Prior Administration Of Naloxone Research Articles

Medial prefrontal cortex oxytocin-opioid receptors interaction in spatial memory processing in rats

Medial prefrontal cortex (mPFC), a forebrain structure, is involved in many brain functions such as learning and memory. In the present study, the effect of intra-mPFC microinjection of oxytocin, atosiban, morphine and naloxone was investigated on memory processing. Two guide cannulas were implanted into the right and left sides of the mPFC in ketamine and xylazine-anesthetized rats. To assess spatial memory function MWM test was performed by four training sessions of four trials. On day 5, a probe test was conducted after drugs microinjection. Significant differences were observed in learning activities during training days before microinjection of drugs. Intra-mPFC microinjections of oxytocin (5 and 10 ng/site) significantly increased memory related activities. This effect of oxytocin was inhibited by prior microinjection of atosiban (20 ng/site). On the other hand, morphine microinjection at doses of 5 and 10 μg/site into the mPFC significantly decreased memory related activities that were prevented by prior administration of naloxone (5 μg/site) and oxytocin (5 and 10 ng/site). In addition, intra-mPFC combined microinjections of low doses of oxytocin (2.5 ng/site) and naloxone (1 μg/site) improved memory function. By increasing the doses of oxytocin (5 ng/site) and naloxone (5 μg/site), a more documented improving effect was observed. These results showed that memory performance was impaired by activation of mPFC opioid receptors in rats. In addition, oxytocin in the mPFC improved memory function and prevented memory impairment-induced by morphine. Moreover, an interaction between oxytocin and opioid systems was also appeared in the present study.

Opioid overdose history and awareness of naloxone in patients seeking outpatient detoxification.

The goal of this study was to investigate whether patients were knowledgeable about naloxone, and whether they would accept overdose (OD) education and naloxone distribution (OEND), if available. This is a cross-sectional study to ascertain participants knowledge about OEND. A questionnaire was designed requesting information regarding age, gender, ethnicity, previous OD experience, type of substance(s) used, availability and use of naloxone for reversal, other treatment interventions utilized if witnessed OD, ways of seeking help for OD, knowledge about OEND, and willingness to accept OEND. Study was conducted at the ambulatory detoxification clinic of a tertiary healthcare institution. Consecutive 131 patients, who presented for primary treatment of opioid detoxification during their visits to the ambulatory detoxification clinic between a predefined timeline from October 2014 through February 2015, were invited to participate, and all 131 agreed to be included in the study. A total of 124 participants returned completed questionnaires (95 percent response rate.) RESULTS: Overall, 68 (52 percent) of the participants indicated that they would accept OEND. A logistic regression analysis showed that younger participants (95% CI: 0.9-1, p = 0.02) and those who identified as non-white (95% CI: 0-0.8, p = 0.01) had higher odds for accepting OEND. Furthermore, prior administration of naloxone was significantly associated with OEND acceptance (95% CI: 1.6-68.6, p = 0.01). Results indicate more than half of participants presenting for outpatient detoxification from opioids have had an OD or witnessed an OD. More than half of the participants were willing to accept OEND. This study provides evidence that patients starting their recovery are willing to accept naloxone.

Effects of intra-hippocampal microinjection of vitamin B12 on the orofacial pain and memory impairments induced by scopolamine and orofacial pain in rats

In the present study, we investigated the effects of microinjection of vitamin B12 into the hippocampus on the orofacial pain and memory impairments induced by scopolamine and orofacial pain. In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Orofacial pain was induced by subcutaneous injection of formalin (1.5%, 50μl) into the right vibrissa pad, and the durations of face rubbing were recorded at 3-min blocks for 45min. Morris water maze (MWM) was used for evaluation of learning and memory. Finally, locomotor activity was assessed using an open-field test. Vitamin B12 attenuated both phases of formalin-induced orofacial pain. Prior administration of naloxone and naloxonazine, but not naltrindole and nor-binaltorphimine, prevented this effect. Vitamin B12 and physostigmine decreased latency time as well as traveled distance in Morris water maze. In addition, these chemicals improved scopolamine-induced memory impairment. The memory impairment induced by orofacial pain was improved by vitamin B12 and physostigmine used alone. Naloxone prevented, whereas physostigmine enhanced the memory improving effect of vitamin B12 in the pain-induced memory impairment. All the above-mentioned chemicals did not alter locomotor activity. The results of the present study showed that at the level of the dorsal hippocampus, vitamin B12 modulated orofacial pain through a mu-opioid receptor mechanism. In addition, vitamin B12 contributed to hippocampal cholinergic system in processing of memory. Moreover, cholinergic and opioid systems may be involved in improving effect of vitamin B12 on pain-induced memory impairment.

