Opiate Receptor Antagonist Research Articles

Opiate receptor avidity in the thalamus is sexually dimorphic in the elderly.

Opiate receptor avidity (B(')(max)/K(D)), was measured in the subcortex of nine females (five healthy subjects, four Alzheimer patients) and 15 males (seven healthy subjects, eight Alzheimer patients), 51-75 years of age, with the opiate receptor antagonist 6-deoxy-6-beta-[(18)F]fluoronaltrexone (cyclofoxy, CF) and a positron emission tomograph. CF avidity was 27.5% less in the thalamus of healthy women compared to healthy men and 48.5% less in Alzheimer disease female patients compared to male patients.

Administration of opiate receptor antagonist inhibits mucosal atrophy of the gut in fasting rats.

The objective of this study was to determine whether the opiate mu receptor antagonist naloxone would prevent atrophy of the gut in 24-h-fasted rats. Male Sprague-Dawley rats (n = 76, body weight 200-225 g) were catheterized in the jugular vein on Day 0. The rats were fed standard rat chow for 4 days. On Day 4, the diet was changed to the standard liquid diet, and the rats were allowed free access to the liquid diet. On Day 7, the rats were randomized into five groups: (1) free fed, (2) free fed plus naloxone, (3) pair fed, (4) fasting, (5) free fed plus morphine, (6) fasting plus naloxone. Either naloxone (0.16 mg/kg/h) or morphine (0. 21 mg/kg/h) was continuously infused via venous catheter for 24 h. On Day 8, 24 h after fasting or free feeding, the animals were sacrificed. Twenty-four hours of fasting caused atrophy of the jejunum and elevated morphine levels in the brain (free fed, 931. 3 +/- 122.3 fmol/g, vs fasting, 1419.0 +/- 150.0, P < 0.05). Morphine infusion reduced villus height, mucosal weight, and protein content in jejunum as compared with the free fed rats receiving saline. Administration of naloxone caused an increase in villus height (fasting, 587.0 +/- 25.8 microm, vs fasting plus naloxone, 670.0 +/- 17.4, P < 0.05), mucosal weight (fasting, 17.4 +/- 1.8 mg/cm, vs fasting plus naloxone, 22.6 +/- 1.9, P < 0.05), and protein content (fasting, 13.5 +/- 0.7 microg/cm, vs fasting plus naloxone, 16.7 +/- 0.6, P < 0.05) in jejunum. Mucosal atrophy of the jejunum is caused by endogenous opioid in fasting rats.

Effects of Repeated Nicotine Administration and Footshock Stress on Rat Mesoprefrontal Dopamine Systems: Evidence for Opioid Mechanisms

We have examined the effects of nicotine pre-treatment on mesoprefrontal dopamine (DA) function in the presence and absence of acute stress, and the involvement of endogenous opiate peptide systems (EOPS). Acute electrical footshock stress preferentially increases DA utilization in medial prefrontal cortex (mPFC) compared to nucleus accumbens (NAS) and striatal terminal fields, and this is correlated with profound locomotor immobility. Our recent studies have demonstrated that repeated, but not acute, nicotine pre-treatment significantly reduced mPFC DA utilization and footshock stress-induced immobility responses. There is increasing evidence that the biochemical and behavioral effects of nicotine are mediated by EOPS, and we hypothesized that the stress-reducing effects of repeated nicotine administration in these studies were mediated by EOPS. Accordingly, rats pre-treated subcutaneously with repeated nicotine were given a single dose of the opiate receptor antagonist naloxone (0.1–10.0 mg/kg, i.p.) or saline as a co-treatment with nicotine or saline 10 min prior to acute footshock stress. Naloxone had no effects on non-stressed or acute footshock stress-induced mPFC DA utilization, but dose-dependently antagonized repeated nicotine's attenuation of stress-induced mesoprefrontal DA utilization and immobility responses. Furthermore, naloxone dose-dependently blocked repeated nicotine's augmentation of accumbal DA utilization. These results suggest that EOPS may be involved in mediating repeated nicotine administration effects on mesoprefrontal dopaminergic and immobility responses to acute footshock stress.

