurious behavior (SIB) and neurodevelopmental disorders. Significant ( p < .01) between group differences (SIB Group > Control Group) were found for the NCCPC Total Score, and for the Vocal, Social/Personality, and Eating/Sleeping subscales of the NCCPC. These results are not consistent with models of SIB in which pain sensitivity is assumed to be attenuated because of opioid system activity and are suggestive of intact and possibly amplified pain expression.

Role of nitric oxide (NO) in the hyperbaric oxygen (HBO2)‐induced long‐lasting activation of endogenous opioid systems in mice

Exposure to HBO2 causes a long‐lasting analgesic effect in patients with chronic pain (Kiralp et al., J. Int. Med. Res. 32:258–262, 2004). To determine the duration of antinociceptive effect in an animal model following exposure to HBO2, male NIH Swiss mice (20–30 g) were exposed to HBO2 at 2.5 ATA for 60 min then removed to room air for varying durations of time (5, 15, 30, 60, 90, 120, 150 or 180 min) prior to antinociceptive testing. The antinociceptive effect of HBO2 remained robust up to 90 min but subsided by 120 min. By contrast, mice exposed to 70% nitrous oxide for 60 min exhibited antinociception only through the 15‐min interval. When administered prior to HBO2 exposure, both naltrexone and L‐NAME antagonized the antinociceptive effect seen 90 min later. When administered prior to antinociceptive testing, naltrexone but not L‐NAME antagonized the antinociceptive effect of HBO2. These results suggest that there is a critical role of NO during HBO2 exposure that is required for expression of the opioid‐mediated antinociceptive effect 90 min later. (Supported in part by NIH Grant GM‐77153, ASPET SURF Program and the Chico Hyperbaric Center).

Placebo effects on human μ-opioid activity during pain

Placebo-induced expectancies have been shown to decrease pain in a manner reversible by opioid antagonists, but little is known about the central brain mechanisms of opioid release during placebo treatment. This study examined placebo effects in pain by using positron-emission tomography with [(11)C]carfentanil, which measures regional mu-opioid receptor availability in vivo. Noxious thermal stimulation was applied at the same temperature for placebo and control conditions. Placebo treatment affected endogenous opioid activity in a number of predicted mu-opioid receptor-rich regions that play central roles in pain and affect, including periaqueductal gray and nearby dorsal raphe and nucleus cuneiformis, amygdala, orbitofrontal cortex, insula, rostral anterior cingulate, and lateral prefrontal cortex. These regions appeared to be subdivided into two sets, one showing placebo-induced opioid activation specific to noxious heat and the other showing placebo-induced opioid reduction during warm stimulation in anticipation of pain. These findings suggest that a mechanism of placebo analgesia is the potentiation of endogenous opioid responses to noxious stimuli. Opioid activity in many of these regions was correlated with placebo effects in reported pain. Connectivity analyses on individual differences in endogenous opioid system activity revealed that placebo treatment increased functional connectivity between the periaqueductal gray and rostral anterior cingulate, as hypothesized a priori, and also increased connectivity among a number of limbic and prefrontal regions, suggesting increased functional integration of opioid responses. Overall, the results suggest that endogenous opioid release in core affective brain regions is an integral part of the mechanism whereby expectancies regulate affective and nociceptive circuits.

Beta-adrenergic and Opioidergic Modulation of Cortisol Secretion in Response to Acute Stress

