Morphine physical dependence intensification by hypoglycemia: NMDA receptor involvement

The destruction of N-methyl-D-aspartate (NMDA) receptor-bearing neurons by insulin-induced hypoglycemia has long been known to be due to excessively released aspartate and glutamate. In this study, the effects of NMDA-bearing neuron destruction by insulin-induced hypoglycemia on the development of morphine (M) physical dependence, which was found related to functional states of NMDA receptors, were investigated. NMDA receptor antagonists CGP 39551 and MK-801 were used to see whether they could change intensity of precipitated abstinence syndrome by preventing destruction. Therefore, two groups of fasting rats injected IP with physiological saline, and another two groups given IP 10 mg/kg CGP 39551 and 0.5 mg/kg MK-801 received 15 IU/kg crystalline zinc insulin IP. After 2 h, the rats were orally given 2 x 4 ml of 5% glucose solution. On the third day, two pellets containing 75 mg base M were SC implanted to all rats. On the sixth day, they were IP given 2 mg/kg naloxone (NL). Then jumps, wet-dog shakes, and defecation were counted while diarrhea and ptosis were rated for 15 min. The rats given insulin manifested significantly more intense NL-precipitated abstinence syndrome than controls. The rats administered CGP 39551 showed a less intense physical dependence than those injected with only insulin. But, the intensity was still significantly higher than controls. In the rats that received MK-801, the abstinence syndrome was more or less equal to that in controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects exerted by otilonium bromide administration on precipitated opioid withdrawal syndrome in rats

An opioid withdrawal syndrome was induced in rats by repeated morphine administration and final naloxone injection. The withdrawal causes alteration of several physiological signs. The aim of the study was to prevent the altered physiological profiles by utilising otilonium bromide. Morphine was administered in three daily i.p. injections for 4 days at doses of 9, 16 and 25 mg/kg (1st day), 25, 25 and 50 mg/kg (2nd day), 50, 50 and 50 mg/kg (3rd day) and 50, 50 and 100 mg/kg (4th day). Naloxone was injected (30 mg/kg) i.p. 180 min after the last morphine injection. Otilonium bromide was administered orally at 0, 2, 4 and 8 mg/kg, 120 min before the naloxone administration. Signs like faecal and urine excretion, rectal temperature and pain threshold levels, salivation, jumping and wet dog shakes were affected in different ways. Notably the administration of otilonium bromide in rats receiving morphine together with naloxone decreased the intensity of certain withdrawal symptoms, such as excretion of faeces, wet dog shake behaviour, and elevated the nociceptive threshold values. The effects exhibited by otilonium bromide administration may be explained through its calcium antagonist activity interfering with a mechanism involved in the regulation of these previously mentioned withdrawal symptoms. The use of this drug is thus suggested as a possible control of some acute opioid withdrawal signs in heroin addicts.     

Chronic variable stress or chronic morphine facilitates immobility in a forced swim test: reversal by naloxone

The behaviors displayed in a forced swim test were investigated in rats previously exposed to a chronic variable stress treatment or chronic administration of morphine. In addition, to further explore the participation of an endogenous opiate mechanism in these behavioral effects, naloxone was either administered during the chronic treatment (prior to each stress or morphine exposure) or immediately prior to the forced swim test. Animals were submitted daily to a different stressor for 1 week or injected with morphine (10 mg/kg, IP) for 6 days, whereas controls were unmanipulated except for the injection process. On the day following the last stressor, control and stressed animals were administered saline or naloxone (2 mg/kg, IP) 15 min prior to the forced swim test. Morphine treated animals were similarly tested on the third day following the last morphine injection. In a separate group of rats, naloxone (2 mg/kg, IP) was administered daily 10 min prior to each stressor of the chronic stress regime or each daily morphine injection. A significant increase in the time spent in immobility was observed in stressed animals as well as in rats chronically treated with morphine. In both groups, this potentiated immobility was attenuated by naloxone pretreatment prior to the forced swim test or when given before each daily stressor or morphine injection. In addition, the concurrent exposure to stress or morphine along with naloxone administration enhanced struggling in the first 5 min of the forced swim test.(ABSTRACT TRUNCATED AT 250 WORDS)     

Context-specific morphine withdrawal in rats: Duration and effects of clonidine.