Social aggressiveness of female and subordinate male crickets is released by opiate receptor antagonist

1. In the cricket Gryllus bimaculatus, effects of opiate receptor antagonist naloxone, 9 or 30 microg per animal, on aggressive behavior were investigated. 2. Naloxone had no significant impact on aggression of isolated and dominant males. In contrast, the drug caused a dramatic release of social aggression in female and subordinate male crickets. 3. The results suggest that activity of the opioid system contributes to suppress aggression in subordinate males, as well as in females, during social contacts.

Upregulation of an opioid-mediated antinociceptive mechanism in transgenic mice over-expressing substance P in the spinal cord

In transgenic mice expressing ectopic substance P fibres in the spinal white matter, a normally innocuous mechanical stimulus induces hyperalgesia and allodynia which are reversed by substance P and N-methyl- d-aspartate receptor antagonists. This period of enhanced excitation is followed by a rebound overshoot in these animals. As previous evidence indicates opioid mechanisms in a similar rebound in normal animals, the present study was done to determine the effects of systemic administration of morphine and the opiate receptor antagonist, naloxone, on the stimulus-induced responses in the tail withdrawal reflex. Once baseline reaction times had been taken, different combinations of saline, naloxone and morphine were administered intraperitoneally to transgenic and control mice of either sex. A mechanical conditioning stimulus of 450 g was then applied to the tip of the tail for 2 s. This stimulus was innocuous in control mice given saline or naloxone, but provoked a nociceptive response in transgenic mice given these compounds. In control and transgenic mice, following morphine administration there was an antinociceptive effect. In control mice the subsequent mechanical stimulus had no effect. However, in transgenic mice the mechanical stimulus produced a further antinociception. Naloxone blocked the effect of morphine and the subsequent conditioning stimulus in both control and transgenic mice. The results indicate that while morphine is equally effective on the withdrawal reflex in both types of animal, in the transgenic mice morphine reveals an intrinsic, naloxone-sensitive antinociceptive mechanism. The data are interpreted to suggest that over-expression of substance P or some other factor in the spinal cord of transgenic mice is associated with the up-regulation or facilitation of an opiate-mediated intrinsic antinociceptive mechanism. This is a novel observation because the genetic manipulation in this transgenic mouse results in a transient over-expression of nerve growth factor during development that leads to the formation of ectopic primary afferent fibres in the spinal cord containing substance P. These fibres persist indefinitely after the nerve growth factor levels return to normal. Opioid mechanisms, which are likely of dorsal horn origin, do not fall under the direct influence of nerve growth factor mechanisms and therefore the intriguing possibility is raised that opioid mechanisms in the spinal cord are regulated at least in part by substance P-related mechanisms.

Safety, efficacy, and long-term results of a modified version of rapid opiate detoxification under general anaesthesia: a prospective study in methadone, heroin, codeine and morphine addicts.

In the present study a method of rapid opiate detoxification under general anaesthesia has been evaluated regarding the safety, the efficacy in preventing withdrawal symptoms, and the long-term results. In addition, it was investigated whether the profile and severity of withdrawal symptoms depend on the type of opiate abused (methadone, heroin, codeine, morphine). Seventy-two opiate addicts were detoxified in an intensive care unit (ICU). Anaesthesia was induced and maintained using propofol infusion. Patients were endotracheally intubated. The opiate receptor antagonist naltrexon was administered into the stomach via a nasogastric tube. Withdrawal symptoms before and after the detoxification treatment were assessed using an objective and a subjective opiate withdrawal scale (OOWS, SOWS). After detoxification patients entered a long-term naltrexone maintenance programme as well as a supportive psychotherapy programme. Vital organ function was monitored using haemodynamic and respiratory parameters as well as body temperature. Organ function parameters were stable during the whole treatment in all patients and no anaesthetic complications were registered. Minor side effects such as bradycardia or hypotension were observed in 20 patients. Compared to patients with pre-existing heroin, codeine, or morphine abuse respectively, patients from the methadone maintenance programme had significantly higher (P<0.01) OOWS as well as SOWS values after the treatment. Twelve months after the detoxification 49 patients (68%) were abstinent from opiates whereas 17 patients had relapsed during the period of follow-up. Six patients were lost during follow-up. Rapid opiate detoxification under general anaesthesia is a safe and efficient method to suppress withdrawal symptoms. This treatment may be of benefit in patients who particularly suffer from severe withdrawal symptoms during detoxification and who have failed repeatedly to complete conventional withdrawal. Methadone patients have more withdrawal symptoms than other opiate addicts.

