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PubMed1993

Sites of action of naloxone in precipitating withdrawal jumping in morphine-dependent mice: investigations by the ED50 value and CNS content of naloxone.

The sites of action of naloxone and the possible interaction between supraspinally and spinally administered naloxone in precipitating withdrawal jumping were investigated by comparing the ED50 value and central nervous system (CNS) content of naloxone after three different administration routes in morphine-dependent mice. ED50 values of naloxone for i.c.v., i.t. and s.c. routes were 18.8 nmol, 1.95 nmol and 50.6 nmol/kg, respectively. Jumping occurred most often within 5 min after i.t administered naloxone, but it took more than 10 min to reach the most frequent jumping after s.c. and i.c.v. administered naloxone. After equi-effective doses (ED50) of naloxone were administered i.c.v., i.t. or s.c., the content of naloxone in the brain was 70 times lower after s.c. than that after i.c.v. injection. The concentration of naloxone in the spinal cord was 37 times lower after s.c. than that after i.t. injection. The ED50 values of naloxone and the time courses of jumping suggest that spinal sites appear to be more important than the supraspinal sites and comparisons of naloxone-content suggest that there is a synergistic interaction between supraspinal- and spinal-naloxone after systemic administration.

Animals↗

PubMed2005

Incidence and characteristics of naloxone use in postoperative pain management: a critical examination of naloxone use as a potential quality measure.

The administration of naloxone may be an important monitor of the quality and safety of postoperative pain management. However, studies that support the use of naloxone as a quality measure are absent. The purposes of this study are to determine the incidence and factors associated with naloxone administration in the postoperative setting and to critically examine naloxone as a potential quality measure. Participants included all postoperative adult inpatients at an academic hospital who received naloxone and an equal number of matched control patients who did not receive naloxone during the calendar year 2003. Medical record audits were performed to examine patient demographics, relevant medical history, postoperatively administered analgesics and central nervous system depressants, documented sedation and respiratory assessments, reason provided for naloxone administration, and patient outcome. Naloxone was administered to .53% (56/10,511) of all adult inpatient postoperative patients. Patients who received naloxone were significantly older and received more central nervous system depressants than cohorts. No significant differences were found in comorbidities, route of opioid administration, or amount of opioids taken by the two groups. Reversal of excessive opioid-induced sedation was the primary reason provided for naloxone administration. However, 25% of the patients were later determined to have a new diagnosis that contributed to sedation. Examination of naloxone administration proved useful in uncovering deficits in structures and processes of care. However, caution is warranted when using naloxone as a quality measure to avoid the implication that higher use indicates opioid analgesic over-treatment or error.

Adult↗

PubMed2003

Naloxone and its quaternary derivative, naloxone methiodide, have differing affinities for mu, delta, and kappa opioid receptors in mouse brain homogenates.

Naloxone and naloxone methiodide both act on opioid receptors but naloxone methiodide has limited access to the brain. Naloxone methiodide has been shown to have a lower affinity for opioid receptors than naloxone in the rat and guinea pig but has not been tested in the mouse. We aimed to investigate this by using [3H]DAMGO, [3H]DPDPE and [3H]U-69,593 to compare the ability of naloxone and naloxone methiodide to displace binding to mu, delta and kappa opioid receptors in mouse brain homogenates. Significant binding was observed for each receptor type and the binding affinity for naloxone versus naloxone methiodide was found to be 15:1 for mu, 6:1 for kappa and 330:1 for delta receptors. Therefore, naloxone methiodide does have a lower affinity for opioid receptors than naloxone in mouse brain tissue, which must be taken into consideration in experimental designs.

Analgesics, Opioid↗

PubMed1986

Pharmacokinetics of morphine and its surrogates. VIII: Naloxone and naloxone conjugate pharmacokinetics in dogs as a function of dose and as affected by simultaneously administered morphine.

