Small Doses Of Naloxone Research Articles

Small dose of naloxone as an adjuvant to bupivacaine in intrapleural infiltration after thoracotomy surgery: a prospective, controlled study.

BackgroundSevere pain always develops after thoracotomy; intrapleural regional analgesia is used as a simple, safe technique to control it. This study was performed to evaluate whether a small dose of naloxone with local anesthetics prolongs sensory blockade.MethodsA prospective, randomized double-blinded controlled study was conducted on 60 patients of American Society of Anesthesiologists statuses I and II, aged 18 to 60 years, scheduled for unilateral thoracotomy surgery. After surgery, patients were randomly divided into two groups: through the intrapleural catheter, group B received 30 ml of 0.5% bupivacaine, while group N received 30 ml of 0.5% bupivacaine with 100 ng of naloxone. Postoperative pain was assessed using the visual analog pain scale (VAS). Time for the first request for rescue analgesia, total amount consumed, and incidence of postoperative complications were also recorded.ResultsThe VAS score significantly decreased in group N, at 6 h and 8 h after operation (P < 0.001 for both). At 12 h after injection, the VAS score increased significantly in group N (P < 0.001). The time for the first request of rescue analgesia was significantly longer in group N compared to group B (P < 0.001). The total amount of morphine consumed was significantly lower in group N than in the bupivacaine group (P < 0.001).ConclusionsAddition of a small dose of naloxone to bupivacaine in intrapleural regional analgesia significantly prolonged pain relief after thoracotomy and delayed the first request for rescue analgesia, without significant adverse effects.

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The effect of small doses of naloxone on sexual exhaustion, plasma prolactin and testosterone levels in male rabbits

The objective of this work was to study the effect of small doses of naloxone (Nx) on plasma prolactin (PRL) and testosterone levels, and to correlate hormone changes induced by the opioid antagonist with sexual exhaustion in adult male rabbits. Two groups of 8 adult New Zealand White male rabbits were divided into 2 groups: Group 1 (n=8) was treated with daily intramuscular injections of 0.5 mg of naloxone at 08:00 and at 20:00 hours for 15 days. Group 2 was treated with saline injections. Copulatory behaviour was similar on the first day and during seven days of treatment with Nx in both groups; mounts and copulations averaged 8.1 to 7.21. After 15 days of treatment with Nx, a significant increase in mount/copulation events was observed in naloxone treated rabbits as compared with controls (11.1 vs 7.6) (P<0.001). Mounts and copulations in the Nx treated rabbits was significantly higher than control rabbits (P<0.001) (9.4 vs 7.6) seven days after treatment with Nx was discontinued. During the first week of treatment, plasma testosterone levels in Nx treated rabbits were similar to those of the control group. At the end of the first week of treatment with Nx, there was a continuous increase in testosterone levels and high levels of the androgen were still detectable seven days after naloxone treatment was discontinued. There was a significant overall effect of treatment (P<0.001). It was concluded that endogenous opioids are important modulators of sexual behaviour in rabbits.

Antagonist Treatment of Opioid Withdrawal

Although antagonist drugs are receiving increasing attention in the treatment of opioid withdrawal, the mechanisms of interaction of opiate agonists and antagonists remain largely to be investigated. We focused on the effects of very low quantities of opiate antagonists, for their potential utility in detoxification. Upon reviewing the evidence on the administration of small doses of naloxone and naltrexone in the presence of agonist drugs, the effects of low-dose naltrexone during opiate administration and withdrawal are described. The application of a translational methodology allowed completing the clinical design with behavioral and cellular information obtained from a specifically developed animal model. The initial results indicate that low doses of naltrexone may help to reduce the manifestation of opioid withdrawal. They also offer suggestions for further investigations and confirm the utility of a translational research approach to the clinical neurobiology of drug addiction.