Selective mu and delta, but not kappa, opiate receptor antagonists inhibit the habituation of novelty-induced hypoalgesia in the rat.

There is now extensive evidence demonstrating that exposure to novel stimuli induces hypoalgesia and that this effect habituates over repeated exposure to the stimuli. Moreover, it has been shown that administration of the nonselective opiate receptor antagonist naloxone can attenuate the rate of habituation of novelty-induced hypoalgesia. The present experiments were conducted to determine the relative influence of different opiate receptor subtypes in the attenuation of the habituation of novelty-induced hypoalgesia. In experiments 1-3, different groups of male, Wistar rats (275-300 g) were administered vehicle, 0. 5, 1.0 or 2.0-nmol doses of the mu-selective antagonist Cys(2)-Tyr(3)-Orn(5)-Pen(7)-amide (CTOP), the delta-receptor selective antagonist naltrindole, or the kappa-selective antagonist nor-binaltorphimine (nor-BNI). In experiment 4, animals were administered vehicle, 5, 25 or 75-nmol doses of nor-BNI. All injections were delivered to the right lateral ventricle 30 min prior to exposure to a novel hot-plate apparatus (48.5 degrees C), once a day for eight consecutive days. Paw-lick latencies in vehicle-treated animals were long during the initial exposures and declined over repeated tests, suggesting the habituation of novelty-induced hypoalgesia. The rate of habituation was significantly attenuated by administration of 1.0-nmol and 2.0-nmol doses of CTOP, by a 2.0-nmol dose of naltrindole, but was unaffected by all doses of nor-BNI. These results support the involvement of the mu and delta, but not the kappa, opiate receptor subtypes in the habituation of novelty-induced hypoalgesia.

Inhibition by Naloxone of Promoter Activity of the Neurofilament Gene in SK-N-SH Cells

Chronic administration of morphine is known to decrease the levels of neurofilaments (NFs) in the ventral tegmental area. We ligated a promoter region of the mouse 68-KDa neurofilament (NF-68) gene to the pGL3-enhancer vector containing a luciferase gene, transfected it into SK-N-SH cells and then analyzed transcriptional activity in the cells treated with agonists or antagonists of opiate receptors. The activity of the NF-68 promoter was suppressed by naloxone about 55% at 10(-5) M and 30% at 10(-7) M at 48 h, but suppressed not by morphine. Naltrexone at 10(-5) M suppressed the promoter activity about 20%, but levallorphan, DAMGO, DPDPE and U50488 did not. The inhibition by naloxone was dose-dependent and not reversed by morphine. The inhibitory effect of naloxone was not observed in N18TG-2 cells and PC12 cells. Experiments with various deletion mutants revealed that a region responsible for naloxone suppression spans from -328 to -101 in the gene. These results suggest that naloxone has the ability to suppress transcriptional activity in some neurons.

Morphine stimulates mesangial cell TNF-alpha and nitrite production.

Intravenous opiate abusers are susceptible to develop heroin and HIV-associated nephropathies; however, the role of opiates in the development of these kidney lesions is not clear. Patients with opiate addiction are prone to recurrent infections. The effect of morphine was studied on the generation of TNF-alpha with or without LPS (lipopolysaccharide) by cultured mouse mesangial cells. In addition, the effect of morphine was evaluated on mesangial cell nitrite production. To evaluate the role of opiate receptors, we studied the effect of naloxone and naltrexone on mesangial cell TNF-alpha and nitrite production. To determine the role of TNF-alpha on mesangial cell nitrite production, we examined the effect of anti-TNF-alpha antibody on morphine-induced nitrite production. Assay of TNF-alpha and nitrite production was carried by ELISA and Griess method respectively. Morphine alone did not enhance the generation of TNF-alpha by mesangial cells, however, an enhanced (P < 0.001) TNF-alpha production was observed when mesangial cells were first treated with morphine for 18 h and then activated further with LPS. Maximum release of TNF-alpha was seen at a concentration of 10(-12) M of morphine. Opiate receptor antagonists (naloxone and naltrexone) inhibited the effect of morphine. Morphine also amplified (P < 0.0002) the effect of LPS on mesangial cell nitrite production. Anti-TNF-alpha antibody attenuated morphine induced nitrite generation. We conclude that morphine stimulates the generation of TNF-infinity by LPS-activated mesangial cells. This effect of morphine seems to be opiate receptor mediated and has a downstream effect in the form of mesangial cell nitrite generation. The present in vitro study provides the basis for a hypothesis that morphine may be playing a role in the development of heroin and HIV-associated nephropathies.

