Low Doses Of Naloxone Research Articles

Low Dose Naloxone Does Not Improve Nausea and Pruritus Associated with Bolus IV Morphine Administration

Low Dose Naloxone Does Not Improve Nausea and Pruritus Associated with Bolus IV Morphine Administration

Mediation of nitric oxide in inhibitory effect of morphine against electroshock-induced convulsions in mice

Nitric oxide (NO) and morphine have been coupled in many physiological as well as pathological processes. The present study examined the involvement of the l-arginine/NO pathway in the anticonvulsant properties of systemic morphine (2–30 mg/kg) against electroshock seizures (ECS) in mice. Morphine decreased the intensity of maximal electroshock seizures (MES) and increased the threshold for ECS. Neither the NOS substrate l-arginine (30, 60, and 100 mg/kg), the reversible nonspecific NOS inhibitor N G-nitro- l-arginine methyl ester ( l-NAME; 3, 10, and 30 mg/kg), the irreversible specific inducible NOS inhibitor aminoguanidine (20, 50, and 100 mg/kg), nor the opioid receptor antagonist naloxone (0.1, 0.3, and 1 mg/kg) did alter per se the ECS threshold or the intensity of MES at doses used. However, both naloxone and l-NAME, but not aminoguanidine, inhibited the anticonvulsant effects of morphine (30 mg/kg) against ECS, while l-arginine potentiated the anticonvulsant effects of lower doses of morphine (2 or 10 mg/kg). Low doses of naloxone (0.1 or 0.3 mg/kg) or l-NAME (3 mg/kg), which did not alter morphine effect per se, showed additive anticonvulsant effects against MES. Thus, the l-arginine/NO pathway seems to play a role in the anticonvulsant properties of morphine against ECS and this mediation involves the constitutive, but not the inducible, form of nitric oxide synthase.

The involvement of endogenous opioids and nitricoxidergic pathway in the anticonvulsant effects of foot-shock stress in mice

The involvement of endogenous opioids and nitric oxide (NO) in the anticonvulsant effects of stress against pentylenetetrazole (PTZ)- or electroconvulsive shock-induced seizures was assessed in mice. The prolonged and intermittent foot-shock stress, which induced opioid-mediated analgesia, had significant protective effects against both seizure types which was reversible by naloxone (0.3, 1 or 2 mg/kg), while brief and continuous foot-shock did not alter the seizure susceptibility. Pre-treatment with non-specific nitric oxide synthase (NOS) inhibitor, N G-nitro- l-arginine methyl ester ( l-NAME, 1, 2, 5, 10 or 30 mg/kg), but not with specific inducible NOS (iNOS) inhibitor, aminoguanidine (50 or 100 mg/kg), blocked the stress-induced anticonvulsant effects. The lower doses of naloxone (0.3 mg/kg) and l-NAME (2 mg/kg) showed additive effects in blocking the stress-induced anticonvulsant properties. l-arginine at a per se non-effective dose of 20 mg/kg potentiated the stress-induced anticonvulsant properties, an effect which was inhibited by l-NAME but not by aminoguanidine. Furthermore, a low dose of morphine (0.5 mg/kg) showed potentiation with stress in increasing PTZ seizure threshold. This potentiation was reversed by either naloxone or l-NAME at low doses but not by aminoguanidine. Taken together, these results show that NO synthesis, through constitutive but not iNOS, is involved in opioid-dependent stress-induced anticonvulsant effects against electrical and PTZ-induced convulsions.

Opiate Withdrawal-Induced Fos Immunoreactivity in the Rat Extended Amygdala Parallels the Development of Conditioned Place Aversion

Low doses of naloxone have been shown to affect the motivational aspects of opiate withdrawal in morphine-dependent rats. Conditioned place aversion to opiate withdrawal is one of the most sensitive of motivational indices of opiate withdrawal and is thought to be mediated by the basal forebrain. Expression of the transcription factor Fos is known to increase during opiate withdrawal, but its presence during low-dose antagonist-precipitated withdrawal has not previously been established. In order to determine if there is a relationship between withdrawal-induced neuronal activity and conditioned place aversion, immunocytochemical localization of Fos was examined in the basal forebrain of opiate-dependent animals receiving one of several doses of naloxone (0, 3.25, 7.5, 15, 30, or 1000 μg/kg). In separate groups of opiate-dependent animals, naloxone doses of 3.25 - 30 μg/kg were paired with a specific chamber in a single-pairing conditioned place aversion paradigm. Significant increases in both immunocytochemical detection of Fos and conditioned place aversion were seen at doses ≥ 7.5 μg/kg. The shell of the nucleus accumbens and central nucleus of the amygdala were most sensitive to low doses, thus supporting the hypothesis that the extended amygdala plays a role in opiate-induced condition place aversion.