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine: Part 2. Synthesis and pharmacological activity of 1,6-diaryl-5,7(1 H)dioxo-2,3-dihydroimidazo[1,2- a][1,3,5]triazines

Synthesis and pharmacological activity of 1,6-diaryl-5,7(1 H)dioxo-2,3-dihydroimidazo-[1,2- a][1,3,5]triazines ( C) are presented. The title compounds were obtained from 1-arylimidazolinurea derivatives in cyclization reaction with difunctional carbonyl reagents—phosgene (method I) or carbonyldiimidazole (CDI) (method II). Their molecular structures were confirmed by the X-ray analysis of 1-phenyl-6-(4-chlorophenyl)-5,7(1 H)-dioxo-2,3-dihydroimidazo[1,2- a][1,3,5]triazine ( C2) crystals. Compounds C exhibited significant depressive action on the central nervous system (CNS) of the laboratory animals, correlated with very low acute toxicity (LD 50>2000 mg kg −1 i.p.), and showed antinociceptive activity in behavioural models. Reversion of this effect by small dose of naloxone (5 mg kg −1) can suggest opioid-like mechanism of antinociception produced by these and other carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Additionally, an effect on the serotonin neurotransmission pathway was also observed. The receptor mechanism of activity for investigated compounds was confirmed only for the opioid μ receptor in binding affinity assay test. Same tests performed for the serotonin 5-HT 2 and benzodiazepine BZD receptors showed no affinity for tested compounds. The opioid-like and serotonergic activities are similar to these described earlier for chain carbonyl 1-aryl-2-iminoimidazolidine derivatives containing urea moiety, mainly due to similar chemical structure, although compounds C are not able to adopt any of the higher energy conformations of urea derivatives. Rigid location of aromatic ring (Ar′) at N6, acting as a spacer blocking any direct access to the carbonyl groups (e.g. through the hydrogen bonding), could be responsible for lack of affinity toward 5-HT 2 expressed in the binding assay test.

Time course of naloxone-precipitated withdrawal after acute methadone exposure in humans

This study examined naloxone-precipitated withdrawal symptoms from 24 to 168 h after pretreatment with a single 30-mg i.m. dose of methadone in 6 male subjects who were experienced users of opioid drugs but were not currently dependent. The study showed that acute physical dependence signs and symptoms could be reliably precipitated with a small dose of naloxone (0.75 mg/70 kg i.m.) for as long as 96 h (4 days) after a single dose of methadone. The intensity of symptoms at 24 h postmethadone was similar to that observed at 96 h; no precipitated withdrawal effects were observed at 168 h (7 days) after methadone administration. The magnitude of precipitated withdrawal effects at 96 h was not attenuated by the administration of a prior naloxone challenge at 24 h post-methadone. Agonist effects (pupillary constriction; subjective effects) were detectable at 24 h but not at 96 h post-methadone. The results suggest that methadone engenders long-lasting physical dependence effects that can be detected beyond the dissipation of acute agonist effects. Methadone pretreatments may provide a convenient mechanism for the production and examination of long-term μ-opiate receptor physical dependence.

Spinal antinociception: Comparison of a dermorphin tetrapeptide analogue, [ d-arginine 2, sarcosine 4]-dermorphin (1–4) and morphine in rats

Intracerebroventricular injections of [ d-arginine 2, sarcosine 4]-dermorphin (1–4)(DAS-DER 1–4) and morphine produced a dose-dependent inhibition of the tail-flick response to thermal stimulation. The ED 50 value for each drug was 3.23 (1.35–7.73) nmol/rat and 32.0 (13.3–76.6) nmol/rat, respectively. When injected into the spinal subarachnoid space, the ED 50 value was 0.035 (0.015–0.086) nmol/rat for the tetrapeptide and 11.9 (5.7–25.2) nmol/rat for morphine, respectively. Antinociception induced by DAS-DER 1–4 and morphine, through the intracerebroventricular and intrathecal routes, was clearly reduced by pretreatment with a small dose of naloxone. After spinal transection, the antinociceptive potency of systemically-administered morphine was significantly reduced while that of DAS-DER 1–4 was unaltered. The activity of DAS-DER 1–4 and morphine was also reversed by naloxone in spinal animals. It is concluded that DAS-DER 1–4, a dermorphin analogue, has a minor supraspinal action but acts mainly at the level of the spinal cord, in contrast to the action of morphine.