Opiate receptor avidity in the thalamus is sexually dimorphic in the elderly

Opiate receptor avidity (B(')(max)/K(D)), was measured in the subcortex of nine females (five healthy subjects, four Alzheimer patients) and 15 males (seven healthy subjects, eight Alzheimer patients), 51-75 years of age, with the opiate receptor antagonist 6-deoxy-6-beta-[(18)F]fluoronaltrexone (cyclofoxy, CF) and a positron emission tomograph. CF avidity was 27.5% less in the thalamus of healthy women compared to healthy men and 48.5% less in Alzheimer disease female patients compared to male patients.

Microinjections of an opiate receptor antagonist into the bed nucleus of the stria terminalis suppress heroin self-administration in dependent rats

Recent anatomical evidence suggests that the shell of the nucleus accumbens, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala, together referred to as the extended amygdala, may play a role in opiate dependence. The bed nucleus of the stria terminalis and the shell of the nucleus accumbens have a moderately high density of opiate receptors, which allows for manipulation of opiate neurotransmission with receptor antagonists. The goal of this study was to determine the role these regions play in opiate reinforcement, and whether dependence alters the reinforcing effects of opiates by examining the effect of local administration of the opiate receptor antagonist methylnaloxonium on heroin self-administration in dependent and nondependent rats. Previous studies revealed that blockade of the reinforcing effects of opiates with systemic administration of opiate receptor antagonists results in an increase in heroin self-administration in nondependent rats, and a greater increase in dependent rats. In the present study, methylnaloxonium dose-dependently suppressed heroin intake when injected into the bed nucleus of the stria terminalis and shell of the nucleus accumbens of dependent rats, and had no effect in nondependent rats. These results demonstrate that opiate receptors in parts of the extended amygdala may be responsible for the reinforcing effects of opiates in dependent animals and suggest that activity in this system may be recruited during the development of dependence.

Cardiotropic effects of Met-enkephalin and somatostatin under conditions of neurotensin receptor blockade.

Pretreatment with the neurotensin receptor antagonist decreased the severity and time of Met-enkephalin-induced inhibition of vagal chronotropic effects in cats. The opiate receptor antagonist naloxone produced a delayed inhibitory effect on the synchronizing component of the vagal chronotropic effect under conditions of neurotensin receptor blockade. Cardiotropic effects of somatostatin remained unchanged during neurotensin receptor blockade. These data indicate one-way and two-way interactions between peptides modulating parasympathetic cardiac regulation.

Naloxone Fails to Prolong Seizure Length in ECT

Electroconvulsive shock (ECS) in animals has been shown to enhance endogenous opiate systems. The anticonvulsant effects of ECS are also partially blocked by the opiate receptor antagonist naloxone, leading some investigators to postulate that the anticonvulsant effects of ECS are mediated by activation of endogenous opiates. If such a phenomenon occurs in humans, then naloxone might prolong seizure length in electroconvulsive therapy (ECT). In the present study, nine patients were given 2.0 mg intravenous (i.v.) naloxone 2 minutes prior to one-half of their ECT treatments. Motor seizure length was measured via the cuff technique. EEG tracings were read by an investigator blind to naloxone status. There was no difference between the two groups in either EEG or nonblindly evaluated motor seizure length. It is concluded that a dose of 2 mg naloxone does not effectively increase seizure length in ECT.

Naloxone reverses disinhibitory/aggressive behavior in 5,7-DHT-lesioned rats; involvement of GABA A receptor blockade?