Opioidergic, GABAergic and serotonergic neurotransmission in the dorsal raphe nucleus modulates tonic immobility in guinea pigs

Tonic immobility (TI) is an innate defensive behavior that can be elicited by physical restriction and postural inversion and is characterized by a profound and temporary state of akinesis. Our previous studies demonstrated that the stimulation of serotonin receptors in the dorsal raphe nucleus (DRN) appears to be biphasic during TI responses in guinea pigs (Cavia porcellus). Serotonin released by the DRN modulates behavioral responses and its release can occur through the action of different neurotransmitter systems, including the opioidergic and GABAergic systems. This study examines the role of opioidergic, GABAergic and serotonergic signaling in the DRN in TI defensive behavioral responses in guinea pigs. Microinjection of morphine (1.1nmol) or bicuculline (0.5nmol) into the DRN increased the duration of TI. The effect of morphine (1.1nmol) was antagonized by pretreatment with naloxone (0.7nmol), suggesting that the activation of μ opioid receptors in the DRN facilitates the TI response. By contrast, microinjection of muscimol (0.5nmol) into the DRN decreased the duration of TI. However, a dose of muscimol (0.26nmol) that alone did not affect TI, was sufficient to inhibit the effect of morphine (1.1nmol) on TI, indicating that GABAergic and enkephalinergic neurons interact in the DRN. Microinjection of alpha-methyl-5-HT (1.6nmol), a 5-HT2 agonist, into the DRN also increased TI. This effect was inhibited by the prior administration of naloxone (0.7nmol). Microinjection of 8-OH-DPAT (1.3nmol) also blocked the increase of TI promoted by morphine (1.1nmol). Our results indicate that the opioidergic, GABAergic and serotonergic systems in the DRN are important for modulation of defensive behavioral responses of TI. Therefore, we suggest that opioid inhibition of GABAergic neurons results in disinhibition of serotonergic neurons and this is the mechanism by which opioids could enhance TI. Conversely, a decrease in TI could occur through the activation of GABAergic interneurons.

Amisulpride‐Induced Seizurogenic Effect: A Potential Role of Opioid Receptor‐Linked Transduction Systems

This study was designed to investigate the role of opioid receptors, gamma-aminobutyric acid (GABA) receptors, mast cells and histamine receptors (H(1) subtype) in the seizurogenic effect of amisulpride on mice. A single injection of amisulpride (180 mg/kg) was employed to evaluate the seizurogenicity of the drug in mice. Seizures were assessed in terms of a composite seizure severity score (SSS), time of the onset of straub-like tail, onset of jerky movements of whole body, convulsions and death. Amisulpride administration (180 mg/kg) induced a significant pro-convulsant effect in mice as measured in terms of the SSS (21.12 ± 2.71) and a significant decrease in the time latency of the onset of straub-like tail (132.45 ± 12.31), jerky movements of whole body (153.28 ± 14.12), convulsions (184.97 ± 13.11) and death (100%). Moreover, prior administration of naloxone, cetrizine, sodium cromoglycate and gabapentin, respectively, attenuated this seizurogenic activity that amisulpride exerted on mice (p < 0.05). Therefore, it may be suggested that amisulpride exerts a seizurogenic effect on mice possibly via an opioid receptor activation-dependent release of histamine from the mast cells and a simultaneous inhibition of GABA release.