Regional Distribution of the Opioid Receptor Agonist N‐(methyl‐11C)pethidine in the Brain of the Rhesus Monkey Studied with Positron Emission Tomography

The regional distribution and kinetics in the brain of Rhesus monkeys of N-(methyl-11C)-pethidine have been studied by positron emission tomography, PET. 11C-Pethidine reached the brain with peak radioactivities appearing within 6-10 min. after administration. Highest radioactivities were measured in areas corresponding to the thalamus, the striatal area and also the lowest transection of the temporal lobes, with an uptake of 2.7-3.1 times the homogenous dilution of the radioactive dose. Low radioactivities were seen in the cerebellum and the occipital lobes. This distribution corresponds to the regional density of opioid receptors using in vitro binding techniques. The 11C-pethidine derived radioactivity left the brain with an initial half-life of 40-60 min., followed by an elimination which paralleled the plasma elimination of unlabelled pethidine. After pretreatment of the monkey with a small dose of naloxone, the radioactivities decreased about 40% in areas corresponding to the thalamus, striatum and lowest section of the temporal lobes, indicating competition for the same binding sites. By the use of a three-compartment model, it was possible to get an estimate of 11C-pethidine receptor binding characteristics in the brain. The ratio of Kon/Koff, equal to Bmax./Kd, was 0.06-0.1. This indicates that pethidine is bound with low affinity to the opioid receptors and is a poor ligand for studies of opioid receptor function with PET. Brain kinetics of 11C-pethidine is mainly determined by its blood kinetics.

Enhancement of blood-brain barrier permeability to sodium fluorescein by stimulation of mu opioid receptors in mice.

The effects of opioids on the permeability of the blood-brain barrier (BBB) were examined in mice with sodium fluorescein as an indicator of the permeability. The brain was perfused with saline 30 min after injection of sodium fluorescein (40 mg/kg, i.v.) and examined by fluorometry. Morphine hydrochloride (0.3-10 mg/kg, s.c.) markedly increased the brain level of sodium fluorescein dose-dependently without influencing the plasma level, when administered 20 min before sodium fluorescein injection. Intracerebroventricularly (i.c.v.) injected morphine hydrochloride (0.5 and 1.0 microgram) increased the brain sodium fluorescein level. Buprenorphine (0.1 and 0.5 mg/kg, s.c.) was also effective. However, pentazocine, ethylketazocine, U-50488H and SKF-10047 had no significant influence. The i.c.v. administration of [D-Ala2, MePhe4, Gly(ol)5]enkephalin (0.1 microgram) and [D-Ala2, D-Leu5]enkephalin (0.5 microgram) but not of [D-Thr2, Leu5]enkephalin-Thr increased the brain level of sodium fluorescein significantly. A small dose of naloxone (i.p.) significantly inhibited the effects of morphine, buprenorphine, [D-Ala2, MePhe4, Gly(ol)5]enkephalin and [D-Ala2, D-Leu5]enkephalin. ICI-174864 coadministered i.c.v. with [D-Ala2, D-Leu5]enkephalin was ineffective in antagonizing the effect of the latter. These findings suggest that the stimulation of mu opioid receptors results in an increase in BBB permeability to sodium fluorescein.

Behavioural characterization of substance P-induced nociceptive response in mice

Intrathecal injection of substance P produced a behavioural syndrome, consisting of reciproacal hindlimb scratching and biting or fore- and hind-licking. Pretreatment with either an analogue of substance P, (D-Pro2, D-Trp7,9)-substance P (DPDT-SP) or (D-Arg1, D-Pro2,4, D-Trp7,9, Leu11)-substance P, given intrathecally, reduced the response to substance P in a dose-dependent manner. The behaviour induced by substance P was also inhibited by intrathecal, intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection of morphine. Intrathecal or subcutaneous injection of naloxone showed a biphasic effect on substance P response; the substance P-induced nociceptive response was increased by a small dose of naloxone, while it was inversely decreased by a large dose of naloxone. The results with analogues of substance P support the hypothesis that substance P, injected intrathecally, acts directly on substance P receptors in the spinal cord. The nociceptive response induced by substance P appears to be controlled by endogenous opioids in the spinal cord.