The modulatory action of beta-adrenergic and opioidergic pathways on the cortisol response to acute stressors was investigated using gonadectomized male miniature pigs. Three types of stressors, nose-snare (NS, for 2 min. each on four occasions at 30 min. intervals); high intensity cracker blasts (CB, two blasts at 3 min intervals) and ACTH (1 i.u./kg BW, i.v.) were utilized 80 min after start of blood sampling. For assessment of cortisol blood samples were withdrawn every 20 min for 200 min. In addition, animals received i.v. injections of either isoproterenol (5 microg/ kg) or propranolol (0.5 mg/kg) or naloxone (1 mg/kg) 15 or 30 min before the application of stressor. Stress of repeated NS application as well as ACTH treatment, resulted in immediate secretion of cortisol (p<0.001). Blast of crackers resulted in a transient increase in cortisol (p<0.05). Isoproterenol stimulated the basal cortisol secretion for about 20 min in unstressed pigs (p <0.01) but propranolol had no effects. Isoproterenol also reinforced (p<0.05) the effect of CB, but had no effect on the cortisol response to nose-snare. In contrast, response to NS was reduced (p=0.02) by propranolol. Neither isoproterenol nor propranolol altered the cortisol response to ACTH application. Pretreatment with naloxone significantly increased the cortisol response to NS (p<0.01) and to CB (p<0.01), but had no effects on ACTH-induced cortisol release. In conclusion, the beta-adrenergic involvement is evident in the cortisol response to acute stress of nose-snare. Furthermore, the results indicate that activation of endogenous opioid system during stress mitigates adrenal response.

Microinjection of Naltrexone into the Central, but not the Basolateral, Amygdala Blocks the Anxiolytic Effects of Diazepam in the Plus Maze

The amygdala is involved in behavioral and physiological responses to fear, and the anxiolytic properties of several drugs are localized to this region. Activation of endogenous opioid systems is known to occur in response to stress and a growing body of literature suggests that opioid systems regulate the properties of anxiolytic drugs. These experiments sought to elucidate the role of opioid receptors in the central (CeA) and basolateral (BLA) nuclei of the amygdala in regulating the anxiolytic properties of ethanol and diazepam. Male rats fitted with cannula received bilateral microinjections of the nonselective opioid receptor antagonist naltrexone (NAL) immediately followed by systemic delivery of either ethanol (1 g/kg) or diazepam (2 mg/kg) in the elevated plus maze. Both diazepam and ethanol decreased anxiety-like behavior. Delivery of NAL into the CeA blocked the anxiolytic properties of diazepam. Delivery of NAL into the BLA slightly increased open arm avoidance, but had no effect on the anxiolytic properties of diazepam. Microinjection of NAL into either nucleus failed to block the effects of ethanol. These results were specific to the anxiolytic properties of diazepam, since baseline behaviors were unaffected by microinjection of NAL. Microinjection of lidocaine produced results distinct from NAL and failed to block the anxiolytic actions of diazepam. These studies indicate distinct roles for opioid receptor systems in the CeA and BLA in regulating the anxiolytic properties of diazepam in the elevated plus maze. Further, opioid receptor systems in the CeA and BLA do not regulate the anxiolytic properties of ethanol in this test.

Motivational Effects of Cannabinoids and Opioids on Food Reinforcement Depend on Simultaneous Activation of Cannabinoid and Opioid Systems

Strong functional interactions exist between endogenous cannabinoid and opioid systems. Here, we investigated whether cannabinoid-opioid interactions modulate motivational effects of food reinforcement. In rats responding for food under a progressive-ratio schedule, the maximal effort (break point) expended to obtain 45 mg pellets depended on the level of food deprivation, with free-feeding reducing break points and food-deprivation increasing break points. Delta-9-tetrahydrocannabinol (THC; 0.3-5.6 mg/kg intrapeitoneally (i.p.)) and morphine (1-10 mg/kg i.p.) dose-dependently increased break points for food reinforcement, while the cannabinoid CB1 receptor antagonist rimonabant (SR-141716A; 0.3-3 mg/kg i.p.) and the preferential mu-opioid receptor antagonist naloxone (0.3-3 mg/kg i.p.) dose-dependently decreased break points. THC and morphine only increased break points when food was delivered during testing, suggesting that these treatments directly influenced reinforcing effects of food, rather than increasing behavior in a nonspecific manner. Effects of THC were blocked by rimonabant and effects of morphine were blocked by naloxone, demonstrating that THC's effects depended on cannabinoid CB1 receptor activation and morphine's effects depended on opioid-receptor activation. Furthermore, THC's effects were blocked by naloxone and morphine's effects were blocked by rimonabant, demonstrating that mu-opioid receptors were involved in the effects of THC and cannabinoid CB1 receptors were involved in the effects of morphine on food-reinforced behavior. Thus, activation of both endogenous cannabinoid and opioid systems appears to jointly facilitate motivational effects of food measured under progressive-ratio schedules of reinforcement and this facilitatory modulation appears to critically depend on interactions between these two systems. These findings support the proposed therapeutic utility of cannabinoid agonists and antagonists in eating disorders.