Rats previously injected with morphine in a particular environment (paired rats) emitted more withdrawal symptoms in that environment than did rats previously injected with morphine in another environment (unpaired rats) after both 1 day and 5 days of morphine abstinence. Thus, reexposure to an environment previously associated with morphine can elicit context-specific withdrawal even after several days of morphine abstinence. Clonidine (0.06 mg/kg) reduced most of the withdrawal symptoms seen 5 days after morphine abstinence in both the paired and unpaired rats. However, clonidine enhanced many of the withdrawal symptoms in both groups of rats during naltrexone-precipitated withdrawal 1 day after morphine abstinence. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

PEDB: the Prostate Expression Database

Naloxone is generally considered to be a pure antagonist, but it may produce several behavioral effects, such as hyperalgesia or stimulation of respiration. We studied the effect of naloxone on gastric emptying and gastrointestinal transit in rats. Six to eight Wistar rats (200-250 g) were used for each experiment. Either saline or naloxone (0.01-10 mg/kg) was injected intraperitoneally at 0 min. At 30 min, radiolabeled saline or milk 1 mL was infused into the stomach. At 60 min, gastric emptying and gastrointestinal transit were calculated by measuring the radioactivity in the gastrointestinal tract. Naloxone significantly inhibited gastric emptying of saline (P = 0.002) and of milk (P < 0.05), but not the gastrointestinal transit of either (P > 0.05). Gastric emptying of saline showed a significant peak (P < 0.05) in the dose-response curve at 0.7 mg/kg. Therefore, naloxone significantly inhibits gastric emptying of saline and milk, but not the gastrointestinal transit of either. IMPLICATIONS: Although naloxone is generally considered to be a pure opioid receptor antagonist, it delays gastric emptying of saline or milk, as does morphine in the rat. However, it is uncertain from our results whether naloxone inhibited gastric emptying by antagonizing the effects of endogenous opioids.     

Effects of N-methyl-D-aspartate receptor antagonists on discriminative stimulus effects of naloxone in morphine-dependent rats using the Y-maze drug discrimination paradigm

The present study assessed the ability of various site-selective N-methyl-D-aspartate (NMDA) receptor antagonists to affect the discriminative stimulus properties of naloxone in morphine-dependent rats. Adult male Wistar rats were trained to discriminate 0.1 mg/kg of s.c. naloxone from saline using a Y-maze shock-avoidance procedure. Naloxone-appropriate responding was exhibited as a function of naloxone dose (0.01-1.0 mg/kg, ED50 = 0.03 mg/kg) and was also observed when morphine treatment temporarily was discontinued (8-96 hr, peak at 24 hr). Discriminative stimulus effects of naloxone (0.1-3.0 mg/kg) were antagonized by morphine (10-100 mg/kg). Ligands of peripheral opioid receptors failed to either substitute for naloxone (methylnaloxone, 0.1-3.0 mg/kg) or attenuate naloxone's stimulus effects (loperamide, 1-30 mg/kg). In rats treated with the training dose of naloxone, administration of dizocilpine (0.03-0.3 mg/kg) and D-CPPene (1-10 mg/kg) decreased levels of naloxone-appropriate responding, whereas memantine (1-30 mg/kg), ACEA-1021 (10 and 50 mg/kg) and eliprodil (3-30 mg/kg) seemed to have little or no effects. Meanwhile, all NMDA receptor antagonists produced a decrease in the occurrence of two or more of the following opioid withdrawal signs: weight loss, forelimb tremor, ptosis, diarrhea and "wet-dog"-like shaking. Additionally, dizocilpine (0.1 mg/kg), D-CPPene (5.6 mg/kg) and ACEA-1021 (50 mg/kg) but not memantine (10 mg/kg) or eliprodil (30 mg/kg) significantly reduced the naloxone-appropriate escape area selection when administered during the period of suspended morphine treatment 24 hr after the last morphine injection. Thus, NMDA receptor antagonists appear to inhibit the discriminative stimulus effects of both naloxone-precipitated and spontaneous morphine withdrawal, and this ability depends on the type of antagonist applied.     

Visual processing of straight lines in dyslexic and normal children

Morphine, administered to Sprague-Dawley rats over a period of 65 hr either by the simultaneous implantation of two 75 mg pellets, or by a series of twice daily 20 or 30 mg/kg injections, produced dependence as indicated by the precipitation of the abstinence syndrome with the antagonist, naloxone. Plasma morphine levels, analyzed fluorometrically at various times during the treatment procedures, revealed peak concentrations that were 3 or 4 fold higher for injected animals than the maximum steady-state level established in the pellet-implanted animals. The calculated plasma concentration of the drug over time was not statistically different for the groups. It is noted that although the 2 methods of morphine administration produce a qualitatively identical dependent state, the pellet implantation technique causes greater weight loss and a higher incidence of jumping and wet-dog shakes during withdrawal.     