Changes in sympathetic nerve activity during morphine abstinence in the rat.

The aim of the study was to examine sympathetic nerve activity, heart rate and blood pressure during naloxone-precipitated withdrawal reactions in morphine-dependent rats. In two groups of rats, one group conscious and the other anaesthetized with chloralose, renal sympathetic nerve activity (rSNA), heart rate (HR) and mean arterial blood pressure (MAP) were recorded before and during naloxone-precipitated abstinence. The conscious rats showed a biphasic pattern in the withdrawal responses. Initially, after small doses of naloxone, rSNA and HR increased and increased somatomotor activity including 'wet-dog' shakes were observed. However, upon further administration of naloxone, rSNA and HR promptly decreased while MAP increased. As rSNA was lowered, the withdrawal behaviour of the rats was markedly diminished and the animals rested calmly in the cages. In contrast, the anaesthetized group reacted with an immediate decrease in rSNA after the lowest dose of naloxone, followed by an increase in MAP and HR after higher doses of naloxone, although rSNA was still decreased. In both groups, rSNA remained below pre-naloxone control levels when the increased MAP was lowered to the pre-naloxone level with sodium nitroprusside, indicating a central origin of the sympathetic inhibition. It is concluded that naloxone elicits a biphasic rSNA response in the conscious, morphine-dependent rat. This includes an initial increase upon low naloxone doses followed by a pronounced inhibition of rSNA after higher doses. In chloralose-anaesthetized rats, rSNA declined already after low doses of naloxone. It is suggested that there might be a tonic, excitatory input on rSNA, mediated by the activation of opiate receptors by high levels of circulating morphine in the addicted animal. Naloxone will therefore decrease the tonic sympathetic nerve activity in these rats.

Opiate-induced seizures: A study of μ and δ specific mechanisms

Two groups of experiments were conducted to determine if morphine- and enkephalin-induced seizures are specifically mediated by the μ and δ receptor, respectively. In the first experiments, designed to assess the ontogeny of μ- or δ-seizures, rats from 6 h to 85 days of age received implanted cortical and depth electrodes as well as an indwelling cannula in the lateral ventricle. Various amounts of the μ-receptor agonists, morphine and morphiceptin, and the δ agonists, d-Ala 2- d-Leu 5-enkephalin (DADL) and Tyr- d-Ser-Gly-Phe-Leu-Thr (DSLET), were then administered intracerebroventricularly (icv) with continuous EEG monitoring. The second experiments entailed use of the nonspecific opiate antagonist, naloxone, as well as the specific δ antagonist, ICI 154,129, against seizures induced by icv-administered morphine, morphiceptin, DADL, or DSLET. Both morphine and morphiceptin produced electrical seizure activity in rats as young as 5 days after birth. The drugs produced similar seizure activity in terms of electrical morphology, observed behavior, ontogeny, threshold dose, and reversibility with small doses of naloxone. In the pharmacologic experiments, icv naloxone blocked all opiate-induced seizures. ICI 154,129 blocked DSLET seizure, had little effect on enkephalin or DADL seizures, and no effect on morphine or morphiceptin seizures. These data indicate that DSLET seizures are δ-specific but that all other opiate-induced seizures studied may involve multiple opiate receptor-mediated mechanisms.