Alcohol Withdrawal and Conditioning

This review contains the proceedings from a symposium held at the RSA conference in 2003 on "Alcohol Withdrawal and Conditioning." The presentations covered a range of interactions between conditioning and alcohol withdrawal, in both animal behavior and the clinic. Dr. D.N. Stephens first described his studies exploring the consequences of alcohol dependence and repeated experience of withdrawal on the conditioning process. His data suggested that repeated withdrawal from moderate alcohol intake impairs amygdala-dependent mechanisms for learning about aversive events. Dr. H. Becker then detailed studies examining the consequences of repeated ethanol withdrawal experience on subsequent ethanol drinking behavior in mice, and conditions in which motivational properties of odor cues that are associated with different phases of ethanol withdrawal influence such relapse behavior. The data suggested that cues associated with acute withdrawal or "recovery" from withdrawal may serve as modulating factors in influencing subsequent ethanol drinking behavior, and that the timing of the cues determines their consequences. Dr. F. Weiss described recent findings from animal models of relapse that suggested the efficacy of alcohol-associated contextual stimuli in eliciting alcohol-seeking behavior resembles the endurance of conditioned cue reactivity and cue-induced cocaine craving in humans. The interactive effects of stress and ethanol-related environmental stimuli were found to be dependent on concurrent activation of endogenous opioid and corticotropin-releasing factor systems. Conditioning factors (i.e., exposure to drug-associated stimuli) and stress could therefore interact to augment vulnerability to relapse. Dr. C. Drummond then addressed the clinical aspects of conditioning during alcohol withdrawal and described studies showing exposure of alcoholics to alcohol-related cues elicited greater subjective and physiological responses than exposure to neutral cues. The former responsivity showed a relationship with a measure of motivation to drink alcohol. Finally, Dr. C. Cunningham provided a summary of the concepts involved in the presentations and discussed the conditioning processes that affect behavior during and after alcohol withdrawal.

Stress Enhancement of Craving During Sobriety: A Risk for Relapse

This report of the proceedings of a symposium presented at the 2004 Research Society on Alcoholism Meeting provides evidence linking stress during sobriety to craving that increases the risk for relapse. The initial presentation by Rajita Sinha summarized clinical evidence for the hypothesis that there is an increased sensitivity to stress-induced craving in alcoholics. During early abstinence, alcoholics who were confronted with stressful circumstances showed increased susceptibility for relapse. George Breese presented data demonstrating that stress could substitute for repeated withdrawals from chronic ethanol to induce anxiety-like behavior. This persistent adaptive change induced by multiple withdrawals allowed stress to induce an anxiety-like response that was absent in animals that were not previously exposed to chronic ethanol. Subsequently, Amanda Roberts reviewed evidence that increased drinking induced by stress was dependent on corticotropin-releasing factor (CRF). In addition, rats that were stressed during protracted abstinence exhibited anxiety-like behavior that was also dependent on CRF. Christopher Dayas indicated that stress increases the reinstatement of an alcohol-related cue. Moreover, this effect was enhanced by previous alcohol dependence. These interactive effects between stress and alcohol-related environmental stimuli depended on concurrent activation of endogenous opioid and CRF systems. A.D. Lê covered information that indicated that stress facilitated reinstatement to alcohol responding and summarized the influence of multiple deprivations on this interaction. David Overstreet provided evidence that restraint stress during repeated alcohol deprivations increases voluntary drinking in alcohol-preferring (P) rats that results in withdrawal-induced anxiety that is not observed in the absence of stress. Testing of drugs on the stress-induced voluntary drinking implicated serotonin and CRF involvement in the sensitized response. Collectively, the presentations provided convincing support for an involvement of stress in the cause of relapse and continuing alcohol abuse and suggested novel pharmacological approaches for treating relapse induced by stress.

