Mianserin attenuates naloxone-precipitated withdrawal signs in rats acutely or chronically dependent upon morphine

The effects of the atypical antidepressant and serotonin antagonist mianserin on the expression of opiate withdrawal was examined using an acute and a chronic model of morphine dependence. In the first experiment, rats, trained to perform a food-reinforced, autoshaped lever touch response, were injected with naloxone (5 mg/kg) 4 hr after treatment with a single moderate dose of morphine (15 mg/kg). Mianserin (0.25, 1.0 and 2.5 mg/kg) attenuated the naloxone-induced suppression of autoshaped responding. Colonic temperatures were also monitored. Morphine treatment resulted in significant hyperthermia, while precipitation of withdrawal by naloxone produced hypothermia. Mianserin also attenuated the naloxone-induced hypothermia. In the second experiment, rats were implanted s.c. with a single 75-mg morphine or placebo pellet. Withdrawal was precipitated with naloxone (5 mg/kg) 24, 48 and 120 hr post implantation. Mianserin (2.5 mg/kg) blocked or attenuated signs of withdrawal precipitated by naloxone. Naloxone-precipitated weight loss was also attenuated 48 and 120 hr post implantation. At 120 hr post implantation, rats were decapitated 1 hr after the administration of naloxone and trunk blood was collected. Mianserin did not block the naloxone-induced rise in plasma corticosterone levels. Thus, several signs of withdrawal (e.g., behavioral effects, weight loss and hypothermia) seem to involve serotonergic mediation and can be blocked by mianserin, while others (e.g., rise in plasma corticosterone), which may be unaffected by mianserin, may be a reflection of a compensatory response to withdrawal stress, rather than a mediator of maladaptive consequences of withdrawal that are not mediated by serotonin.     

Delayed activation of tuberoinfundibular dopamine neurons and suppression of prolactin secretion in the rat after morphine administration

The effect of morphine administration on the subsequent stimulation of prolactin (PRL) secretion and the release of dopamine from tuberoinfundibular neurons was examined in this study. The administration of morphine (15 mg/kg s.c.) resulted 4 hr later in suppressed serum PRL concentrations. In addition, the increase in serum PRL concentrations induced by restraint stress was attenuated greatly in rats treated 4 hr earlier with morphine. The morphine-induced attenuation of the PRL response to restraint stress was time-dependent and dose-related. The suppressive effect of morphine on PRL secretion was observed 3 to 6 hr after its administration and at doses of 10 to 20 mg/kg. A single injection of morphine also resulted 4 hr later in an attenuation of the PRL response to a second injection of morphine (7.5 mg/kg); however, the increase in serum PRL concentration produced by alpha-methyltyrosine (250 mg/kg) was unaltered by prior morphine administration. The suppressive effect of morphine on PRL secretion was not observed in rats treated with the opiate antagonist naloxone (2.5 mg/kg). Associated with the delayed suppressive effect of morphine on serum PRL concentrations was a delayed increase in the concentration of dopamine in hypophysial portal plasma and an increase in the turnover of dopamine in the median eminence. The morphine-induced stimulation of the release of dopamine into hypophyseal portal blood was attenuated significantly in animals treated with naltrexone (1 mg/kg). It is concluded that morphine exerts a biphasic effect on both the secretion of PRL and the release of dopamine from tuberoinfundibular neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