Effective medical treatment for impulsive aggression and several impulse control disorders is needed. Disinhibited, impulsive behavior of e.g. murderers, arsonists, suicidal patients, and patients suffering from antisocial personality or substance abuse disorders has been associated with signs of a deficiency in brain serotonin (5-HT) systems. Depletion of brain 5-HT consistently produces disinhibition and aggression also in experimental animals. The present series of experiments using a modified Vogel’s conflict test indicates that the disinhibitory behavior of 5-HT-lesioned rats can be reversed by the commonly used opiate receptor antagonist naloxone at doses (0.1–5.0 mg/kg, s.c.) that do not significantly affect behavior in sham-lesioned controls. Moreover, this effect of naloxone, which resembles that previously observed after administration of negative modulators of γ-aminobutyric acid A (GABA A)/benzodiazepine receptor complexes, was reversed by a low inert dose (2.0 mg/kg, i.p.) of amobarbital. Furthermore, both naloxone (5.0 mg/kg, s.c.) and Ro 15-4513 (1.0 mg/kg, p.o.; a partial inverse agonist at benzodiazepine receptors) significantly decreased the number of attacks and the time spent in aggressive acts in 5,7-DHT-lesioned male residents. These results taken together with previous behavioral and neurochemical data suggest that the behavioral effects of naloxone observed here may involve an antagonistic action at brain γ-aminobutyric acid A (GABA A)/benzodiazepine receptor complexes. Thus, naloxone, its stable analogue naltrexone or other weak negative modulators of brain GABA A/benzodiazepine receptor complexes may represent a new pharmacological principle for the treatment of impulse control disorders.

Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases☆, ☆☆, ★

Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases☆, ☆☆, ★

Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal and dermatological diseases

The perception of pruritus is modified by endogenous opiates via central opiate receptors in a histamine-independent manner. The aim of this pilot study was to evaluate the efficacy and safety of naltrexone, an orally active opiate antagonist, in the treatment of severe, otherwise intractable pruritus of different origin in an open-label clinical trial. A total of 50 patients with pruritus caused by internal diseases, hydroxyethyl starch, contact with water, cutaneous lymphoma, atopic dermatitis, xerosis cutis, macular amyloidosis, psoriasis, and other skin disorders as well as with pruritus of unknown origin were randomly selected to receive naltrexone 50 mg daily. The pruritus intensity was rated by the patients before and during therapy in a visual analogue scale. A significant therapeutic response was achieved in 35 of the 50 patients within 1 week (confidence limits of 0.55 and 0.82 at a confidence level of 0. 95). Naltrexone was of high antipruritic effect in 9 of 17 cases of prurigo nodularis and contributed to healing of the skin lesions. Tachyphylaxis was infrequent (6/50), occurred late, and could be counterbalanced by raising the dosage in 2 patients. Adverse drug effects were restricted to the first 2 weeks of treatment and included nausea (11/50), fatigue (3/50), dizziness, heartburn, and diarrhea (1/50 each). The study suggests that oral opiate antagonists might be a well-tolerated and effective therapy for pruritic symptoms in many diseases.

Effects of serotonergic and opioidergic drugs on escape behaviors and social status of male crickets.

We examined the effects of selective serotonin depletion and opioid ligands on social rank and related escape behavior of the cricket Gryllus bimaculatus. Establishment of social rank in a pair of males affected their escape reactions. Losers showed a lower and dominants a higher percentage of jumps in response to tactile cercal stimulation than before a fight. The serotonin-depleting drug alpha-methyltryptophan (AMTP) caused an activation of the escape reactivity in socially naive crickets. AMTP-treated animals also showed a lower ability to become dominants. With an initial 51.6+/- 3.6% of wins in the AMTP group, the percentage decreased to 26+/-1.6% on day 5 after injection. The opiate receptor antagonist naloxone affected fight and escape similarly as AMTP. In contrast to naloxone, the opioid agonist [d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin decreased escape responsiveness to cercal stimulation in naive and subordinate crickets. We suggest that serotonergic and opioid systems are involved in the dominance induced depression of escape behavior.