The Effects of Low-dose Naloxone in Intravenous Fentanyl Patient-Controlled Analgesia

The Effects of Low-dose Naloxone in Intravenous Fentanyl Patient-Controlled Analgesia

Effects of Low-dose Naloxone on Postoperative Analgesia and Side Effects in Intravenous Patient-Controlled Analgesia after a Total Hysterectomy

Effects of Low-dose Naloxone on Postoperative Analgesia and Side Effects in Intravenous Patient-Controlled Analgesia after a Total Hysterectomy

Naloxone in the Prevention of the Adverse Cognitive Effects of ECT: A Within-Subject, Placebo Controlled Study

Electroconvulsive therapy (ECT) is a highly effective treatment for major depression, but is also associated with characteristic cognitive side effects. Several reports document that endogenous opioids and their receptors are activated by electroconvulsive shock (ECS) and that naloxone in doses sufficient to block endogenous opioid receptors may reverse ECS-induced retrograde amnesia. This placebo-controlled, randomized, within-patient study was conducted to examine the potential of naloxone, given in doses sufficient to block opioid receptors (high dose), to ameliorate acute anterograde and retrograde memory impairments following ECT. Compared to placebo and low dose naloxone, high dose naloxone administered immediately before ECT resulted in significant reductions in anterograde amnesia, and better performance on an attention task. Both low and high dose naloxone improved verbal fluency. There were no beneficial effects of high dose naloxone on retrograde amnesia, and an indication that high dose naloxone may have worsened retrograde amnesia for shape stimuli. There were no effects of high dose naloxone on seizure duration, vital signs, and subjective side effects. The study is consistent with prior research in which change in behavioral and physiological measures was produced principally by naloxone doses sufficient to block endogenous opioid receptors and offers evidence of the potential for ameliorating some adverse cognitive effects associated with ECT.

Naloxone challenge in smokers. Preliminary evidence of an opioid component in nicotine dependence.

This study used an opioid antagonist challenge procedure to evaluate the responsivity of the endogenous opioid system in nicotine-dependent individuals, as evidenced by naloxone-induced alterations in both behavioral (withdrawal, craving) and neuroendocrine (cortisol levels) parameters. Twenty subjects (9 smokers and 11 nonsmokers) participated in 4 laboratory sessions during which they were challenged with 0, 0.8, 1.6, or 3.2 mg/70 kg of naloxone and then monitored for 1 hour for subjective signs and symptoms of opiate-like withdrawal, nicotine craving, and alterations in cortisol levels. Nicotine-dependent subjects evidenced naloxone dose-dependent increases in withdrawal signs and symptoms. Lower doses of naloxone also produced increases in urges to smoke (craving) and tiredness in smokers. Smokers, when compared with nonsmokers, had lower prenaloxone baseline levels of cortisol and attenuated cortisol release in response to challenge with naloxone. These results provide preliminary evidence to suggest that long-term exposure to cigarette smoke is associated with alterations in the responsivity of the endogenous opioid system and the hypothalamic-pituitary-adrenal axis that may contribute to the development of nicotine dependence.

Cardiac function is a risk factor for paralysis in thoracoabdominal aortic replacement