和厚朴酚与厚朴酚在缓解大鼠吗啡戒断反应中对β-内啡肽的影响

背景现代药理证实和厚朴酚与厚朴酚具有中枢抑制作用和肌肉松弛作用,且有报道证实其可缓解动物吗啡依赖戒断症状.目的探讨和厚朴酚与厚朴酚在缓解吗啡戒断反应中对β-内啡肽的影响.设计随机对照实验.单位湖北民族学院医学院药理学教研室.对象实验于2003-04-13/29进行,取成年雄性SD大鼠100只,其中30只大鼠作为对照组随机分成生理盐水组、和厚朴酚组和厚朴酚组各10只,另外70只大鼠作为吗啡依赖组,随机分成生理盐水组,和厚朴酚5,40,80mg/kg组与厚朴酚5,40,80 mg/kg组7组,各10只.方法对照组中3个亚组分别腹腔注射生理盐水0.2 mL、和厚朴酚与厚朴酚各80 mg/kg.吗啡依赖组大鼠逐日增量皮下注射吗啡6 d,建立急性吗啡依赖大鼠及吗啡自然戒断模型,在第6天900最后一次给吗啡后,1030腹腔注射给药,生理盐水组给予生理盐水0.2 mL,其他6组分别给予和厚朴酚、厚朴酚各5,40和80 mg/kg.于1100分别观察吗啡依赖组每只大鼠1 h内各项自然戒断症状.主要观察指标①各组大鼠脑脊液中β-内啡肽水平.②比较吗啡依赖组中7个亚组大鼠自然戒断症状评分.结果①脑脊液中β-内啡肽水平对照组中和厚朴酚与厚朴酚组显著高于生理盐水组(P＜0.01),而且和厚朴酚强于厚朴酚(P＜0.05).吗啡依赖+生理盐水组明显低于对照+生理盐水组(P＜0.01).吗啡依赖组中和厚朴酚与厚朴酚5,40,80 mg/kg组均高于生理盐水组(P＜0.01),而且呈量效关系.②吗啡依赖组大鼠自然戒断症状评分和厚朴酚与厚朴酚各剂量组湿狗样抖动、舔阴,逃避症状得分均低于生理盐水组(P＜0.05,0.01),且剂量越大效果越显著;和厚朴酚与厚朴酚40,80 mg/kg组咬牙、扭体及体质量丢失显著低于生理盐水组(P＜0.01).结论和厚朴酚与厚朴酚可明显抑制吗啡戒断反应,且抑制效应呈量效关系,这一抑制效应与脑内β-内啡肽的增加有关.这种效应对吗啡依赖大鼠和厚朴酚与厚朴酚相当,对正常大鼠和厚朴酚强于厚朴酚.     

Precipitation of abstinence-like syndrome in morphine-dependent mice by pargyline.

In mice rendered morphine-dependent by pellet implantation for 3 days, the administration of pargyline 6 hours after pellet removal intensified narcotic abstinence behavior, particularly the narcotic withdrawal jumping response. Pargyline, 75 mg/kg i.p., caused a 6- to 9-fold increase in the incidence of jumping in mice withdrawing from morphine 6 hours after removal of the pellet, whereas this effect was not observed: 1) 1 hour after the injection of pargyline or 2) in animals still implanted with the morphine pellet. The median effective dose (ED50) of pargyline required to elicit withdrawal jumping in mice implanted with morphine decreased with increasing physical dependence. The ED50 for 72 hours was about one-sixth that after 24 hours of implantation. Additionally, pargyline potentiated naloxone-precipitated withdrawal jumping as evidenced by a reduction of the naloxone ED50 by approximately one-half. Administration of other monoamine oxidase inhibitors such as pheniprazine, iproiazid or tranylcypromine failed to alter the indicence of jumping in dependent mice undergoind abrupt morphine with drawal. Further, dopamine receptor stimulation by amphetamine, pheniprazine or amantadine antagonized the pargyline-induced jumping response. These data suggest that the increased incidence of withdrawal jumping observed after pargyline in morphine-dependent mice is not related to monoamine oxidase inhibition but rather to a possible pargyline-induced decrease in dopaminergic activity.     