Inhibition of morphine-induced tolerance and dependence by a benzodiazepine receptor agonist midazolam in the rat

We investigated whether midazolam administration influenced morphine-induced antinociception and tolerance and dependence in the rat. Antinociception was assessed by the tail-flick (TF) and the hot-plate test (HP 52 degrees C). Morphine tolerance developed after daily single injections of morphine for 11 days. The effect of midazolam on morphine-induced antinociception and tolerance was assessed by giving daily injections of various doses of midazolam for 11 days. The first injection of saline or midazolam was given intraperitoneally and 30 min later morphine (10 mg/kg body weight) was administered subcutaneously. Antinociception was monitored by measuring TF and HP latencies 60 min after the second injection. Midazolam was injected at four different concentrations: 0.03, 0.1, 0.3, and 3 mg/kg body weight. Chronic administration of morphine resulted in the development of tolerance to antinociception in both TF and HP tests, with rats exhibiting baseline antinociception on Day 9. Animals treated with midazolam alone showed little antinociception on Days 3-9. However, midazolam administration in morphine-treated animals attenuated morphine-induced tolerance to antinociception on Days 1-11 as measured by the tail-flick test. Midazolam also decreased the jumping behavior following naloxone injections in morphine-dependent rats. These results suggest that midazolam may prolong the effects of morphine by delaying morphine-induced development of tolerance to antinociception. Midazolam also attenuated a decrease in weight gain induced by chronic injections of morphine.     

Treatment of drug resistant scabies]

The theory that narcotic-induced protracted biological changes are responsible for relapse of opiate-reinforced behavior was examined in the rat. Groups of rats were conditioned to prefer a distinctive environment by pairing it with morphine doses from 1-200 mg/kg, and were retested for persistence of this preference after a 3-week abstinence period. They were then observed for protracted signs such as sensitivity to naloxone, tolerance to morphine analgesia, hyperaggression, or changes in endocrine activity. Acquisition and relapse of the preference, as well as long-term tolerance, were dose related. None of the purported protracted signs showed any consistent relationship to the tendency to relapse. However, relapse correlated significantly with original acquisition scores in all relapsing groups. The results suggest that original conditioning factors, rather than protracted changes, are responsible for the observed relapse.     

Relative sensitivity to naloxone of multiple indices of opiate withdrawal: a quantitative dose-response analysis

In addition to classic somatic signs of opiate withdrawal, a number of behavioral measures are known to be sensitive, reliable indices of naloxone-precipitated opiate withdrawal in rats. It has been suggested that some behavioral indices of withdrawal may be more sensitive to precipitation by naloxone than some somatic signs of withdrawal. The purpose of the present study was to permit a quantitative assessment of the relative sensitivity to naloxone of a variety of behavioral and somatic indices of opiate withdrawal. Male Wistar rats were implanted s.c. with either two morphine (each 75 mg of base) or two placebo pellets. No sooner than 3 days after implantation, naloxone dose-response functions were determined with several behavioral paradigms and ratings of a variety of somatic withdrawal signs. In dependent rats, very low (0.004 or 0.01 mg/kg) doses of naloxone produced the following behavioral effects: 1) a reduction in spontaneous locomotor activity, 2) a disruption of schedule-controlled (fixed ratio 15) operant responding for food, 3) an elevation in intracranial self-stimulation thresholds and 4) a conditioned place aversion. These same doses of naloxone produced no significant effects in nondependent (placebo pellet-implanted) rats. The ED50 values for naloxone precipitation of all behavioral signs of withdrawal were below 0.013 mg/kg; the ED50 values for naloxone precipitation of most somatic withdrawal signs were higher. The behavioral measures used in these studies therefore represent highly sensitive indices of opiate withdrawal.     