Opioid and cannabinoid receptor-mediated regulation of the increase in adrenocorticotropin hormone and corticosterone plasma concentrations induced by central administration of Δ 9-tetrahydrocannabinol in rats

The purpose of this study was to investigate the cannabinoid and opioid mediated regulation on the effects of central Δ 9-tetrahydrocannabinol (Δ 9-THC) administration on hypothalamus–pituitary–adrenal (HPA) axis activity in the male rat. Intracerebroventricular (i.c.v.) administration of Δ 9-THC (25, 50, 100 μg/rat) markedly increased plasma adrenocorticotropin hormone (ACTH) and corticosterone concentrations. Time course effect studies revealed that both hormones secretion peaked at 60 min after Δ 9-THC i.c.v. administration (50 μg/rat), decreased gradually and returned to baseline levels by 480 min. The i.c.v. administration of the specific cannabinoid receptor antagonist SR-141716A (3 μg/rat) significantly attenuated the increase of both hormones secretion induced by Δ 9-THC (50 μg/rat). Nevertheless, higher doses (12.5 and 50 μg/rat) of this compound increased both ACTH and corticosterone plasma concentrations. Subcutaneous (s.c.) administration with the opiate receptor antagonist naloxone (0.3 mg/kg) was without effect but significantly diminished the increase of both hormones secretion induced by Δ 9-THC (50 μg/rat). Taken together, these results indicate that opiate and cannabinoid receptors are involved in the activation of the HPA axis induced by Δ 9-THC. Furthermore, the increase of ACTH and corticosterone secretion after the administration of higher doses of SR-141716A than those required to block such activation, suggests that endogenous cannabinoids are tonically inhibiting the release of both hormones or that this agonist-like activity may be part of an uncharacterized action of this compound not mediated by cannabinoid receptors.

Morphine coupling to invertebrate immunocyte nitric oxide release is dependent on intracellular calcium transients

Morphine significantly stimulated invertebrate immunocyte intracellular calcium level increases in a concentration-dependent manner in cells preloaded with Fura™ 2/AM. Morphine’s action was blocked by prior exposure of the cells to the opiate receptor antagonist naloxone. Various opioid peptides did not exhibit this ability, indicating a morphine-μ 3 mediated process. In comparing the sequence of events concerning morphine’s action in stimulating both [Ca 2+] i and NO production in these cells, we found that the first event precedes the second by 42±7 s. The opiate stimulation of [Ca 2+] i was attenuated in cells leached of calcium, strongly suggesting that intracellular calcium levels regulate cNOS activity in invertebrate immunocytes.

Morphine injected into the paraventricular nucleus of the hypothalamus prevents noncontact penile erections and impairs copulation: involvement of nitric oxide.

Male rats show four to six penile erection episodes when put in the presence of an inaccessible receptive female for 80 min. These noncontact erections occur concomitantly with an increase in nitric oxide production in the paraventricular nucleus of the hypothalamus. This is shown by the increases in the NO2- and NO3- concentrations in the paraventricular dialysate obtained from these males by in vivo microdialysis. The NO2- concentration increased from 0.75 +/- 0. 10 microm to 2.89 +/- 0.39 microm and that of NO3- from 4.13 +/- 0. 58 microm to 9.5 +/- 1.2 microm. Morphine (0.5, 1 and 5 microg), given unilaterally into the paraventricular nucleus 15 min before the introduction of the receptive female, prevented the NO2- and NO3- increases, and noncontact erections, dose-dependently. In contrast, the kappa opioid receptor agonist U-69 593 (5 microg) was ineffective. The effects of morphine on NO2- and NO3-, and on noncontact erections, were prevented by the opiate receptor antagonist naloxone (10 microg) injected into the paraventricular nucleus 15 min before morphine. The NO2- and NO3- concentrations were also increased in the paraventricular dialysate of male rats during copulation, i.e. when in copula penile erections occurred. As found with noncontact erections, morphine, but not U-69 593, injected into the paraventricular nucleus prevented the NO2- and NO3- increases and impaired copulatory behaviour, and naloxone prevented these responses when given before morphine. Although some diffusion of the opiate to surrounding brain areas cannot be completely ruled out, the present results suggest that morphine acts through mu receptors in the paraventricular nucleus to impair noncontact erections and copulation. These effects of morphine are apparently mediated by a prevention of the increased nitric oxide production that occurs in the paraventricular nucleus of the hypothalamus of male rats during sexual activity.