Regional changes in sympathetic nerve activity and baroreceptor reflex function and arterial plasma levels of catecholamines, renin and vasopressin during naloxone-precipitated morphine withdrawal in rats

The aim of the study was to examine regional changes in sympathetic nerve activity (SNA) and baroreceptor function and arterial plasma catecholamines, arginine vasopressin (AVP) and plasma renin activity during morphine withdrawal in chloralose-anesthetized rats. Dependence was induced by s.c. morphine base pellets. Adrenal, renal and splanchnic SNA and SNA from the lumbar sympathetic chain were recorded before and after i.v. injections of naloxone. Baroreceptor function was examined with phenylephrine-induced increases in mean arterial pressure. In separate experiments, arterial plasma norepinephrine, epinephrine, dopamine, plasma renin activity and AVP were measured before and after naloxone-precipitated withdrawal. Naloxone administration elicited an increase in mean arterial pressure and heart rate. Although renal SNA was inhibited by approximately 50%, adrenal SNA and lumbar SNA increased by approximately 400 and 80%, respectively. Splanchnic SNA did not change significantly. The baroreceptor-mediated inhibition of adrenal SNA was facilitated while that for renal SNA was attenuated. The arterial plasma level of norepinephrine was doubled and epinephrine increased almost 20-fold. AVP increased about 15-fold, whereas plasma renin activity showed only a minor increase after naloxone. This study shows that a marked differentiation of the SNA response occurs during morphine withdrawal in rats, which suggests an interaction between opioid receptors and the control of regional sympathetic output. Furthermore, large amounts of AVP and epinephrine are released, which probably contribute to the cardiovascular changes seen in the withdrawal phase.     

Increased analgesic potency of mu agonists after continuous naloxone infusion in rats.

Chronic opioid antagonist administration increases opioid binding sites and potentiates behavioral responses to morphine. The present study was designed to examine in rats the temporal and dosage parameters of naloxone-induced potentiation of morphine analgesia and the effect of continuous infusion of naloxone on the analgesic potency of other mu agonists. Cumulative dose-response curves were generated in a tail-flick procedure for each drug tested. Naloxone-filled osmotic pumps were then implanted s.c. for 1 week after which the rats were retested with the agonist. The potency ratio of morphine (ED50 before naloxone/ED50 after naloxone) showed orderly increases over a range of naloxone doses (0.03-1.0 mg/kg/hr) and increased, then decreased, over a range of time points (6-72 hr) after removal of the osmotic pumps. The relative potency of morphine was 2.1 at 24 hr after a 7-day infusion of 0.3 mg/kg/hr of naloxone. These parameters were then used in tests of other mu agonists. Five drugs produced maximum increases in tail-flick latencies before naloxone. Of these, naloxone increased the analgesic potency of fentanyl, methadone and levorphanol (relative potencies ranged from 1.7-2.1) but not of etorphine and propoxyphene. The naloxone infusion increased the maximum analgesic effect of meperidine, profadol and pentazocine, but had no effect on the analgesic activity of buprenorphine, butorphanol, ethylketocyclazocine and nalbuphine. Our results demonstrate that 7-day naloxone infusion increases the analgesic potency of some, but not all, opioids with mu agonist activity.     

Ketamine- and morphine-induced analgesia and catalepsy. I. Tolerance, cross-tolerance, potentiation, residual morphine levels and naloxone action in the rat

The effects of ketamine and morphine on pain perception and catalepsy were compared in rats. Analgesia, as measured by the latency to withdrawal of the tail from a 55 degrees C water bath (tail-flick latency difference, TFLD), was produced by both ketamine and morphine, but at widely different doses, and in each case the effect was reversed by naloxone. Catalepsy, measured by the duration of loss of righting reflex (DLRR) in catatonic animals, was induced by larger doses of both ketamine and morphine and in each case was reduced by a larger dose of naloxone. DLRR and TFLD tolerance developed rapidly and with a similar time course after daily doses of ketamine or morphine. Rats tolerant to the DLRR effect of ketamine showed cross-tolerance to morphine. Rats tolerant to the DLRR effect of morphine did not show cross-tolerance to ketamine when administered the following day; instead, these rats showed potentiation of the ketamine-induced DLRR. The degree of potentiation noted 24 hr after a single or multiple daily doses of 45 mg/kg of morphine is the same as that seen when 2 mg/kg of morphine is given simultaneously with ketamine. The residual brain level of morphine 24 hr after 45 mg/kg is similar to the level 1 hr after a 2-mg/kg dose. The augmented ketamine response in morphine-tolerant rats is postulated to be a result of residual morphine still present in the brain 24 hr after the last DLRR-inducing dose of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mu-opioid receptor up-regulation and functional supersensitivity are independent of antagonist efficacy