Reversed-phase HPLC assays with electrochemical detection, developed to quantify naloxone, 6 beta-naloxol, and their hydrolyzed conjugates in biological fluids provided assay sensitivities of 10 to 20 ng/mL in plasma, urine, and bile. These fluids were monitored in dogs after iv bolus administrations of 0.47 and 4.7 mg/kg of naloxone. Plasma concentration-time data were well fitted by the sums of two exponentials with two sequential half-lives of 11 +/- 1 (SEM) and 56 +/- 3 min. Pharmacokinetics were dose-independent; total and renal clearances were 1334 +/- 133 mL/min and 42 +/- 9 mL/min, respectively, with a renal clearance of 65 +/- 5 mL/min for the conjugate. The percentage of the dose excreted in the urine as naloxone was 4.4 +/- 1.0%. There was a possible dose-dependent excretion of conjugate with 46 +/- 1 and 22 +/- 5% of the dose renally excreted at the high and low doses, respectively. In incomplete biliary cannulation, 13 and 18% were collected as conjugate in the bile of two bile-cannulated dogs. There was negligible biliary secretion of unchanged naloxone. Neither 6 beta-naloxol nor its conjugates were metabolites of naloxone in dogs. The simultaneous administration of naloxone does not reverse the dose-dependent pharmacokinetic perturbations of morphine. Morphine significantly lessened its own body, renal, and biliary clearances, as well as those of naloxone, and also lowered their apparent overall volumes of distribution. Plasma levels of naloxone and its conjugate were elevated with simultaneous morphine administration. Urinary flow rates were also greatly lessened and initial renal shut-down was implied at the higher morphine dose. Thus, the established competitive antagonistic action of naloxone on morphine does not extend to the reversal of the biological feedback effects of morphine on the metabolism and excretion of itself and simultaneously administered naloxone.

Animals↗

PubMed2004

Naloxone reversal of opioid anesthesia revisited: clinical evaluation and plasma concentration analysis of continuous naloxone infusion after anesthesia with high-dose fentanyl.

PURPOSE: In spite of several advantages, the need for postoperative ventilatory support limits the use of high-dose opioid anesthesia. We prospectively evaluated the effectiveness of naloxone infusion for the reversal of high-dose fentanyl anesthesia. METHODS: Anesthesia was maintained with fentanyl in patients undergoing major abdominal surgery. After anesthesia, the trachea was extubated when intravenous naloxone, which was titrated in separate 50- micro g doses, established an acceptable level of consciousness and arterial blood gas (ABG) status under spontaneous respiration; this was followed by continuous infusion started at the rate of the sum of the bolus doses per hour. The naloxone infusion was terminated based on evaluation of the level of consciousness, ABG, and acute abstinence symptoms. Postoperative pain was evaluated using self-reported four-step categorical terms (none, mild, moderate, and severe). Plasma concentrations of fentanyl and naloxone were analyzed in 12 patients, using high-performance liquid chromatography. RESULTS: Fifty-seven out of 59 eligible patients were successfully extubated at 34 +/- 14 min after termination of fentanyl (total dose, 127 +/- 64 micro g.kg(-1); mean +/- SD) with naloxone (total bolus, 3.4 +/- 2.6 micro g.kg(-1)). All these patients recovered fully without ventilatory support under the naloxone infusion, which was terminated at 11 +/- 7 h. The reduction of the naloxone infusion rate effectively relieved the increased pain, and no supplemental analgesic was used in any patients during the naloxone infusion. Pharmacokinetic analysis did not indicate any correlations between plasma fentanyl and naloxone concentrations. CONCLUSION: The results suggest that naloxone infusion with individual dose titration facilitates the use of high-dose opioid anesthesia, maintaining the advantager of this anesthesia.

Abdomen↗

PubMed1990

Enhanced anorectic potency of naloxone in rats sham feeding 30% sucrose: reversal by repeated naloxone administration.