Tramadol-induced seizurogenic effect: a possible role of opioid-dependent histamine (H1) receptor activation-linked mechanism

The present study has been designed to investigate the role of opioid receptors, mast cells, and histamine receptors (H(1) subtype) in the seizurogenic effect of tramadol on pentylenetetrazole-treated mice. A single injection of pentylenetetrazole (80 mg kg(-1)) was used to elicit seizure activity in mice. Seizures were assessed in terms of the time latency of the onset of Straub-like tail, onset of jerky movements of whole body, convulsions, and death. Tramadol administration (50 mg kg (-1)) caused a marked increase in seizurogenic activity of pentylenetetrazole as measured in terms of a significant decrease in the time latency of the onset of Straub-like tail, jerky movements of whole body, convulsions, and death. Moreover, prior administration of naloxone (2 mg kg(-1)), fexofenadine (100 mg kg(-1)), cetrizine, sodium cromoglycate, and ketotifen (10 mg kg(-1)), respectively, attenuated the seizurogenic activity that tramadol exerted on pentylenetetrazole-treated mice. Therefore, it may be suggested that tramadol exerts a seizurogenic effect on mice via an H(1) receptor activation-linked pathway possibly through an opioid receptor-dependent release of histamine from the mast cells.

Tramadol‐Induced Seizurogenic Effect: A Possible Role of Opioid‐Dependent γ‐Aminobutyric Acid Inhibitory Pathway

The present study has been designed to pharmacologically investigate the role of opioid and gamma-aminobutyric acid receptors on the seizurogenic effect of tramadol. A single injection of pentylenetetrazole (80 mg/kg) was used to elicit seizure activity in mice. Seizures were assessed in terms of the time latency of the onset of Straub's tail phenomenon, onset of jerky movements of whole body, convulsions and death. Tramadol administration (50 mg/kg) caused a marked increase in seizurogenic activity of pentylenetetrazole as measured in terms of a significant decrease in the time latency of the onset of Straub's tail phenomenon, jerky movements of whole body, convulsions and death. Moreover, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, attenuated the seizurogenic activity that tramadol exerted on pentylenetetrazole-treated mice. Furthermore, prior administration of naloxone (2 mg/kg) and gabapentin (25 mg/kg), respectively, also attenuated the seizurogenic activity exerted by tramadol per se. Therefore, it is suggested that tramadol exerts a seizurogenic effect on mice possibly via an opioid-dependent gamma-aminobutyric acid inhibitory pathway.

Morphine reduces penile erection induced by the cannabinoid receptor antagonist SR 141617A in male rats: Role of paraventricular glutamic acid and nitric oxide

The effect of the opiate morphine, on penile erection induced by the cannabinoid CB1 receptor antagonist SR 141716A injected into the paraventricular nucleus of the hypothalamus and on the increase in the concentration of glutamic acid and of NO 2 − and NO 3 −, which occurs concomitantly in the paraventricular dialysate obtained by intracerebral microdialysis, was studied in male rats. Morphine (0.5, 1 and 5 μg), given into the paraventricular nucleus, reduced dose-dependently penile erection induced by SR 141716A (2 μg) injected into the paraventricular nucleus. The reduction of penile erection was parallel to a decrease of the concomitant glutamic acid and NO 2 − and NO 3 − increase that occurs in the paraventricular dialysate in these experimental conditions. Morphine effects on SR 141716A-induced penile erection, glutamic acid and NO 2 − increase were prevented by the prior administration of naloxone, an opioid receptor antagonist (5 μg) given into the paraventricular nucleus. The present results show that the activation of opioid receptors in the paraventricular nucleus impairs penile erection induced by SR 141716A, by reducing the increase in glutamic acid and in NO activity that occurs in this hypothalamic nucleus in these experimental conditions.