Chronic opioid antagonist treatment up-regulates opioid receptors and produces functional supersensitivity. Although opioid antagonists vary from neutral to inverse, the role of antagonist efficacy in mediating the chronic effects of opioid antagonists is not known. In this study, the effects of two putative inverse agonists (naltrexone, naloxone) and a putative neutral antagonist (6beta-naltrexol) were examined. Initially, peak effect (40 min, naltrexone and naloxone; 70 min, 6beta-naltrexol) and relative potency to antagonize morphine analgesia were determined (relative potencies = 1, 2, and 16, 6beta-naltrexol, naloxone, and naltrexone, respectively). Next, mice were infused for 7 days with naloxone (0.1-10 mg/kg/day), naltrexone (10 or 15 mg s.c. pellet), or 6beta-naltrexol (0.2-20 mg/kg/day), and spinal micro-opioid receptor density was examined, or morphine analgesia dose-response studies were conducted. All antagonists up-regulated mu-opioid receptors (60-122%) and induced supersensitivity (1.8-2.0-fold increase in morphine potency). There were no differences in antagonist potency to produce up-regulation or supersensitivity. These data suggest that opioid antagonist-induced mu-opioid receptor up-regulation and supersensitivity require occupancy of the receptor and that antagonist efficacy is not critical. Finally, the ED(50) to precipitate withdrawal jumping was examined in morphine-dependent mice. Naltrexone, naloxone, and 6beta-naltrexol produced withdrawal jumping, although potencies relative to 6beta-naltrexol were 211, 96, and 1, respectively. Thus, antagonist potency to precipitate opioid withdrawal was related to inverse agonist efficacy. Overall, the estimated relative potency of the opioid antagonists was a function of the outcome measured, and inverse agonist activity was not required for mu-opioid receptor up-regulation and supersensitivity.     

Acute supersensitivity to the discriminative stimulus effects of naltrexone in pigeons

The ability of acute morphine injections to augment discriminative stimulus effects and rate-decreasing effects of opioid antagonists was examined in pigeons trained to discriminate among i.m. injections of morphine (5.6 mg/kg), saline and naltrexone (10.0 mg/kg). A single injection of 10.0 or 32.0 mg/kg of morphine 24 hr before naltrexone produced 3- and 10-fold decreases, respectively, in the dose of naltrexone required for complete generalization. When morphine (10.0-100.0 mg/kg) was administered 48 hr before naltrexone, pigeons were not more sensitive to naltrexone as a discriminative stimulus but continued to be more sensitive to the rate-decreasing effects of naltrexone. Conditions that produced the largest increase in sensitivity to the discriminative stimulus effects of naltrexone (32.0 mg/kg of morphine 24 hr before the session) also increased sensitivity to the discriminative stimulus effects and rate-decreasing effects of naloxone, but did not affect the discriminative stimulus effects of diprenorphine, nalorphine or morphine. Increases in sensitivity to the discriminative stimulus effects of naltrexone and naloxone after single injections of morphine approached in magnitude the increases reported previously in pigeons treated chronically (once/daily) with large doses of morphine. However, the lack of generalization to naltrexone after pretreatment with still larger doses of morphine, as well as the failure of nalorphine and diprenorphine to substitute for naltrexone as discriminative stimuli under conditions in which sensitivity to naltrexone was increased, support the view that naltrexone does not produce its discriminative stimulus effects in nondependent animals exclusively through an opioid antagonistic action. The results suggest that morphine induced, acute supersensitivity to the discriminative stimulus effects of naltrexone differs from the supersensitivity to antagonists observed during chronic morphine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