The time-course of naloxone-anorexia was monitored in gastric-fistulated rats sham feeding sucrose (10%, 20%, 30%) solutions. Naloxone reduced sham intake dose dependently without affecting feeding initiation and in a manner which resembled the effects of progressive sucrose dilution. However, when rats sham fed 30% sucrose there was a 2-fold increase in the anorectic potency of naloxone. This exaggerated response was prevented by prior repeated naloxone treatment (5 mg/kg IP, bi-daily), concurrent with the stabilization of sham intake levels (4 days). A further experiment ruled out the possibility that tolerance develops to naloxone effects on this treatment schedule, since intact rats showed a suppression of wet mash consumption following repeated naloxone treatment which was equivalent to an acute naloxone challenge. It is proposed that 1) repeated sucrose sham feeding enhances opioid release and leads to opioid receptor adaptation (down-regulation); 2) repeated (chronic) naloxone treatments have an opposite effect on opioid receptors (up-regulation); 3) the two manipulations, in combination, counteract each other's effects. These behavioural data demonstrate dynamic changes in sham-feeding performance as a function of sucrose concentration and naloxone treatments, reinforce the importance of palatability in naloxone-anorexia, and support opioid involvement in orosensory reward.

Animals↗

PubMedDate not supplied

The effect of quaternary naloxone on the increased naloxone potency induced by morphine.

Using the abdominal constriction test in mice it was shown that the antinociceptive effect of morphine was inhibited by naloxone hydrochloride and its quaternary derivative naloxone methylbromide which presumably only acts peripherally. Pretreatment with a single dose of morphine 2.0 mg/kg s.c. did not alter the antinociceptive effect of a second dose of morphine given 3 h later. However, the antagonistic effect of naloxone against morphine was enhanced at this time. The development of increased naloxone potency was inhibited when naloxone hydrochloride was given together with morphine in the pretreatment. A similar inhibitory effect was observed when the quaternary derivative naloxone methylbromide was used instead of naloxone hydrochloride in the pretreatment regime. As there was no difference between the effects of naloxone hydrochloride and naloxone methylbromide in suppressing the development of increased naloxone potency induced by morphine pretreatment, it was concluded that this phenomenon may be mediated mainly through peripheral opiate receptors.

Analgesics↗

PubMed2006

dextro-Naloxone or levo-naloxone reverses the attenuation of morphine antinociception induced by lipopolysaccharide in the mouse spinal cord via a non-opioid mechanism.

Glial stimulation by intrathecal injection of lipopolysaccharide (LPS) attenuated the tail-flick inhibition produced by morphine given intrathecally in the spinal cord of the male CD-1 mice. The phenomenon has been defined as antianalgesia. The effects of dextro-naloxone or levo-naloxone on the attenuation of morphine-produced tail-flick inhibition induced by LPS were then studied. Pretreatment with dextro-naloxone or levo-naloxone reversed the attenuation of the morphine-produced tail-flick inhibition induced by LPS. Pretreatment with dextro-naloxone or levo-naloxone alone did not affect the morphine-produced tail-flick inhibition. It is concluded that dextro-naloxone and levo-naloxone block the LPS-induced antianalgesia against morphine antinociception via a non-opioid mechanism.

Analgesics, Opioid↗

PubMed1984

Comparison of the effects of naloxone and picrotoxin on schedule-controlled responding in the pigeon: possible GABA-antagonistic effects of naloxone.