Purpose: We studied factors that influence paralysis risk, renal function, and mortality in thoracoabdominal aortic replacement. Methods: We prospectively collected preoperative demographic and intraoperative physiologic data and used univariate and multivariate analyses to correlate this data with risk factors for paralysis. A mathematical model of paraplegia risk was used to study the efficacy of paraplegia reduction strategies. We analyzed preoperative and operative factors for paralysis risk, renal function, and mortality for 217 consecutive patients surgically treated from 1984 through 1996 for 176 thoracoabdominal and 41 thoracic aneurysms at the University of Wisconsin Hospital and Clinics. No patient had intercostal reimplantation or assisted circulation. One hundred fifty patients (group A) received cerebrospinal fluid drainage (CSFD) and low-dose naloxone (1 μg/kg/hour) as adjuncts to reduce the risk of paralysis. Sixty-seven patients (group B) did not receive CSFD and naloxone. Results: Seventeen deficits occurred in 205 surviving patients: 5 of the 147 in group A (expected deficits = 31) and 12 of the 58 in group B (expected deficits = 13) p < 0.001). In a multivariate logistic regression model, acute presentation, Crawford type 2 aneurysm, group B membership, and a decrease in cardiac index with aortic occlusion remained significant risk factors for deficit p < 0.0001). By odds ratio analysis, group A patients had 1/40th the risk of paralysis of group B. The only significant predictor of postoperative renal function was the preoperative creatinine level p < 0.0001); renal revascularization significantly improved renal function. The mortality rate was 1.6% (2) for patients undergoing elective treatment and 21% (19) for patients who had acute presentations. Acute presentation, age, and the preoperative creatinine level were found to be significant factors for operative mortality in a logistic regression model p < 0.001) and defined a group at high risk for death. Conclusions: CSFD and low-dose naloxone significantly reduce the paralysis risk associated with thoracoabdominal aortic replacement. A decrease in the cardiac index with aortic occlusion is a previously unreported variable that defines a subset of patients at higher risk for paralysis. (J Vasc Surg 1998;27:821-30.)

Combined Naloxone and Fluoxetine on Deprivation-Induced Binge Eating of Palatable Foods in Rats

Opioid antagonism and serotonergic stimulation is associated with macronutrient-specific hypophagia in animals. In the present study we evaluated their systemic effect alone, and in combination, at various doses, on the intake of sweet carbohydrate-rich and sweet fat-rich foods, tastes, and nutrients that are typical of binge-food items. Low-dose (1 mg/kg) naloxone, alone, preferentially suppressed fat-rich intake while low-dose (2.5 mg/kg) fluoxetine, alone, preferentially suppressed carbohydrate-rich intake. Each drug at these doses, combined with various doses of the other (2.5–10 mg/kg fluoxetine; 0.01-1 mg/kg naloxone) additively suppressed both kinds of the sweet foods. Naloxone and fluoxetine have therapeutic potential in treating binge-eating disorders. This animal study suggests what shortcomings and benefits might be expected when combining these two agents.

Antinociceptive effects of morphine and U-50,488h on vaginal distension in the anaesthetized rat

The antinociceptive activity of the k- and μ-opioid receptor agonists, (±)-U-50,488H and morphine, was examined in a vaginal distension model in anaesthetized female rats. Vaginal distension induced a reproducible cardiovascular response (CVR) which was inhibited in a dose related manner by morphine ( 0.03 − 1.0 mg kg i.v., ED 50 = 0.16 mg kg ) and (±)-U-50,488H ( 0.08−1.6 mg kg i.v., ED 50 = 0.49 mg kg ). Morphine (0.3 μg/rat) administered i.c.v. inhibited the CVR by 81.6 ± 7.9% whereas (±)-U-50,488H (30–300 μg/rat) was inactive by this route. A low dose of naloxone (30 μg kg i.v.) blocked the effect of morphine but not that of (±)-U- 50, 488H. The k-opioid antagonist, nor-binaltorphimine (10 mg kg s.c.) abolished the response to (±)-U-50,488H but not that of morphine. This demonstrates that both central and peripheral μ-opioid receptors may be involved in morphine-induced antinociception whereas the k-opioid agonist, (±)-U-50,488H, blocks vaginal nociception by acting on peripheral k-opioid receptors.