Additive antinociceptive effect of the combination of diazoxide, an activator of ATP-sensitive K + channels, and sodium nitroprusside and dibutyryl-cGMP

Using the rat paw pressure test, in which increased sensitivity is induced by intraplantar injection of prostaglandin E 2, we assessed the antinociceptive effect of the ATP-sensitive K + channel opener diazoxide and the large-conductance Ca 2+-activated K + channel opener NS-1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl) phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one) on the peripheral hyperalgesia induced by prostaglandin E 2. Diazoxide, administered locally into the right hindpaw (20, 38, 75, 150, 300 and 600 μg), elicited a dose-dependent antinociceptive effect on prostaglandin E 2-induced hyperalgesia (2 μg/paw). The effect of diazoxide at the dose of 300 μg/paw was shown to be local since it did not produce any effect when administered in the contralateral paw. The action of diazoxide (300 μg/paw) as an ATP-sensitive K + channel opener seems to be specific, since its effect was antagonized in a dose-dependent manner by glibenclamide (40, 80 and 160 μg/paw), a specific blocker of these channels, while tetraethylammonium (7.5, 15 and 30 μg/paw), dequalinium (12.5, 25 and 50 μg/paw) or charybdotoxin (0.5, 1 and 2 μg/paw), blockers of voltage-dependent K + channels and of small- and large-conductance Ca 2+-activated K + channels, respectively, were not able to abolish the antinociception induced by diazoxide. The peripheral antinociceptive effect of diazoxide was not prevented by prior administration of naloxone (12.5, 25 and 50 μg/paw), an opioid receptor antagonist, or methylene blue (75, 125 and 300 μg/paw), an agent that inhibits the activation of guanylate cyclase by nitric oxide. A low dose of diazoxide (20 μg/paw) administered together with a low dose of sodium nitroprusside (125 μg/paw) or dibutyryl cGMP (db-cGMP, 50 μg/paw) induced a marked antinociceptive effect similar to that observed when each drug was administered alone. NS1619 (75, 150 and 300 μg/paw), a specific opener of large-conductance Ca 2+-activated K + channels, had no antinociceptive action on prostaglandin E 2-induced hyperalgesia. This series of experiments provides evidence for a peripheral antinociceptive action of diazoxide and supports the suggestion that the activation of ATP-sensitive K + channels could be the mechanism by which sodium nitroprusside and db-cGMP induce peripheral antinociception, excluding the involvement of large-contuctance Ca 2+-activated K + channels in the process.

Morphine actions in the rat forebrain: role of protein kinase C

Acute administration of morphine induces expression of the immediate-early gene (IEG) c-Fos in dorsomedial striatum, portions of cerebral cortex, and in several midline-intralaminar thalamic nuclei, partly via a trans-synaptic mechanism that involves activation of glutamate receptors. Because activation of protein kinase C (PKC) may occur following the activation of glutamate receptors, we determined whether pharmacological inhibition of PKC would attenuate morphine-induced c-Fos expression, and whether acute administration of morphine would induce translocation of PKC. The selective PKC antagonist NPC 15437 given 30 min prior to morphine significantly decreased morphine-induced c-Fos expression in striatum and cingulate cortex, but not in centrolateral thalamus. In another experiment, rats were given an acute dose of morphine, and immunocytochemical analysis was performed for the βI and βII isoforms of PKC. Morphine induced a rapid and transient translocation of PKC βII, but not βI, from perinuclear spots to plasma membrane in numerous cortical and striatal neurons. Prior administration of naloxone blocked this response. Ultrastructural studies confirmed translocation from Golgi apparatus to plasma membrane 15 min after morphine injection. Double immunocytochemistry at the light microscopic level demonstrated co-localization of translocated PKC βII and c-Fos in some cortical neurons 90 min after morphine injection. These results support a role for PKC, especially PKC βII, in the rapid effects of morphine on the brain.

Excitatory effects of fentanyl upon the rat electroencephalogram and auditory-evoked potential responses during anaesthesia