CDK4, a possible critical regulator of apoptosis in rat pheochromocytoma PC12 cells

Rats infused subcutaneously with 9 mg/kg/day nicotine tartrate for 7 days exhibit behavioral abstinence signs following either termination of nicotine infusion or injection of the noncompetitive nicotinic antagonists mecamylamine (s.c.) or hexamethonium (ic.c.v.). This study examined the abstinence precipitating effects of dihydro-beta-erythroidine (DHbetaE), a competitive nicotinic antagonist. Twenty-four nicotine-dependent rats were injected in the third ventricle with 10, 18, or 25 microg DHbetaE in 20 microl saline or with saline alone and observed for abstinence signs over a 20-min period. There was a significant positive linear trend of overall abstinence signs as a function of dose, p < 0.01. In 12 nondependent rats, the high dose of DHbetaE did not induce more abstinence-like signs than saline alone. In a second experiment, 18 nicotine-dependent rats were injected s.c. with 1 or 6 mg/kg of the muscarinic antagonist scopolamine or with saline alone. Few abstinence signs were observed in any group: there was no significant drug effect. The results suggest that nicotine abstinence signs observed in the rat are specific to reduced stimulation of previously overstimulated nicotinic receptors.     

Morphine influences on classical aversive conditioned heart rate in rats.

Investigated in 3 experiments the effects of morphine and the morphine antagonist naloxone on the development of a classical aversive heart rate (HR) conditioned response (CR) to a tone conditioned stimulus (CS) paired with an electric shock unconditioned stimulus (US). In Exp I, groups of rats received either 0.25, 5 or 10 mg/kg, sc, of morphine. Three other groups were given 0.1, 5, or 10 mg/kg of naloxone. All morphine groups showed attenuation HR responses to the CS on preconditioning CS-alone trials. During conditioning, the 10-mg/kg morphine group showed a markedly decremented bradycardia CR and tachycardia unconditioned response (UR), whereas the 5-mg/kg morphine group showed a normal CR in combination with a decremented UR. In the Exp II, 1 mg/kg naloxone given after conditioning failed to reverse the CR and UR losses produced by 10 mg/kg of morphine given prior to conditioning. 10 mg/kg of morphine produced only a minor reduction in a HR CR established in a drug-free state, but the tachycardia UR was severely reduced. Exp III showed that 1 mg/kg of naloxone was effective in reversing analgesia induced by 10 mg/kg of morphine. 10 mg/kg dose of morphine interfered with the learning of a HR CR, perhaps principally by reducing the aversive or emotional consequences of the shock US. Direct cardiovascular effects of morphine seemed to interfere with the performance of the tachycardia UR, but not with the performance of the bradycardia CR. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of specific delta and kappa opioid receptor antagonists on the bidirectional dose-dependent effect of systemic naloxone in arthritic rats, an experimental model of persistent pain

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphine-naloxone interaction in the central cholinergic system: the influence of subcortical lesioning and electrical stimulation

1 The opiate antagonist naloxone, injected or topically applied to the cerebral cortex, had no significant effect on the spontaneous output of cortical acetylcholine (ACh) in rats. 2 Morphine (2.5 mg/kg) administered intravenously inhibited the release of cortical ACh. A subsequent injection of naloxone rapidly reversed morphine-induced inhibition, and produced a sustained increase in the release of ACh. Topical application of naloxone solutions, after morphine, produced a slow and weak reversal of its inhibitory action. 3 Destruction of the medial thalamus abolished both the inhibitory effects of morphine on the cortical ACh release, and its antagonism by naloxone administered after the agonist. 4 Injection of naloxone in a low dose (0.1 mg/kg) increased the release of cortical ACh provoked by electrical stimulation of either the medial thalamus or the reticular formation in normal rats. In the morphine-dependent rat, naloxone also facilitated the evoked release and its action was greater than in control animals. The facilitatory effect of naloxone on the cortical release evoked by stimulation of the medial thalamus was greater than its effect on the release evoked by stimulation of the reticular formation in both normal and morphine-dependent rats. 5 Naltrexone, a narcotic antagonist, also facilitated the electrically stimulated release of cortical ACh. 6 It is suggested that (a) morphine and naloxone act at a subcortical site, probably the medial thalamus, to modify the cortical ACh release and that (b) naloxone may facilitate the electrically-induced release of ACh in the CNS by antagonizing the effect of the endogenous morphine-like factor, enkephalin.     

