Naltrexone HCl Research Articles

A MIXTURE OF NALBUPHINE, AZAPERONE, AND MEDETOMIDINE FOR IMMOBILIZING RINGTAILS (BASSARISCUS ASTUTUS).

We evaluated a combination of nalbuphine HCl (40 mg/mL), azaperone tartrate (10 mg/mL), and medetomidine HCl (10 mg/mL), a combination known as NAM or NalMed-A, in 23 ringtails (Bassariscus astutus) during 29 handling events for a radio-collaring study in southern Oregon, US, from August 2020 to March 2022. The combination was delivered to ringtails by hand injection at 0.075 mL NAM per estimated 1 kg body mass. The mean (± standard deviation, SD) dosage calculated post hoc was 3.366 (±0.724) mg/kg nalbuphine, 0.841 (±0.181) mg/kg medetomidine, and 0.841 (±0.181) mg/kg azaperone. All captured ringtails were effectively immobilized with a mean (SD) induction time of 13.24 (±3.57) min. The medetomidine and nalbuphine components were antagonized with a combination of atipamezole and naltrexone HCl with a mean (SD) recovery time of 2.48 (±1.94) min. This combination appeared to be safe and effective for immobilizing ringtails with a low volume dose, smooth antagonism, and rapid recovery. In addition, NAM does not contain any drugs that are US Drug Enforcement scheduled, which makes it useful for immobilization procedures by wildlife professionals in the US.

Preparation of a naltrexone HCL potentiometric sensor and its application to pharmaceutical analysis and drug determination in biological fluids

A novel ion selective electrode is fabricated for naltrexone HCl and used in pharmaceutical analysis and drug determination in biological fluids without complicated pretreatments and extractions, using direct potentiometry. The naltrexone complex with sodium tetraphenyl borate (NaTPB) is obtained by in situ soaking PVC membrane electrode in an 1 × 10 -3 M naltrexone solution. The sensor exhibited fast, reproducible and linear sub-Nernstian response over concentration range of 1 × 10 -5 - 1 × 10 -3 M with a detection limit of 5 × 10 -6 M. The membrane sensor was successfully applied to the determination of naltrexone in capsules as well as for its determination in urine and plasma samples.

In vitro evaluation of Naltrexone HCl 1% Topical Cream in XemaTop™ for psoriasis.

Psoriasis is a multifactorial skin disease involving abnormal cell proliferation and inflammation; an efficacious topical treatment is yet to be identified. A formulation containing 1% Naltrexone HCl in XemaTop™ base was compounded, characterized and evaluated in vitro as a possible treatment for psoriasis. A three-dimensional psoriasis tissue model was exposed to the formulation for 2 or 5days and analyzed for the level of markers of cellular proliferation, and inflammatory cytokine IL-6. Using immunohistochemical staining, the level of Ki67 protein significantly decreased in the drug-treated tissues. Western blot analysis showed 86% and 53% down-regulation of other proliferation markers PCNA and CYCLIN D1, respectively, after 5-day exposure. The pro-survival Wnt/β-catenin pathway was compromised as indicated by 57% decrease in the level of β-CATENIN and down-regulation of its down-stream targets including CYCLIN D1 (decreased by 53%), c-MYC (63%), c-JUN (92%) and MET (96%) proteins. Likewise, the PI3K/AKT/mTOR pathway was significantly inhibited by 1% Naltrexone HCl in XemaTop™, suggesting protein synthesis was affected. The production of IL-6 was inhibited by 70% in drug-treated tissues. These results suggest that the compounded drug is efficacious in down-regulating molecular markers associated with the pathogenesis of psoriasis. Low-dose Naltrexone in XemaTop™ was stable within 180days when stored under refrigerated or ambient conditions. These results provide a basis for a clinical evaluation of 1% Naltrexone HCl in XemaTop™ in psoriasis patients.