Background and objective: Previous studies have shown existence of inconsistent data concerning the use of auditory-evoked potential (AEP) and electroencephalogram (EEG) changes to measure the depth of anaesthesia in regimens involving the use of opioids. The present studies characterize the effects of fentanyl on those responses in rats. Methods: The effects of a bolus of fentanyl (6-10 μg kg−1 intravenously) alone or following naloxone (100 μg kg−1 intravenously) were examined using brain responses in rats during light anaesthesia with either propofol (20-30 mg kg−1 h−1) or isoflurane (0.8%). Electrophysiological data were recorded using silver ball electrodes. The rats' tracheas were intubated and a femoral artery cannula was inserted to monitor blood pressure. Body temperature, respiratory and pulse rate, and pedal withdrawal data were also collected. Parameters measured before and following administration of naloxone and fentanyl or of fentanyl alone were compared using repeated-measures ANOVA. Results: Fentanyl significantly increased the latency of the major peak from the AEP during propofol and isoflurane anaesthesia (F = 13.2 and 13.5, respectively; P < 0.05) and the amplitude differential between two waveform complexes, and the second differential index (F = 28.3 and 57.2, respectively; P < 0.01). The spectral edge frequency and median frequency from the EEG tended to increase. These effects were abolished by the prior administration of naloxone. Conclusions: These excitatory effects were inconsistent with the classical concept of brain activity depression indicating a deepening of anaesthesia.

Opioid peptides and behavioral and physiological responses of dairy cows to social isolation in unfamiliar surroundings.

To test whether endogenous opioid peptides are involved in the behavioral and physiological responses of cattle to stress, 12 Holstein cows were either placed in social isolation in unfamiliar surroundings for 15 min or remained in their home stalls, either with or without naloxone treatment, following a Latin square design. Vocalizations (judged as high or low frequency), defecation/urination, and heart rate were recorded, latency to respond to local thermal stimulation of the leg by means of a laser was measured to detect pain sensitivity, and blood was sampled and assayed for cortisol concentrations. Naloxone in the home stall increased cortisol concentrations and tended to reduce response latencies to the laser but did not induce vocalization. Social isolation increased the incidence of high-frequency vocalization and of defecation/urination, heart rate, cortisol concentrations, and response latencies to the laser. Prior administration of naloxone increased the incidence of low-frequency vocalization in isolation, but it had no effect on heart rate or on responses to the laser and only limited effect on cortisol concentrations when the cows were isolated. Brief periods of social isolation in unfamiliar surroundings seem to be stressful to cows, as indicated by increased heart rate, hypothalamic-pituitary-adrenocortical axis activity, and vocalization. Isolation also reduces pain sensitivity, suggesting a stress-induced analgesia. However, we found no evidence that naloxone-sensitive opioid receptors were involved in these responses.

An endogenous opiate mechanism seems to be involved in stress-induced anhedonia

This study assessed the effect of an uncontrollable stressor on the preference for a palatable solution (sucrose 1%), and on the preference for a context associated with a single administration of d-amphetamine (3 mg/kg i.p.) by means of the conditioning place preference test. We also evaluated the effect of prior naloxone (2 mg/kg, i.p.) administration on the influence of this stressful stimulus in both tests. Animals previously submitted to a 120-min — but not 60-min — restraint period showed a selective reduction in the preference for sucrose intake as compared to unstressed animals. Similarly, an identical restraint exposure elicited a diminished preference for the place previously paired with amphetamine. Both stress-induced effects were blocked by prior naloxone administration. These data demonstrate that a highly aversive experience decreased the reinforcing efficacy of sucrose and amphetamine, suggesting that uncontrollable stress may lead to an impaired capacity to experience pleasure, which could resemble the anhedonia observed in clinical depression. Furthermore, an endogenous opiate mechanism activated by stress seems to be involved in stress-induced anhedonia since naloxone normalized the reduction of the rewarding induced by both reinforcers.

Opiate microinjections in the locus coeruleus area of the cat enhance slow wave sleep.

The effects on sleep/wakefulness states of morphine, morphiceptin (specific mu agonist), DPDPE (delta agonist) and U-50,488H (kappa agonist) microinjections in the Locus coeruleus area (LC) were studied in cats. Morphine (0.8-1.75 nmols in 50 nl of saline) and morphiceptin (1.75 nmols) in LC significantly increased the total time spent in slow wave sleep (SWS) and the mean duration of SWS episodes. Prior naloxone administration blocked the morphine hypnogenic effects. The total time spent in SWS was unaffected by delivery of equimolar doses of DPDPE or U-50,488H in LC; however, the mean duration of the SWS episodes increased significantly after U-50,488H microinjections in LC. Thus, when acting in the LC, opiates have a SWS-enhancing effect and this effect appears to be mediated by mu receptors, although kappa receptors may have a subsidiary action.