The subnucleus reticularis dorsalis is involved in antinociception produced by a low dose of naloxone during carrageenan-induced inflammation

The present study was designed to investigate a role of the subnucleus reticularis dorsalis (SRD) in the analgesia produced by a low dose of naloxone during carrageenan-induced inflammation. Male Sprague–Dawley rats were divided into the following two groups: (1) rats with bilateral lesions of the SRD ( n=13) and 2) sham-operated rats ( n=24). In each group, effects of a low dose of naloxone (5 μg/kg, i.p.) on thermal nociception were examined 4 h, 7 and 28 days after the induction of unilateral inflammation. Carrageenan (6 mg in 0.15 ml saline) was injected subcutaneously into the plantar surface of the left hindpaw. The analgesic effect was assessed by prolongation of the paw withdrawal latency (PWL) to heating. Prior to carrageenan injection, a low dose of naloxone did not prolong PWLs in either group. Four hours after carrageenan, a low dose of naloxone produced a prolongation of PWLs in both sham-operated and SRD-lesioned rats. Seven days after carrageenan, naloxone failed to produce analgesia in the SRD-lesioned rats but did produce analgesia in the sham-operated rats. At 28 days, a low dose of naloxone induced hyperalgesia in the inflamed paw of both groups, whereas naloxone was ineffective in the contralateral non-inflamed paw. These results suggest that the SRD plays a role in naloxone-induced analgesia during the subacute phase of inflammation (e.g. 7 days after induction of inflammation).

Ischemic Preconditioning is Mediated by a Peripheral Opioid Receptor Mechanism in the Intact Rat Heart

Previously, our laboratory has shown that opioid receptors are involved in ischemic preconditioning (PC) in the intact rat heart; however, it is not known whether this cardioprotection is mediated by central or peripheral mechanisms. To test this hypothesis, both naloxone (NL), the non-selective opioid receptor antagonist and naloxone methiodide (QNL), its quaternary derivative which does not cross the blood–brain barrier, were used to determine if opioid receptor-induced myocardial protection occurs via a central or peripheral locus of action in inactin-anesthetized, open-chested, Wistar rats. In group I, the control group was subjected to 30 min of occlusion and 2 h of reperfusion. In group II, ischemic PC was elicited by three 5-min occlusion periods interspersed with 5 min of reperfusion. In group III, QNL (10 mg/kg, i.v.) was administered 10 min before the 30 min of occlusion. Groups IV and V consisted of a dose–response effect of QNL on ischemic PC in which QNL (0.3 or 10 mg/kg, i.v., respectively) was given 10 min prior to ischemic PC. In addition, in groups VI and VII, one of two doses of naloxone (1 or 3 mg/kg, i.v.) was administered 10 min before ischemic PC. Infarct size (IS) as a percentage of the area at risk (AAR) was determined by tetrazolium staining. Ischemic PC reduced IS to 9±2% (P<0.05)vcontrol (53±4%). The low dose of QNL partially blocked the cardioprotective effect of ischemic PC; whereas the high dose completely abolished its cardioprotective effect. The high dose of QNL had no effect on IS alone. Similarly, the low dose of NL did not antagonize the cardioprotective effect of ischemic PC; however, the high dose completely abolished ischemic PC. These results indicate that the cardioprotective effect of ischemic preconditioning is mediated by a peripheral opioid receptor mechanism in the intact rat heart.

Effects of naloxone on amphetamine induced striatal dopamine release in vivo: A microdialysis study

The opiate antagonist naloxone (NX) alters amphetamine (AMPH) induced behaviors including locomotor activity, rearing and stereotypy. However, the exact nature of the NX induced alteration of AMPH induced behaviors is controversial, with some studies using high (5–40 mg kg ) doses of NX reporting an inhibition, and others using low (≤ 1–2 mg kg ) doses observing a potentiation. As these behaviors are mediated by AMPH induced dopamine (DA) release, the effect of NX on the latter was examined by microdialysis in an effort to resolve the controversy. Saline and NX pretreated groups subsequently administered AMPH were compared in vivo across nine separate 10 min intervals as well as by grouped intervals. NX alone (0.8 mg kg ) and saline exerted statistically equivalent effects on striatal DA release with the exception of the fifth interval, where a small but significant increase was seen after NX. On the other hand, the same dose of NX significantly enhanced AMPH induced striatal DA release relative to saline pretreated animals during each of four separate intervals, from 30 to 70 minutes following AMPH (1.5 mg kg ), and across all nine intervals combined. NX pretreatment (0.8 mg kg ) followed by a higher dose of AMPH (3.0 mg kg ) produced a significantly greater cumulative effect on DA release than saline pretreatment over the last six combined intervals (30–90 min) and over two grouped intervals (30–50 min and 40–60 min inclusive). However, a comparison of single rather than paired or grouped intervals revealed no significant differences. Previous studies have also examined the effect of NX on AMPH induced striatal DA release using in vivo microdialysis. However, the doses used were invariably high (5 mg kg ) and the results on striatal DA release always inhibitory. The present results suggest that NX potentiates AMPH induced striatal DA release when lower doses of NX are used. These results combined with those of previous studies also suggest that NX exerts a biphasic effect on AMPH induced DA release, with lower doses potentiating release and higher doses inhibiting release. This is close agreement with behavioral observations and may be due to the effect of low versus high doses of NX on intraterminal calcium influx.