691 In vitro evaluation of naltrexone HCl 1% topical cream in xematop for psoriasis

Psoriasis is a multifactorial skin disease involving abnormal cell proliferation and inflammation; an efficacious topical treatment is yet to be identified. A topical formulation containing 1% naltrexone HCl in xematop base was compounded, characterized and evaluated in vitro as a possible treatment for psoriasis. A three-dimensional psoriasis tissue model was exposed to the formulation for 2 or 5 days and analyzed for the level of markers of cellular proliferation, and inflammatory cytokine IL-6. Using immunohistochemical staining, the level of Ki67 protein significantly decreased in the drug-treated tissues. Western blot analysis showed 86% and 53% down-regulation of other proliferation markers PCNA and CYCLIN D1, respectively, after 5-day exposure. The pro-survival Wnt/β-catenin pathway was compromised as indicated by 57% decrease in the level of β-CATENIN and down-regulation of its downstream targets including CYCLIN D1 (decreased by 53%), c-MYC (63%), c-JUN (92%) and MET (96%) proteins. Likewise, the PI3K/AKT/mTOR pathway was significantly inhibited by 1% naltrexone HCl in xematop, suggesting protein synthesis was affected. The production of IL-6 was inhibited by 70% in drug-treated tissues. These results suggest that the compounded drug is efficacious in down-regulating molecular markers associated with the pathogenesis of psoriasis. Low-dose naltrexone in xematop was stable within 180 days when stored under refrigerated or ambient conditions. These results provide a basis for a clinical evaluation of 1% naltrexone HCl in xematop in psoriasis patients.

Intranasal abuse potential of an abuse-deterrent oxycodone formulation compared to oxycodone immediate release and placebo in nondependent, recreational opioid users

To assess the intranasal (IN) human abuse potential of ELI-200, a novel immediate-release (IR) oxycodone formulation containing sequestered naltrexone. Randomized, double-blind, double-dummy, active and placebo-controlled, five-way crossover study. Pharmacodynamics, safety, and pharmacokinetics (PKs) were evaluated for up to 36 hours postdose. Single site in Canada (INC Research Toronto). Healthy male and female nondependent recreational opioid users underwent a naloxone challenge and drug discrimination qualification test. Single IN dose of ground ELI-200 (30-mg oxycodone hydrochloride [HCl]/3-mg naltrexone HCl), crushed 30-mg oxycodone HCl IR (Roxicodone®), placebo, fixed placebo, and single oral dose of intact ELI-200 (30mg/3mg). Peak effect (Emax) for bipolar Drug Liking (0-100 point visual analog scale). Of the 44 randomized subjects, 37 completed all five treatment periods. All active treatments showed significantly higher (p<0.001) median Drug Liking Emax relative to placebo. Significant reductions (p<0.001) in median Drug Liking [Emax] were observed for IN ELI-200 [56.0] compared to IN oxycodone IR [100.0]. Secondary positive or objective measures (High, Good Drug Effects, Overall Drug Liking, Take Drug Again, and maximum pupil constriction) showed significantly lower Emax for IN ELI-200 (p<0.001) compared to IN oxycodone IR. IN administration of ELI-200 demonstrated significantly decreased effects on subjective and physiologic measures, and greater nasal irritation, compared to IN oxycodone IR. These findings, along with the PK profile of naltrexone, demonstrated that when ELI-200 capsules were ground and administered intranasally, the naltrexone component was rapidly released and conferred meaningful abuse-deterrent properties.

An update on naltrexone/bupropion extended-release in the treatment of obesity

ABSTRACTIntroduction: As the prevalence of obesity continues to increase, the need for effective long-term treatment strategies for overweight and obesity is critical. Pharmacology fills a large treatment gap between behavioral therapy, which is insufficient for the majority of patients, and devices and surgery, which are available to only a subset of patients. Naltrexone HCl and bupropion HCl Extended-Release (naltrexone XR/bupropion XR) was approved by the Food and Drug Administration for chronic weight management in 2014.Areas covered: This review illustrates the efficacy and safety of naltrexone XR/bupropion XR by examining data from clinical trials. It also provides an overview of the market and presents the pharmacodynamics and pharmacokinetics of naltrexone and bupropion.Expert opinion: The efficacy and safety profile of naltrexone XR/bupropion XR makes it a viable option for many patients who could benefit from its distinctive mechanism. The medication was shown to produce additive weight loss when combined with an intensive behavioral modification program and it may improve food cravings and eating behaviors. Compared to the other three antiobesity medications approved since 2012, naltrexone XR/bupropion XR is neither a controlled substance nor an injectable agent.