乌拉地尔对吗啡戒断大鼠的高血压和心加速有抑制作用

本实验采用皮下递增注射吗啡５天后,经纳络酮催瘾建立吗啡戒断模型,观察中枢５－ＨＴ－Ａ受体激动剂乌拉地尔（ｕｒａｐｉｄｉｌ）对吗啡依赖大鼠戒断后的平均动脉压（ｍＡＢＰ）和心率（ＨＲ）的影响。实验结果表明,侧脑室微量注射乌拉地尔具有明显抑制吗啡戒断后血压升高的作用,并呈量效关系,乌拉地尔对吗啡戒断后心率加速虽也有抑制作用,但不呈量效关系,用另一种特异性５－ＨＴ１Ａ受体激动剂８－ＯＨ－ＤＰＡＴ兴奋中枢５     

Microiontophoretically applied morphine and naloxone on single cell activity in the parafasciculus nucleus of naive and morphine-dependent rats

Responses of parafasciculus (PF) thalamic neurons to microiontophoretically applied morphine and naloxone were examined in morphine-naive and morphine-dependent rats. The PF neurons exhibited high responsiveness (65%) to microiontophoretically applied morphine. Five different patterns of response to morphine in naive animals were obtained from the PF neurons. In morphine-dependent rats, the total responsiveness to microiontophoretic application of morphine was reduced dramatically (to 30%) and the response patterns to morphine were significantly (P less than .01) altered; this indicates that the PF neurons exhibit tolerance to morphine. Naloxone applied together with morphine only blocked the morphine-induced decreases in firing rates, but not the increases to which naloxone exhibited opiate agonist effects. Microiontophoretic application of naloxone alone, before morphine ejections in morphine-naive rats, induced changes in 51% of the PF neuronal population studied. Most of them (73%) responded with decreased firing rates. In morphine-dependent rats, more units responded to naloxone ejection (64%) as compared with the morphine-naive group. Excitation was the dominant response (73%) to naloxone treatment. The application of naloxone alone in naive and morphine-dependent rats demonstrated that the PF units responded in a characteristic dose-response manner to incremental naloxone administration. The present observations support our previous experiments using systemic applications of morphine and naloxone in freely behaving animals.     

Pharmacological actions of a novel mixed opiate agonist/antagonist: naloxone benzoylhydrazone

NalBzoH (6-desoxy-6-benzoylhydrazido-N-allyl-14-hydroxydihydronomorphin one) is a novel opiate with potent actions at both mu and kappa receptors. Analgesic studies in mice examining increasing doses of NalBzoH with a fixed dose of morphine revealed a biphasic curve. NalBzoH at doses as low as 1 microgram/kg partially antagonized morphine analgesia. Higher NalBzoH doses continued to inhibit morphine analgesia in a dose-dependent manner, with the 1-mg/kg dose antagonizing completely morphine analgesia. As the NalBzoH dose increased beyond 1 mg/kg analgesia returned. NalBzoH also prduced a similar analgesic response when administered alone in mice and also was active in rats. NalBzoH had excellent p.o. activity, with an analgesic potency in mice equivalent to s.c. administration. Naloxone reversed NalBzoH analgesia far less effectively than morphine analgesia. In contrast, Win44,441 antagonized both morphine and NalBzoH analgesia with a similar potency, consistent with a kappa mechanism for NalBzoH analgesia. Repeated administration of NalBzoH resulted in tolerance. There was no analgesic cross-tolerance between NalBzoH and either morphine or the kappa 1-selective agent U50,488H, implying a selective kappa 3 mechanism of analgesia. In addition to blocking morphine analgesia, low doses of NalBzoH also partially reversed the inhibition of gastrointestinal transit in mice produced by morphine, antagonized completely morphine lethality and precipitated withdrawal in morphine-dependent mice, confirming its antagonist activity in mu receptors. The duration of NalBzoH's kappa and mu actions differed dramatically. In mice, analgesia typically lasted less than 2 hr whereas the same NalBzoH dose antagonized completely morphine analgesia, a mu action, for 16 hr. Full sensitivity to morphine did not return for 32 hr.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose utilization in the rat brain during chronic morphine treatment and naloxone-precipitated morphine withdrawal