Naloxone-induced supersensitivity of oxytocin neurones to opioid antagonists

Here we report that a single administration of naloxone to conscious rats produces no significant increase in oxytocin release, but when repeated 3-4 days later results in a large release of oxytocin. Plasma oxytocin concentrations were measured in conscious and urethane-anaesthetized rats pretreated with naloxone or isotonic saline on Day 1. On Days 2, 3 or 4, a second dose of naloxone was given, producing an increase in oxytocin secretion in naloxone-pretreated groups (P < 0.05 vs. controls) on Day 3 and 4, but not on Day 2. The specificity of the opioid antagonist supersensitivity was determined by injection of the kappa-antagonist nor-binaltorphimine (nor-BNI). Pretreated rats (naloxone, saline or nor-BNI, Day 1) received an additional acute nor-BNI injection (Day 4) which increased plasma oxytocin concentration in the three groups. However, this increase was higher in naloxone-pretreated rats with no differences between the nor-BNI- and saline-pretreated animals. Measurements of electrical activity of single supraoptic nucleus oxytocin neurons and of plasma oxytocin concentration (Day 4) showed that naloxone modestly enhanced the responsiveness of oxytocin neurons to cholecystokinin (CCK) in naloxone-pretreated rats (by comparison with saline-pretreated rats), but had only a small effect on basal firing rate that did not differ between naloxone-pretreated rats and saline-pretreated rats. To investigate whether naloxone-pretreatment modified the effect of morphine on CCK-induced oxytocin release, on Day 4 CCK was injected i.v. with or without morphine. Morphine at a dose of 0.1 mg/kg did not affect CCK-induced oxytocin release, whereas 1 mg/kg of morphine blocked this release in both saline- and naloxone-pretreated rats. The results suggest that naloxone induces opioid antagonist supersensitivity on oxytocin secretion, mainly by up-regulating kappa-opioid mechanisms on oxytocin nerve terminals in the posterior pituitary.     

Ontogeny of morphine withdrawal in the rat.

The present studies examined behavioral changes during precipitated morphine withdrawal in 7- to 42-day-old rat pups. One group of rats was injected with morphine sulfate (10.0 mg/kg) twice daily for 6.5 days. Another group of 7-day-old rats received a lower dose of morphine (3.0 mg/kg). Controls were saline injected or untreated litters (7-day-old pups only). On Day 7, a target pup was injected with saline or naltrexone (0.3–20.0 mg/kg). Preweaning pups were observed in a warm chamber with the litter. Forty-two-day-old rats were tested individually. Morphine-treated pups tested with naltrexone showed significant alterations in behavior that varied at different ages. For example, rolling, stretching, and head and paw moves were observed at the younger ages, whereas burrowing, diarrhea, jumps, teeth chatter, and wet dog shakes occurred in the older rats. These data indicate that morphine-abstinent rats demonstrate withdrawal signs that are within the developmental repertoire of the rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid antagonist profile of SC nor-binaltorphimine in the formalin paw assay

The antinociceptive effects of mu and kappa agonists were examined after the systemic administration of the opioid antagonists nor-binaltorphimine (nor-BNI) and naloxone in the late response or tonic nociceptive phase of the mouse formalin assay. Initially, SC morphine (ED50, 0.97 mg/kg), racemic U-50488H (ED50, 0.79 mg/kg), (-)U-50488 (ED50, 0.41 mg/kg), and another agonist PD 117,302 (ED50, 0.28 mg/kg) were found to produce graded increases in the level of antinociception as measured by this procedure; naloxone, administered immediately before morphine and U-50488H, antagonized their antinociceptive actions. The effects of morphine and U-50488H then were evaluated 10 min to 96 h after the administration of nor-BNI. Subcutaneous nor-BNI at 30.0 mg/kg, but not at 3.0 or 10.0 mg/kg, attenuated the antinociceptive effects of morphine and U-50488H when the interval separating nor-BNI and the agonists was kept constant at 1 h. Time-course analysis of the effects of combinations of nor-BNI with morphine led to irregular findings: 10.0 mg/kg of nor-BNI lessened the effects of morphine (2.0 mg/kg) if the dosing interval was 10 min, whereas 30.0 mg/kg of nor-BNI attenuated the effects of morphine (2.0 mg/kg) if the dosing interval was 1 or 4 h; 10.0 mg/kg of nor-BNI also diminished the antinociceptive effects of U-50488H (1.7 mg/kg) only if the interval spacing the two drugs was 24 h. In comparison, a threefold higher dose of nor-BNI (30.0 mg/kg) reduced the effects of U-50488H (1.7 mg/kg) if the interval was 1 h or more. In these latter experiments, the antagonist effects of SC nor-BNI (30.0 mg/kg) were evident up to 96 h posttreatment. These results show that the mu opioid antagonist activity of nor-BNI is variable and that the kappa opioid antagonist selectivity of nor-BNI is a function of dose and treatment interval and is long-lasting even after systemic administration.     