Fedotozine blocks hypersensitive visceral pain in conscious rats: action at peripheral κ-opioid receptors

The effect of fedotozine on visceral hypersensitivity was evaluated in conscious rats. One hour after colonic irritation (0.6% acetic acid intracolonically), a 30 mmHg colonic distension was applied for 10 min. Irritation increased the number of abdominal contractions induced by colonic distension (23.4±4.1 versus 4.8±1.4 in saline-treated rats, P<0.001). Facilitation of colonic pain was reversed in a dose-dependent manner by fedotozine ((+)-(-1 R)-1-phenyl-1-[(3,4,5-trimethoxy)benzyloxymethyl]- N, N-dimethyl- n-propylamine), (±)-U-50,488H ( trans-(±)-3,4-dichloro- N-methyl- N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide) and morphine (respective ED 50 values 0.67, 0.51 and 0.23 mg/kg s.c.). The κ-opioid receptor antagonist, nor-binaltorphimine, abolished the effects of fedotozine and (±)-U-50,488H but not those of morphine. Low doses of naloxone (30 μg/kg s.c.) blocked the effect of morphine but not of fedotozine or (±)-U-50,488H. After intracerebroventricular administration, morphine was very potent (ED 50 1.7 μg/rat), (±)-U-50,488H poorly active (58% of antinociception at 300 μg/rat) and fedotozine inactive up to 300 μg/rat. These results show that fedotozine blocks hypersensitive visceral pain by acting on peripheral κ-opioid receptors in animals. © 1997 Elsevier Science B.V.

Naloxone reverses the inhibitory effect of γ-hydroxybutyrate on central da release in vivo in awake animals: a microdialysis study

γ-Hydroxybutyrate (GHB) is a 4-carbon anesthetic that acts primarily by inhibiting presynaptic dopamine (DA) release in vivo. A number of studies have reported a reversal of many of the central effects of GHB by the allegedly pure opiate antagonist naloxone (NX) but its mechanism of action is unclear. In vivo microdialysis performed in the present preliminary study disclosed a significant inhibitory effect of GHB (500 mg/kg) on striatal DA release which was completely reversed by a low dose of NX (0.8 mg/kg). The results indicate that NX likely inhibits many of the central effects produced by GHB primarily through its reversal of the GHB induced inhibition of central DA release.

Alpha-Adrenoceptor and opioid receptor modulation of clonidine-induced antinociception.

1. The antinociceptive action of clonidine (Clon) and the interactions with alpha 1, alpha 2 adrenoceptor and opioid receptor antagonists was evaluated in mice by use of chemical algesiometric test (acetic acid writhing test). 2. Clon produced a dose-dependent antinociceptive action and the ED50 for intracerebroventricular (i.c.v.) was lower than for intraperitoneal (i.p.) administration (1 ng kg-1 vs 300 ng kg-1). The parallelism of the dose-response curves indicates activation of a common receptor subtype. 3. Systemic administration of prazosin and terazosin displayed antinociceptive activity. Pretreatment with prazosin produced a dual action: i.c.v. Clon effect did not change, and i.p. Clon effect was enhanced. Yohimbine i.c.v. or i.p. did not induce antinonciception, but antagonized Clon-induced activity. These results suggest that alpha 1- and alpha 2-adrenoceptors, either located at the pre- and/or post-synaptic level, are involved in the control of spinal antinociception. 4. Naloxone (NX) and naltrexone (NTX) induced antinociceptive effects at low doses (microgram kg-1 range) and a lower antinociceptive effect at higher doses (mg kg-1 range). Low doses of NX or NTX antagonized Clon antinociception, possibly in relation to a preferential mu opioid receptor antagonism. In contrast, high doses of NX or NTX increased the antinociceptive activity of Clon, which could be due to an enhanced inhibition of the release of substance P. 5. The results obtained in the present work suggest the involvement of alpha 1-, alpha 2-adrenoceptor and opioid receptors in the modulation of the antinociceptive activity of clonidine, which seems to be exerted either at spinal and/or supraspinal level.