Rates of local cerebral glucose utilization (LCGU) were measured in morphine-dependent and morphine-abstinent rats. Morphine pellets were implanted s.c. (one pellet 7 days before glucose utilization measurement and two pellets 4 days before the measurement) to produce opioid dependence. LCGU rates in 85 brain regions of placebo- and morphine-pelleted rats were similar. In contrast, LCGU rates, 5 hr after implantation of one morphine pellet, were decreased significantly in six areas. The lack of a chronic morphine effect on LCGU suggests tolerance to morphine. Additional support for this view was that an additional dose of morphine (8 mg/kg s.c.) in morphine-dependent rats was also ineffective in altering LCGU and in an antinociception (hot plate) test. Furthermore, plasma morphine levels in chronically treated animals were greater than those in acutely treated animals. Naloxone-precipitated morphine withdrawal enhanced LCGU, most notably in thalamic and limbic areas, but also in some hypothalamic and hindbrain regions. The findings identify brain areas that may be important in the opioid abstinence syndrome. Furthermore they suggest that adaptations in the brain produce tolerance to morphine, reflected in LCGU rates and latencies in the hot-plate test.     

Quantitative opioid withdrawal signs in rats: effects exerted by clothiapine administration

Summary— An opioid withdrawal syndrome, which causes alteration of several physiological signs, was induced in rats by repeated morphine administration and final naloxone injection. The aim of this study was prevention of the altered physiological profiles by utilising clothiapine, which is capable of affecting fecal and urinary excretion, rectal temperature, pain threshold levels and salivatory behaviour. Morphine was administered in three daily intraperitoneal (ip) injections for 4 days at doses of 9, 16 and 25 mg/kg (d 1), 25, 25 and 50 mg/kg (d 2), 50, 50 and 50 mg/kg (d 3) and 50, 50 and 100 mg/kg (d 4). Naloxone was injected (30 mg/kg) ip 180 min after the last morphine injection. Clothiapine was administered orally 0.7, 2 and 6 mg/kg 2 hours before the naloxone administration. Signs such as fecal and urine excretion, rectal temperature and latency times to thermal stimulus, salivation, jumping and wet dog shakes were affected in different ways by morphine, naloxone, clothiapine and combination of them. Notably the administration of clothiapine in rats receiving morphine and naloxone decreased the intensity of certain withdrawal symptoms, such as altered excretion of feces, temperature values, salivation, jumping and wet dog shakes behaviour, and elevated the nociceptive threshold values. The effects exhibited by clothiapine administration may be explained through its antimuscarinic, antiadrenergic and antidopaminergic activities interfering with the mechanisms involved in the regulation of these previously mentioned withdrawal symptoms. The use of this drug is thus suggested as a possible control of the acute phase of opioid withdrawal in heroin addicts.     

Effects of beta-funaltrexamine in normal and morphine-dependent rhesus monkeys: observational studies

The behavioral effects of the opioid receptor alkylating agent beta-funaltrexamine (beta-FNA) were assessed in normal (drug-naive) and morphine-dependent rhesus monkeys. In normal monkeys, beta-FNA (10 mg/kg s.c.) produced muscle relaxation and stupor, which could be reversed by the opioid antagonist Win 44,441. Given as a 48-hr pretreatment, beta-FNA antagonized the behavioral effects of acute morphine, but not those of two kappa agonists, ethylketazocine and Mr 2033 (UM 1072). In morphine-dependent monkeys, beta-FNA (10 mg/kg, s.c. and 0.003 mg i.c.v.) precipitated severe abstinence which lasted for 3 days. beta-FNA was more than 13,000 times more potent in precipitating withdrawal after i.c.v. than s.c. administration, whereas naltrexone and Win 44,441 were equipotent by these routes. Deprivation-induced abstinence (14 hr) and withdrawal of similar severity precipitated by naltrexone, Win 44,441 or naloxonazine were suppressed completely by 17.5 mg/kg of morphine. In contrast, 320 mg/kg of morphine failed to suppress completely a withdrawal syndrome of the same severity elicited by s.c. or i.c.v. beta-FNA. These data are consistent with the view that beta-FNA has reversible opioid agonist and insurmountable mu selective antagonist activity in the rhesus monkey.     