The effects of naloxone and picrotoxin were determined alone and in conjunction with pentobarbital, diazepam or clonazepam, in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of food presentation. Naloxone (10.0-80.0 mg/kg i.m.) and picrotoxin (0.1-0.56 mg/kg i.m.) alone produced only dose-related decreases in responding in both fixed-ratio and fixed-interval components. Pentobarbital (3.0 and 10.0 mg/kg i.m.) administered in combination with naloxone and picrotoxin shifted dose-response curves for both naloxone and picrotoxin to the right. In contrast, both diazepam (1.0-10.0 mg/kg p.o.) and clonazepam (0.3-3.0 mg/kg p.o.) attenuated the rate-decreasing effects of 0.56 mg/kg of picrotoxin, but not those of 80.0 mg/kg of naloxone. Dose-effect curves for naloxone and picrotoxin were then determined during daily administration of 10.0 mg/kg of diazepam. Dose-response curves for both naloxone and picrotoxin were shifted to the right under these conditions. These data support previous evidence that naloxone exerts gamma-aminobutyric acid-antagonistic effects in addition to its potent opioid-antagonistic effects.

Animals↗

PubMed1991

Involvement of histamine in naloxone-resistant and naloxone-sensitive models of swim stress-induced antinociception in the mouse.

The antinociceptive activity of histamine in male mice has been demonstrated using chemical and thermal noxious stimuli and its involvement in naloxone-sensitive and naloxone-insensitive models of stress-induced antinociception investigated. In the abdominal constriction test, histamine and dimaprit but not histidine, induced antinociception. Compound 48/80 and H1 antagonists (diphenhydramine, mepyramine and promethazine) and large doses of H2 antagonists (cimetidine and zolantidine) produced antinociception in this test. Antinociception induced by histamine was refractory to mepyramine, metiamide and naloxone. Histamine and non-antinociceptive doses of its antagonists had no influence on the naloxone-resistant warm water swim stress-induced antinociception. In the hot-plate test, histamine agonists, except the H3 agonist (R) alpha-methyl histamine (alpha-MeHA), were antinociceptive but all these agents augmented the naloxone-sensitive room temperature swim stress-induced antinociception, after either intraperitoneal or intraventricular injection. The antinociceptive action of dimaprit was not antagonized by zolantidine which, like other histamine antagonists excluding metiamide, also produced antinociception and enhanced room temperature swim stress-induced antinociception. These findings suggest that histamine is involved in pathways mediating antinociception in the mouse and that such pathways are activated in a naloxone-sensitive model of stress-induced antinociception but not in a naloxone-insensitive model.

Animals↗

PubMed1998

Hydromorphone-naloxone combinations in opioid-dependent humans under a naloxone novel-response discrimination procedure.

Naloxone-hydromorphone combinations were tested in participants trained to discriminate naloxone from placebo under a novel-response drug discrimination procedure while maintained on methadone. Naloxone alone produced dose-related increases in naloxone-appropriate responding, little or no "novel"-appropriate responding, and increases in opioid antagonist adjective ratings (n = 5). Hydromorphone alone produced dose-related increases in novel-appropriate responding, little or no naloxone-appropriate responding, and increases in opioid agonist adjective ratings (n = 6). When combined with naloxone, hydromorphone produced dose-related decreases in naloxone-appropriate responding and antagonist adjective ratings (n = 6). These findings are consistent with nonhuman data and suggest that this procedure may be useful as a human laboratory model of opioid withdrawal.

Adult↗

PubMed2003

D-cycloserine-Naloxone interactions in opioid-dependent humans under a novel-response naloxone discrimination procedure.

Six participants currently in opioid maintenance treatment were trained to distinguish between naloxone (0.15 mg/70 kg, intramuscularly [i.m.]) and placebo under an instructed novel-response drug-discrimination procedure. Doses of the partial glycine agonist D-cycloserine (0-500 mg/70 kg, per os [P.O.]) alone and combined with naloxone (0.15 mg/70 kg) were then tested. D-cycloserine alone produced minimal drug-appropriate responding, no significant changes in self-reported effects, and increases only in systolic blood pressure. When combined with the naloxone, D-cycloserine partially attenuated naloxone-appropriate responding. D-cycloserine attenuated naloxone-induced increases in visual analog scale ratings of "like naloxone" and scores on the Lysergic Acid Diethyl Amide subscale of the Addiction Research Center Inventory (D. R. Jasinski, 1977; W. R. Martin, J. W. Sloan, J. D. Sapiro, & D. R. Jasinski, 1971). Naloxone attenuated D-cycloserine-induced increases in systolic blood pressure. These results suggest that D-cycloserine at doses up to 500 mg/70 kg may have some limited usefulness in relieving symptoms of opioid withdrawal.