Naloxone fails to block ECT-induced prolactin increase

The rapid, but transient, prolactin (PRL) induring the electroconvulsive therapy (ECT) is well known (Ohman et al. 1976; Skrabanek et al. 1981; Papakostas et al. 1984), although the underlying mechanism mediating this effect remains speculative. It has been suggested that endogenous opioid peptides may be involved (Skrabanek et al. 1981; Deakin et al. 1983): these substances, among other effects, increase PRL in man, and this increase can be blocked by small doses of naloxone (Grossman and Rees 1983; Morley 1983). The question then arises whether or not the ECT-induced PRL increase is mediated via stimulation of opioid secretion. In this study, the role of opioids in the ECTinduced prolaetin increase was tested by the administration of the opioid receptor antagonist, naloxone, to five female melancholic patients who were undergoing treatment with ECT. The patients' ages ranged between 38 and 63 years. With the exception of low doses of benzodiazepines (flunitrazepam) given at bed time, they were free from psychotropics or any other drugs

Met-Enkephalin-Arg 6-Phe 7-like immunoreactive substances mediate electroacupuncture analgesia in the periaqueductal gray of the rabbit

The present study was undertaken to investigate whether the C-terminal extended Met-enkephalin heptapeptide (Met-enkephalin-Arg 6-Phe 7, MEAP) played a role in mediating the analgesic effect of electroacupuncture in rabbits. MEAP and its degrading enzyme inhibitor captopril as well as antiserum against MEAP were injected into the periaqueductal gray (PAG) via a previously implanted cannula. Their effects on nociception were tested by the escape response latency (ERL) elicited by radiant heat applied on the skin of the snout. (1) Microinjection of MEAP (30–240 nmol) into PAG produced a dose-dependent analgesic effect which was 2.5 times more potent than Met-enkephalin (MEK) and 3 times less potent than morphine. The complete reversal of the analgesia elicited by 240 nmol of MEAP by a small dose of naloxone (0.1 mg/kg, i.v.) indicates that the effect of MEAP is mediated by naloxone sensitive opioid receptors. (2) In rabbits, a dose-dependent analgesia was elicited by an intra-PAG injection of captopril (60–240 nmol). A single dose of 240 nmol captopril increased ERL by more than 100%. This effect could be reversed by 30 nmol of naloxone injected into the same site, or by antiserum recognizing MEAP (1 μL, titer 1:1500) but not by antiserum recognizing MEK (1 μl, 1:8000) suggesting that captopril was able to protect MEAP from degradation. (3) Intra-PAG injection of 60 nmol of captopril significantly potentiated the after effect of electroacupuncture (EA) induced analgesia. This effect could be blocked either by 30 nmol (but not 7.5 nmol) of naloxone, or by 1 μl (but not 0.1 μl) of MEAP antiserum. These results suggest that MEAP may cause analgesia by acting in PAG, and could be operative in EA analgesia.

The antagonistic effects of naloxone on hypermotility in mice induced by dynorphin-(1-13) using a multi-dimensional behavioral analysis

The effects of intracerebral injection of dynorphin-(1-13) on spontaneous locomotor activity were investigated by using a newly devised multi-dimensional behavioural analyser based on a capacitance system. With this equipment, nine different measures of behavior exhibited by the mouse can be recorded. It was found that dynorphin-(1-13) (0.3 and 1 microgram) produced a significant increase in the linear locomotion recorded on the 1/1 and 1/2 counters. In addition, dynorphin-(1-13) (0.3 micrograms) significantly increased the grooming behavior recorded on the 1/16 counter. As the dynorphin-(1-13)-induced behavioural effects were reversed by pretreatment with relatively small doses of naloxone (0.5, 1 and 2 mg/kg), the dynorphin-induced increases in linear locomotion and grooming are probably mediated through opiate receptors in the brain.

Effects of ketazocine, ethylketazocine and phenazocine on schedule-controlled behavior: Antagonism by naloxone

Dose-effect curves were determined for phenazocine (0.64–2.5 mg/kg), ketazocine (1.25–80 mg/kg) and ethylketazocine (1.25–80 mg/kg) in pigeons responding under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of grain presentation. All three opioid agonists decreased responding with the larger doses. The effects of phenazocine were completely antagonized by small doses of naloxone (0.01–1 mg/kg), whereas the effects of ethylketazocine required larger doses of naloxone (1–10 mg/kg) to be completely antagonized. The behavioral effects of ketazocine were partially attenuated by naloxone, but were not antagonized completely even by a 10 mg/kg dose of naloxone. These data from the pigeon are consistent with previous interpretations that the effects of phenazocine are mediated by actions at a mu opioid receptor, whereas the effects of ketazocine and ethylketazocine are mediated by actions at a kappa opioid receptor.