石菖蒲水煎剂对吗啡依赖大鼠戒断症状的治疗作用

目的：观察石菖蒲水煎剂对吗啡依赖大鼠戒断症状的治疗作用。方法：采用连续递增皮下注射吗啡,建立吗啡依赖动物模型;给石菖蒲实验组大鼠不同剂量（2.5 g/kg、5 g/kg、7.5 g/kg）的石菖蒲水煎剂灌胃后,用纳络酮催瘾（0.5 mg/kg）,观察每组大鼠戒断反应中出现的咬牙、湿狗样抖动、扭体等六种戒断症状,评价大鼠戒断反应的强度。结果：与盐水对照组比较,石菖蒲水煎剂对吗啡依赖大鼠的戒断症状均有不同程度的抑制作用,其中以5 g/kg剂量组的作用最为突出（P〈0.01）。结论：石菖蒲水煎剂能明显抑制吗啡依赖大鼠的戒断症状。     

Adrenal vein and arterial levels of catecholamines and immunoreactive metenkephalin in canine endotoxin shock and their response to naloxone

The alterations in plasma levels of immunoreactive metenkephalin (ir-metenkephalin) and catecholamines in adrenal vein and arterial blood in response to endotoxin, as well as the effects of subsequent naloxone administration, have been investigated in a canine model. Animals were anaesthetised with alpha chloralose and allowed to breathe spontaneously. The left lumbar adrenal vein was cannulated and an intermittent choke allowed retrograde sampling of the adrenal effluent. Severe shock was produced by the administration of a large bolus of E. coli endotoxin (5 mg/kg) followed by a continuous infusion (2 mg/kg per hour). One hour after induction of shock the circulating volume was expanded using a colloidal gelatin solution. Thirty minutes later one group of five animals received a bolus of naloxone (2 mg/kg) followed by a continuous infusion of (1.5 mg/kg per hour), while a control group of five animals was given an equivalent volume of isotonic saline. The production of endotoxin shock was associated with marked increases in adrenal vein and systemic levels of adrenaline and noradrenaline. Naloxone administration transiently limited the fall in adrenal vein levels of adrenaline and noradrenaline (P less than 0.05) following volume replacement and was associated with a sustained increase in systemic adrenaline levels (P less than 0.05). Changes in mean arterial pressure confirmed a significant haemodynamic response to naloxone (P less than 0.05). Alterations in ir-metenkephalin levels in the adrenal vein closely followed the changes in catecholamines, whereas arterial levels rose progressively and were unaffected by naloxone. We conclude that in canine endotoxin shock the opiate antagonist naloxone can transiently increase catecholamine levels in the adrenal effluent and produce a more sustained rise in systemic adrenaline levels. Moreover, the adrenal medulla is not the only source of circulating ir-metenkephalin.     