Adult↗

PubMed1988

Effects of zolantidine a brain-penetrating H2-receptor antagonist, on naloxone-sensitive and naloxone-resistant analgesia.

The action of zolantidine, a histamine H2-receptor antagonist which penetrates the brain, was characterized on the analgesia elicited by brief continuous footshock of 3 intensities. Zolantidine inhibited the analgesia elicited by exposure to 3.5 mA for 3 min, with maximum inhibition observed 30 min after a dose of 5 mg/kg. This inhibition was not dose-related, possibly due to inhibition of the metabolism of histamine in brain by this drug at larger doses. While zolantidine alone, or in combination with naloxone, attenuated this analgesic response, naloxone alone had no such effect, further supporting the non-opiate nature of this response. Conversely, naloxone, but not zolantidine, strongly inhibited the analgesia elicited by 2.0 mA for 3 min, confirming the apparent opiate nature of this analgesic mechanism. Although a combination of zolantidine and naloxone still significantly attenuated this response, a tendency toward reversal of the antagonism by naloxone was observed with this combination of drugs, consistent with previous findings. Furthermore, the analgesia elicited by 2.5 mA for 3 min was resistant to both naloxone and zolantidine, alone or in combination. These results further strengthen the hypothesis that histamine and H2-receptors in brain are important mediators of endogenous antinociception and also support the possible existence of an additional non-opiate, non-H2-analgesic mechanism.

Analgesia↗

PubMed1995

A synergistic adrenocorticotropin response to naloxone and vasopressin in normal humans: evidence that naloxone stimulates endogenous corticotropin-releasing hormone.

Naloxone stimulates pituitary-adrenal function by blocking an endogenous inhibitory opioidergic tone which modulates pituitary adrenocorticotropin (ACTH) release. In animals, this action of naloxone is mediated by increased corticotropin-releasing hormone (CRH) secretion, but such a mechanism is disputed in humans. CRH and arginine vasopressin (AVP) are known to have a synergistic effect on ACTH secretion in both humans and animals. In vitro, this synergism is independent of L-type voltage-dependent Ca2+ channel function. The aims of this study were therefore: (i) to determine if the combined administration of naloxone and AVP is synergistic regarding ACTH release; (ii) to assess the effect of nifedipine, which blocks L-type Ca2+ channels, on the ACTH response to combined naloxone/AVP stimulation. Seven healthy volunteers were studied using a placebo-controlled, single-blind protocol. Naloxone (125 micrograms/kg) and/or AVP (10 units) were given in all four possible combinations, and oral nifedipine (20 mg) was also given with naloxone and AVP as an additional test. The mean AUC and the mean peak change in ACTH levels following combined naloxone/AVP administration were both significantly greater than the arithmetic sum of the ACTH responses to naloxone and AVP given on separate occasions (AUC: 1,576.4 +/- 417.9 vs. 567.1 +/- 106.1 pmol.min.l-1, p < 0.002; peak change: 37.9 +/- 14.0 vs. 11.8 +/- 2.0 pmol/l, p < 0.007). Nifedipine reduced the ACTH response to combined naloxone/AVP stimulation by 43% (AUC: 1,576.4 +/- 417.9 vs. 897.0 +/- 186.2; p < 0.05), but it remained greater than the sum of the individual responses (897.0 +/- 186.2 vs. 576.1 +/- 106.1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1975

Fixed-ratio escape and avoidance-escape from naloxone in morphine-dependent monkeys: effects of naloxone dose and morphine pretreatment.