Evidence for changes in brain enkephalin contents associated to male rat sexual activity

Indirect evidence suggests that ejaculation might activate endogenous opioid systems, which exert an inhibitory influence on male rat sexual behaviour. The objective of the present study was to search for putative long-term changes in the contents of immunoreactive (IR) Met-enkephalin (IR-Met), Leu-enkephalin (IR-Leu) and opioid octapeptide Met–Arg 6–Gly 7–Leu 8 (IR-Oct) in specific brain areas, after the execution of different amounts of sexual activity. Additionally, basal contents of these enkephalins were compared between sexually active (SA) and persistent sexually inactive (SI) rats. Immunoreactivity to enkephalins was determined by radioimmunoanalysis, in the frontal cortex, the hypothalamus and midbrain of SA and SI rats, as well as 24 or 48 h after males had one ejaculation or copulated to exhaustion. Twenty-four hours after sexual activity, there was a generalised increase in enkephalin contents that returned to control values at the 48 h measurement in all brain areas, but the hypothalamus, where IR-Met and IR-Oct remained elevated. No differences in the magnitude of the changes were found between rats that ejaculated once and sexually satiated males. IR-Oct concentration in the hypothalamus of SI rats appeared significantly higher than in SA animals, with no differences in IR-Met and IR-Leu. Results give direct evidence of the activation of endogenous opioid systems by male rat sexual activity. The occurrence of long lasting increases in the contents of IR-Met and IR-Oct in the hypothalamus of rats that copulated was detected. Finally, an intrinsically elevated octapeptide concentration in the hypothalamus of SI rats was found.

Antidepressant-type effect of the NK3 tachykinin receptor agonist aminosenktide in mouse lines differing in endogenous opioid system activity

The influence of the tachykinin NK3 receptor agonist, aminosenktide on the immobility in the forced swimming test was studied in mouse lines selectively bred for divergent magnitudes of stress-induced analgesia. The high analgesia (HA) line is known to display enhanced, and the low analgesia (LA) line displays reduced activity of the opioid system. Aminosenktide at doses of 125 μg/kg or 250 μg/kg intraperitoneally (IP) reduced, in naltrexone-reversible manner, the immobility more of opioid receptor-dense HA than of unselected mice, but was ineffective in the opioid receptor-deficient LA line. The effect of aminosenktide was quite similar to the antiimmobility action of desipramine (10 mg/kg IP), a prototypic antidepressant agent. None of the compounds increased animals’ locomotion as found with an open field test; therefore their antiimmobility effect cannot be attributed to a change in general motility. The results claim that aminosenktide causes an antidepressant effect, and endogenous opioids are involved in this process.

Differential behavioral effects of peripheral and systemic morphine and naloxone in a rat model of repeated acute inflammation.

It has been reported that opioid antinociceptive effects are enhanced in animal models of inflammation, but it remains unclear whether this sensitization to morphine is related to predominant central or peripheral increased effects. The authors compared the behavioral effects of intraplantar and intravenous morphine and naloxone in a rat model of repeated acute carrageenan-induced inflammation in which enhanced responses to noxious stimuli result from sensitization in peripheral tissues or central sensitization. The antinociceptive effects of intraplantar morphine (50, 75, 100, 150, and 200 microg), intravenous morphine (0.3, 0.6, and 1 mg/kg), and the pronociceptive effects of intraplantar naloxone methiodide (150 microg) and intravenous naloxone (1 mg/kg) against noxious pressure (vocalization thresholds to paw pressure) in rats were assessed 3 h after one or two carrageenan plantar injections performed 7 days apart. After the first carrageenan injection, intraplantar and intravenous morphine produced significant increase of vocalization thresholds to paw pressure in inflamed but not in noninflamed paws. After the second carrageenan injection, the antinociceptive effects of intraplantar morphine were significantly reduced compared with those obtained after the first carrageenan injection, whereas effects of intravenous morphine were significantly enhanced and present in both hind paws. Intravenous naloxone demonstrated similar pronociceptive patterns after the first and second carrageenan injection. Intraplantar naloxone methiodide produced pronociceptive effects in inflamed hind paw that were significantly enhanced after the second carrageenan injection. When inflammation is enhanced by recurrent stimulations, the antinociceptive effects of systemic morphine are enhanced. This increase is more likely related to central than peripheral sites of action, beyond endogenous opioid system activation.