The antinociceptive potencies of oxycodone, noroxycodone and morphine after intracerebroventricular administration to rats

The antinociceptive activity of noroxycodone (NOR) was determined and its potency compared with that of oxycodone (OXY) and morphine (MOR) after intracerebroventricular (icv) administration to Sprague-Dawley rats. The antinociceptive potencies of OXY and NOR relative to MOR were 0.44 and 0.17, respectively. Administration of naloxone (55 nmol icv) abolished the antinociceptive response produced by the subsequent administration of OXY (227 nmol icv), indicating that the antinociceptive effects of OXY are mediated by opioid receptors. In addition, the same dose of naloxone (55 nmol icv) markedly reduced the antinociceptive effects of NOR (332 nmol icv) and MOR (93 nmol icv) indicating the involvement of opioid receptors in the antinociceptive activities of NOR and MOR. NOR, administered by the icv route, also produced excitatory effects throughout the antinociceptive dose range, the severity of which was reduced but not abolished by prior administration of naloxone (55 nmol icv). As excitatory effects have not been observed in patients receiving OXY, it is unlikely that NOR contributes to the analgesic activity of OXY administered systematically to humans.

Behavioural effects of deltorphins in rats

When given i.c.v. in rats deltorphins induced a syndrome of behavioural stimulation consisting of increased locomotion rearing and sniffing. The increased locomotor activity and rearing were dose-related over the range of 0.13 to 3.8 nmol/rat for [D-Ala 2]deltorphin II (DADELT II) and 1.04 to 20.8 nmol/rat for deltorphin. The δ-selective antagonist, naltrindole (10 mg/kg i.p.), completely abolished the behavioural stimulation induced by 1.3 nmol/rat of DADELT II and shifted the dose-response curve to the right, without decreasing the maximum effect. The μ-preferring antagonist, naloxone, was able to antagonize the DADELT II-induced locomotor activity but only at very high doses (10 and 20 mg/kg i.p.). The i.v. administration of a large dose (10 mg/kg) of the μ 1-selective antagonist, naloxonazine, did not affect the DADELT II response. At doses up to 38 nmol/rat, the i.c.v. injection of DADELT II never induced analgesia. At doses over 20.8 nmol/rat, deltorphin always induced spontaneous controlateral barrel rotations and circling, responses which were not blocked by prior administration of naloxone or haloperidol. In studies performed on the social behaviour of rats, i.c.v. administration of 0.38 nmol/rat of DADELT II was ineffective, while 1.3 nmol/rat increased the number of social contacts. Regression analysis showed that the increase in social contacts was a primary effect of the peptide, not correlated with the increased locomotor activity.

Stimulation-produced analgesia in the mouse: evidence for laterality of opioid mediation

The effect of naloxone on periaqueductal gray matter (PAG) stimulation-produced analgesia (SPA) was examined in pentobarbital anesthetized Swiss-Webster mice. Electrodes were placed either in dorsolateral or ventrolateral PAG, and SPA threshold was assessed using the hind paw-flick test (paw withdrawal from radiant heat). SPA threshold did not differ between dorsal and ventral PAG, and naloxone equally attenuated SPA from both areas. SPA threshold for the paw contralateral to the stimulation site was half that for the ipsilateral paw. Elevation of SPA threshold by naloxone was greater for the contralateral than ipsilateral paw. Exposure to analgesic neck pinch prior to SPA almost completely abolished the antinociceptive effect of contralateral PAG stimulation without affecting SPA on the ipsilateral paw. This effect of pinch was itself reversed by prior naloxone administration. We suggest that the substrate of opioid mediated SPA from PAG in the mouse has principally a contralateral organization.