Naloxone reverses the inhibitory effect of γ-hydroxybutyrate on central DA release in vivo in awake animals: a microdialysis study

γ-Hydroxybutyrate (GHB) is a 4-carbon anesthetic that acts primarily by inhibiting presynaptic dopamine (DA) release in vivo. A number of studies have reported a reversal of many of the central effects of GHB by the allegedly pure opiate antagonist naloxone (NX) but its mechanism of action is unclear. In vivo microdialysis performed in the present preliminary study disclosed a significant inhibitory effect of GHB (500 mg/kg) on striatal DA release which was completely reversed by a low dose of NX (0.8 mg/kg). The results indicate that NX likely inhibits many of the central effects produced by GHB primarily through its reversal of the GHB induced inhibition of central DA release.

Biochemical Evidence of Functional Interaction Between μ‐ and δ‐Opioid Receptors in SK‐N‐BE Neuroblastoma Cell Line

Radioligand binding assays and functional experiments revealed that the SK-N-BE neuroblastoma cell line expresses a similar ratio of mu- and delta-opioid receptors, both negatively coupled to adenylyl cyclase through pertussis toxin-sensitive G proteins. Our findings also indicate that some functional interaction occurred between the two opioid subtypes; in fact, long-term exposure to [D-Ala2-N-methyl-Phe4-Gly-ol5]enkephalin (DAMGO), a mu-selective agonist, sensitized the functional response of the delta-selective agonist but not vice versa. It is interesting that in acute interaction experiments, we observed a shift to the right of the concentration-effect curve of either DAMGO or [D-Pen2,5]enkephalin (DPDPE), a delta-selective agonist, as a result of DPDPE or DAMGO administration, respectively. In addition, low doses of naloxone, an antagonist selective for mu receptors, increased the inhibitory effect [D-Ala2-D-Met5]enkephalinamide (DAME), a mixed mu/delta agonist, on adenylyl cyclase activity. Taken overall, these data support the hypothesis of the existence of a cross talk between mu and delta receptors in the SK-N-BE cell line.

Effect of morphine on dynorphin B and GABA release in the basal ganglia of rats

In vivo microdialysis was used to study the effects of systemic, as well as intracerebral administration of morphine and naloxone on dynorphin B release in neostriatum and substantia nigra of rats. The release of dopamine (DA), γ-aminobutyric acid (GABA), glutamate (Glu) and aspartate (Asp) was also investigated. Systemic injection of morphine (1 mg/kg s.c.) induced long-lasting increases in extracellular dynorphin B and GABA levels in the substantia nigra, whereas DA, Glu and Asp levels, measured in the same region, were not significantly affected. No effect on striatal neurotransmitter levels was observed following systemic morphine administration. Local perfusion of the substantia nigra with morphine (100 μM) through the microdialysis probe also increased nigral dynorphin B and GABA levels. Perfusion of the neostriatum with morphine (100 μM) significantly increased GABA and dynorphin B levels in the ipsilateral substantia nigra, but no effect was observed locally. Naloxone blocked the effect of systemic morphine administration on nigral dynorphin B and GABA release, already at a dose of 0.2 mg/kg s.c. Naloxone alone, given either systemically (0.2–4 mg/kg s.c.) or intracerebrally (1–100 μM), did not affect dynorphin B or amino acid levels, either in neostriatum or in substantia nigra. However, naloxone produced a concentration-dependent increase in DA levels. The present results indicate that systemic morphine administration stimulates the release of dynorphin B in the substantia nigra, probably by activating the μ-subtype of opioid receptor, since the effect of morphine on nigral dynorphin B and GABA was antagonized by a low dose of naloxone. The increase in extracellular DA levels produced by high concentrations of naloxone, both in neostriatum and substantia nigra, indicates a disinhibitory effect of this drug on DA release, probably via a non-μ subtype of opioid receptors located on nigro-striatal DA neurones.