Glutamate-induced analgesia: blockade and potentiation by naloxone

Injection of 0.5 microliter L-sodium glutamate (60 mM) into the periaqueductal gray matter of the rat resulted in a short-lived analgesia as assessed by the tail-flick method. Naloxone (1 mg/kg) attenuated glutamate-induced analgesia when injected 30 min but not 5 min before testing. Paradoxically, a higher dose of naloxone (10 mg/kg) significantly potentiated glutamate analgesia when injected 5 min but not 30 min before testing. Moreover, this higher dose also potentiated analgesia when injected 5 min prior to 12 mM glutamate, a dose of glutamate previously found to be ineffective in causing analgesia. Microinjections of either 60 mM or 1 M KCl failed to elicit analgesia, indicating the specificity of the glutamate effect. Taken together with several other lines of evidence, the present findings suggest that glutamate-induced analgesia may be mediated by processes quite different from those underlying morphine analgesia. It is further suggested that a dose-related naloxone antagonism is not a necessary criterion for assessing endogenous opioid activity.     

Effects of administration of phentonium bromide on opioid withdrawal syndrome in rats

This study has tested whether phentonium bromide, a quaternary ammonium anti-muscarinic agent, could reverse the signs of precipitated opioid withdrawal. Rats were treated with either saline or morphine for 4 days, after which half the rats received naloxone and half saline. Each animal also received one of four doses of phentonium bromide (0, 1, 3 and 9 mg kg(-1), i.p.). Administration of phentonium bromide in rats receiving naloxone after chronic morphine treatment reduced the intensity of withdrawal signs such as increased defecation or micturition, salivation and wet-dog shakes, and elevated the nociceptive threshold values. The effects of administration of phentonium bromide might result from its anti-muscarinic activity interfering peripherally with the mechanisms involved in the regulation of the withdrawal symptoms. The use of this drug is thus suggested as a possible means of controlling some of the signs observed during the acute phase of opioid withdrawal in heroin addicts.     

The potential antinarcotic effects of guanfacine

alpha 2-Agonist clonidine has been used for several years in the detoxification of opiate-addicts since it reduces withdrawal symptoms in man although craving for narcotic is not well suppressed. In the present work the potential "anticraving" properties of another alpha 2-agonist guanfacine were studied in rats trained to self-administer morphine. In the special series of experiments the influence of guanfacine on behavioral manifestation of morphine withdrawal in rats was studied. Analgesic action of guanfacine was evaluated by tail-flick procedure. It was shown that guanfacine (2-4 mg/kg, i.p.) essentially inhibited the morphine intravenous self-administration in a dose-dependent manner. These findings can be interpreted as reduction of morphine's positive reinforcing properties by guanfacine and point out on the possibility to prevent morphine abuse by guanfacine. Analgesic effect of guanfacine in tail-flick test was revealed in doses of 1-8 mg/kg, i.p. (50-100% increase in latency of nociceptive reaction, p < 0.05, Student's t-test). In the other experiments the morphine dependence was induced by i.p. injections of this drug during 5 day period with gradually elevated doses from 5 up to 25 mg/kg. Morphine discontinuation and injection of naloxone (0.5 mg/kg, i.p.) on day 6 induced the behavioral symptoms of abstinence ("wet dog shakes" and jumping). Guanfacine (4 mg/kg, i.p., immediately after naloxone) significantly increased the number of jumps and locomotions (p < 0.05), while increase in "wet dog shakes" was not statistically significant. The potentiation of morphine-withdrawal jumping by guanfacine was antagonized by iohimbine and prazosine in doses of 1 mg/kg, i.p. In the same conditions both prazosine and iohimbine removed "wet dog shakes." The results suggest that the potentiation effect of guanfacine on morphine-withdrawal jumping in rats can be mediated through alpha 1- and alpha 2-adrenoreceptors. Nonspecific interaction between prazosine and mentioned effect of guanfacine (which can be resulted from potentiation of blood pressure fall and of motor deficit) cannot be excluded.