Mu 1 opioid receptor involvement in maternal behavior

Previous studies have demonstrated that morphine inhibits the display of maternal behavior in lactating rats. Whether morphine exerts its actions specifically at the mu receptor has not yet been determined. The present study examined this possibility by evaluating whether naloxonazine, an irreversible and selective antagonist of the mu 1 opioid receptor subtype, is able to attenuate morphine's disruptive effect on maternal behavior in primiparous lactating rats. Experiment 1 compared the ability of naloxonazine (AZINE) and naloxone (NAL) to block the action of morphine (MOR) on maternal care. Virgin, Sprague-Dawley rats were mated in our colony and on day 3 postpartum (parturition, day 0) all rats received jugular catheters. On day 6 the mothers received one of the following treatments: MOR alone (10 mg/kg, SC, N=10); MOR (10 mg/kg, SC) 24 hr after AZINE pretreatment (10 mg/kg, IV, N=10); MOR (10 mg/kg, SC) 24 hr after NAL pretreatment (10 mg/kg, IV, N=8); or MOR (10 mg/kg, SC) immediately after NAL (0.5 mg/kg, SC, N=10). MOR alone completely disrupted maternal behavior (0% responded) which was blocked by prior NAL administration (100%). AZINE pretreatment 24 hr earlier partially blocked MOR disruption of MB (40% responded; significantly different from MOR alone). The response of rats pretreated 24 hr earlier with NAL did not differ from MOR alone. AZINE blocked MOR's effect on pup retrieval to an even greater degree (70% responded vs. 10% in MOR alone). Experiment 2 determined the ability of AZINE to interfere with varying doses of MOR on maternal behavior. A separate group of female rats was mated and catheterized on postpartum day 3. On day 5 half the rats received vehicle while the other half AZINE (10 mg/kg, IV). On day 6 all the rats received MOR (SC) at one of the following doses: 2.5, 5.0, 7.5, 10, or 12.5 mg/kg. MOR disrupted full maternal behavior and retrieval in a dose-dependent fashion. Pretreatment with AZINE significantly shifted MOR's full maternal behavior and retrieval dose response curves 1.5-fold and 1.4-fold to the right, respectively. These data indicate that opioid disruption of maternal behavior is mediated, in part, by the mu 1 opioid receptor system.

Effects of d-Ala 2-Met 5-enkephalinamide microinjections placed into the bed nucleus of the stria terminalis upon affective defense behavior in the cat

This study examined the effects of intracerebral injections of d-Ala 2-Met 5-enkephalinamide (DAME) upon hypothalamically eliited hissing behavior in the cat. The bed nucleus of the stria terminalis (BNST) was selected for investigation because of its anatomical connections with the medial hypothalamus, its relatively high concentrations of enkephalins and opiate receptors and its demonstrated ability to modulate hypothalamically elicited aggressive reactions in the cat. DAME microinjected into the BNST in 1.0 or 10.0 μg/0.5 μl quantities resulted in significant dose dependent increases in mean latencies for elicitation of the hissing response. Suppression of hissing following the 1.0 μg dose of DAME was selectively diminished by prior administration of naloxone. These findings suggest that the opiate receptors within the BNST play a role in the regulation of the hissing component of hypothalamically elicited affective defense behavior.

Cold swim stress-induced changes in the levels of opioid peptides in the rat CNS and peripheral tissues

Endogenous opioid peptides have been implicated in stress-induced analgesia and stress-induced feeding behavior. An earlier study from our laboratory showed that rats subjected to cold swim stress consumed significantly more food compared to controls [46]. The present study describes changes in the levels of various opioid peptides in the central nervous system and periphery due to cold swim stress. Male Sprague-Dawley rats were subjected to cold swim stress (1°C for 5 min), then sacrificed by decapitation; brain, pituitary, adrenals and plasma were collected. Tissue extracts were assayed for opioid peptides by RIA. Cold swim stress resulted in analgesia which could be blocked by prior administration of naloxone, as observed by a tail-flick latency test. Cold swim stress caused a 42% decrease in pituitary β-endorphin, but increased the level of this peptide in the hypothalamus and plasma by 36% and 337%, respectively. Dynorphin level decreased by 62% in the hypothalamus, but was not affected in the pituitary. Levels of Leu-enkephalin and Met-enkephalin decreased in the adrenal gland by 37% and 18%, respectively, but were not significantly affected in the CNS. These results indicate that cold swim stress has a differential effect on the level of CNS and peripheral opioid peptides, and that both central and peripheral opioid peptides may be important in stress-induced analgesia and feeding behavior.