Changes in plasma corticosterone levels as a measure of acute dependence upon levorphanol in rats

Changes in plasma corticosterone levels have been utilized as a sensitive and reliable indicator of opiate withdrawal. By using rats prepared with chronic indwelling i.v. catheters, drug injections and sequential blood sampling were accompanied in conscious undisturbed animals. Acute administration of levorphanol tartrate (LT) at 0.5, 1.0 or 2.0 mg/kg b.wt. caused an elevation in circulating corticosterone. With the lowest dose of LT, hormone levels returned to pretreatment values by 180 min. Naloxone hydrochloride (NX), 0.4 mg/kg, administered 3 hr after pretreatment with LT, 0.5 mg/kg, produced a significant elevation in plasma corticosterone. In contrast, animals pretreated with saline did not show the same increase in hormone levels after NX. NX, administered at several doses, along with LT, suppressed the plasma corticosterone increase which is normally observed when LT is given acutely. When NX is administered at sufficient dosage, along with LT pretreatment, the subsequent administration of the antagonist did not elicit the withdrawal response. These data indicate that a similar increase in plasma corticosterone, upon challenge with NX after a single dose of morphine, generalizes to other opiates. Blockade of the initial rise in plasma corticosterone and subsequent increase upon injection of the antagonist speak to the probability of the responses being related and opiate specific.     

Morphine deprivation increases self-administration of the fast- and short-acting mu-opioid receptor agonist remifentanil in the rat

Opiate dependence and withdrawal have long been hypothesized to enhance the reinforcing effects of opiates; however, opiate agonist self-administration in these states has yet to be systematically assessed. To address this issue, the reinforcing property of the short-acting mu-opioid agonist, remifentanil, was assessed in morphine-dependent (MD), morphine-dependent and -withdrawn (MW), and nondependent, control (C) rats. Dependence was established by twice daily administration of increasing doses of morphine for 4 days (10, 20, 30, and 40 mg/kg s.c.) and then maintained with a daily injection of the large dose. Morphine deprivation-induced withdrawal (defined by weight loss and hyperalgesia) was apparent 24, but not 12, h after morphine treatment. Remifentanil self-administration (0.4, 0.8, 1.6, 3.2, or 6.4 mug/kg/infusion) was assessed over 20 successive, daily, 1-h sessions, either 12 or 24 h after the maintenance dose of morphine. Compared with the control group, the MD group demonstrated suppressed remifentanil self-administration, whereas the MW group exhibited enhanced responding for every dose of remifentanil. The increased responding observed in the MW group compared with the control and MD groups resulted in an upward shift in the remifentanil dose-response curve, an effect that was expressed only after repeated exposure to the contingency, demonstrating that morphine withdrawal ultimately enhances the reinforcing effects of remifentanil.     

Inhibition by opioid agonists and enhancement by antagonists of the release of catecholamines from the dog adrenal gland in response to splanchnic nerve stimulation: evidence for the functional role of opioid receptors

The aim of the present study is to examine how opioid agonists and antagonists modify the splanchnic nerve stimulation (SNS)-induced release of catecholamines from the dog adrenal gland in vivo, in an attempt to elucidate whether opioid receptors play a functional role in controlling catecholamine release. Output of epinephrine (EPI) and norepinephrine (NE) was determined from adrenal venous blood by using high-performance liquid chromatography with electrochemical detection. SNS (0.3, 1 and 3 Hz) produced increases in both EPI and NE output in a frequency-dependent manner. Leu-enkephalin (10-100 micrograms/kg i.v.) and morphine (10-100 micrograms/kg i.v.) attenuated the increase in EPI and NE output induced by 1 or 3 Hz of SNS without affecting the basal catecholamine output. A 25 to 40% reduction of the SNS-induced increase in catecholamine output was observed after the treatment with 100 micrograms/kg of leu-enkephalin or morphine. The increase in EPI and NE output induced by 1 and 3 Hz of SNS was enhanced markedly by naloxone (10-1000 micrograms/kg i.v.) and by naltrexone (10-1000 micrograms/kg i.v.). The SNS-induced increase in catecholamine output doubled after treatment with 100 and 1000 micrograms/kg of naloxone or naltrexone. Basal catecholamine output and the increase in output induced by 1 Hz of SNS were unaffected by naloxone or naltrexone. These results suggest that endogenously released opioid peptides inhibit the release of catecholamines by activating opioid receptors in the adrenal gland of the dog.