Lever pressing by rhesus monkeys was maintained by morphine injections during four equally spaced sessions each day. During other periods, lever pressing was maintained by timeout from a continuous naloxone infusion (escape), or by timeout from a stimulus that preceded naloxone injections, or termination of the injections (avoidance-escape). As naloxone dose increased in the escape procedure, response rate increased to a maximum and then decreased. In the avoidance-escape procedure, response rate generally increased as naloxone dose increased, but the changes in rate were small compared to the excape procedure. Substitution of saline for naloxone in the escape procedure led to a very low response rates within three sessions. In the avoidance-escape procedure, rate decrements produced by saline substitution appeared to be related to the behavioral history of the monkey. Previous escape experience led to more rapid decreases in responding when saline was introduced, whereas responding was maintained for 15 sessions in a monkey without prior escape conditioning. Morphine pretreatment produced comparable, dose-dependent decreases in response rates in both procedures. The rate-decreasing effects of morphine were exacerbated when no naloxone was delivered in the escape procedure.

Animals↗

PubMed1986

Opposing actions of cimetidine on naloxone-sensitive and naloxone-insensitive forms of footshock-induced analgesia.

The effects of the opiate antagonist naloxone (10 mg/kg) and the histamine H2-antagonist cimetidine (100 mg/kg; both administered i.p.) were studied on the analgesia elicited by 3 currents of continuous-scrambled AC footshock (FSIA). Repeated analgesic measurements were made in each animal by use of the radiant heat tail-flick test. As shown by others, naloxone effectively inhibited the FSIA produced by 3 min of 2.0 mA, but had no effect on the responses elicited by higher currents (2.5 and 3.5 mA) of the same duration. Cimetidine significantly reduced the naloxone-insensitive FSIA after 3.5 mA, had no effect on that produced by 2.5 mA and potentiated the naloxone-sensitive analgesia elicited by 2.0 mA. These findings add to existing data supporting a role for brain histamine as a mediator of naloxone-insensitive analgesia, and also suggest the possibility that histamine may mediate hyperalgesic responses.

Analgesia↗

PubMed1989

Dissociation of naloxone-sensitive and naloxone-insensitive effects of U-50,488H.

This study was designed to compare the dose-related effects of U-50,488H on the cortical electroencephalogram (EEG) and behavior, following either saline or naloxone pretreatment. Adult female Sprague-Dawley rats were implanted with chronic cortical EEG and temporalis muscle electromyographic (EMG) recording electrodes and with permanent cannulae in the external jugular vein. U-50,488H injection produced initial "psychotomimetic-like" EEG and behavioral effects for about 10-20 min, followed by a predominance of behavioral stupor and associated EEG slow-wave bursts for about 20 min. Naloxone pretreatment completely antagonized the behavioral stupor and associated EEG slow-wave bursts. However, the "psychotomimetic-like" effects were not antagonized by naloxone pretreatment. Thus, dissociation between naloxone-sensitive and naloxone-insensitive effects of U-50,488H was demonstrated.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed1983

Fluid consumption in water-deprived rats after administration of naloxone or quaternary naloxone.

Water-deprived male rats were given access to water, or to a 0.005M sodium saccharin solution, or to a 0.9% sodium chloride solution, during a 30 min test period. Naloxone (0.01-10.0 mg/kg) produced dose-dependent reductions in the consumption of each fluid. Saccharin-drinking was significantly reduced by 0.01 mg/kg naloxone, and water- and saline-drinking by 0.1 mg/kg naloxone. Quaternary naloxone (0.01-10.0 mg/kg) had no effect on drinking under any condition. Access to the saline solution resulted in hyperdipsia, due to a prolongation of the initial bout of avid drinking in the thirsty rats. Naloxone, in small doses, completely abolished this hyperdipsia. Since the quaternary compound had no effect, it was concluded that opiate antagonist suppression of saline-induced hyperdipsia was probably mediated at central opiate receptors.

Animals↗