Food and water intake in the non-deprived pigeon after morphine or naloxone administration

The effects of morphine and naloxone on food- and water-intake are described in the non-deprived pigeon. Morphine (1–4 mg kg −1) produced an initial suppression of both feeding and drinking, effects which could be antagonized with small doses of naloxone. A hyperdipsia occurred after treatment with certain doses of morphine, characterized by a long latency of at least 2 hr. The hyperdipsia, which was not accompanied by an increase in feeding responses, did not appear to be simply a reaction to an initial suppression of drinking. Naloxone selectively reduced food-intake, and had no effect on water-intake over the dose-range examined (0.125–8 mg kg −1). This result is in striking contrast to the results obtained in mammalian species, where drinking may be more sensitive to naloxone treatment than feeding.

Presynaptic effects of morphine and methionine-enkephalin in feline spinal cord

The effects of morphine (applied either iontophoretically in substantia gelatinosa or injected intravenously) and met-enkephalin (iontophoretically) were examined on the terminal excitabilities of single sural C, post-A δ and A δ afferents, in cats that were decerebrated and then spinalized. Small amounts of morphine (0.1–2.0 mg/kg or 15–80 nA) and met-enkephalin (15–80 nA) produced an increase in the threshold for antidromic activation of these sural fibres. In these doses, the opiate and the opioid peptide potentiated the enhancement of sural afferent terminal excitability produced by superficial peroneal (SP) nerve stimulation. The above effects of both agonists were antagonized by small doses of naloxone (0.05–0.15 mg/kg or 20–40 nA). In large amounts, morphine (3.2–6.4 mg/kg or 50–150 nA) and met-enkephalin (60–150 nA) increased the excitabilities of the sural afferent terminals and antagonized the enhancement of the terminal excitability produced by SP nerve stimulation. These actions by large doses of the agonists were not consistently antagonized by naloxone. In some experiments in which the peripheral nerves, except a few post-A δ fibres from which recordings were made, were left intact, intraarterially injected bradykinin (10 μg, to a hind limb) produced a decrease in threshold for antidromic activation of the post-A δ fibres and converted the increase in threshold produced by small amounts of morphine and met-enkephalin into a decrease in threshold. Morphine (0.8–6.4 mg/kg or 30–200 nA) did not consistently alter the excitabilities of muscle group I afferent terminals. The results of these studies indicate that morphine- and met-enkephalin-induced analgesia is, at least, partly due to the ability of the agents to potentiate “presynaptic inhibition” of nociceptive pathways in the spinal cord.

Morphine abstinence and quasi-abstinence effects after phosphodiesterase inhibitors and naloxone

Naive or morphine-dependent rats received a single subcutaneous injection of a phosphodiesterase inhibitor; their behavioral responses were then recorded after a small subcutaneous dose of naloxone. In naive rats, the potent phosphidiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX) produced acutely a state in which a small dose of naloxone (0.03 to 1.0 mg/kg subcutaneously) precipitated a quasi-morphine abstinence syndrome that was difficult to distinguish from the true abstinence syndrome, precipitated by the same dose of naloxone in rats made dependent on morphine. IBMX also intensified the true morphine abstinence syndrome. The potency with which IBMX, theophylline, caffeine and RO 20–1724 exerted these effects corresponded with their potency as inhibitors of cyclic-3′, 5′-AMP phosphodiesterase in rat brain homogenate. These and previous findings indicate that: (i) morphine-abstinence effects express increased activity of a central cyclic AMP mechanism; and (ii) naloxone can potently stimulate behavior in animals not treated with any opiate drug.