In-vivo study of naltrexone hydrochloride release from an in-situ forming PLGA-PEG-PLGA system in the rabbit

A thermosensitive hydrogel of PLGA-PEG-PLGA triblock synthesized via ring opening polymerization using microwave irradiation method was used to control the release of naltrexone HCl drug. In the present work, the injectable prepared hydrogel was dissolved in phosphate buffer with different amounts of naltrexone hydrochloride. The pharmacokinetic profiles of the drug in rabbits were determined using blood and urine samples after subcutaneous injection of drug formulations (naltrexone hydrochloride solution or naltrexone hydrochloride-hydrogel with doses of 5 and 15 mg/kg body weight). The concentrations of naltrexone HCl and its main metabolite (beta-naltrexol) were determined using a calibrated HPLC analytical method. The samples were collected and analyzed for 14 days. The serum concentrations of naltrexone HCl and β-naltrexol were significantly higher in drug-loaded hydrogels, compared to free injected naltrexone. This phenomenon is attributed to an effective accumulation of naltrexone HCl serum concentration during the process of slow release from hydrogel form (i.e. that amount of newly released naltrexone from hydrogel form, was added to that amount of metabolized drug released previously). As a conclusion, PLGA-PEG-PLGA copolymer can be evaluated as a biodegradable controlled release drug delivery system for naltrexone hydrochloride in the future human studies.

Mathematical modelling of buccal iontophoretic drug delivery system

The aim of this work is to numerically model the process of electrophoretic drug transport through buccal mucosa. The process was described for two electrode geometrical placement systems: opposite and concentric. Naltrexone HCl was used as a model drug. COMSOL Multiphysics software was applied for calculations. The modelling revealed that both geometries of iontophoretic port can deliver pharmacologically sufficient drug flux that gets to the reach of the capillary blood vessels region of the tissue. The opposite model, which enabled transdermal and transmucosal administration, proved more promising.

Effect of surfactants and pH on naltrexone (NTX) permeation across buccal mucosa

The objective of this pre-formulation study was to systematically investigate the effects of two surfactants (Brij 58 ® and Tween 80 ®) and change in solution pH on in vitro permeation of naltrexone HCl (NTX-HCl) across tissue engineered human buccal mucosa. For the study, 10 mg/ml solutions of Tween 80 ® (0.1 and 1%, w/v) and Brij 58 ® (1%, w/v) were prepared in standard artificial saliva buffer solution (pH 6.8). For studying pH effects, solution pH was adjusted to either 7.5 or 8.2. As controls, three concentrations of NTX-HCl (2.5, 10 and 25 mg/ml) were prepared. Using NTX standard solution (10 mg/ml; pH 6.8), the permeation was observed between in vitro human and ex vivo porcine mucosa. It was observed that Brij 58 ® increased the permeation rates of NTX significantly. The flux of 10 mg/ml solution (pH 6.8) increased from 1.9 ± 0.6 (×10 2) to 13.9 ± 2.2 (×10 2) μg/(cm 2 h) (approximately 6-fold) in presence of 1% Brij 58 ®. Increasing pH of NTX-HCl solution was found to increase the drug flux from 1.9 ± 0.6 (×10 2) (pH 6.8) to 3.0 ± 0.6 (×10 2) (pH 7.4) and 8.0 ± 3.5 (×10 2) (pH 8.2) μg/(cm 2 h), respectively. Histological analyses exhibited no tissue damage due to exposure of buccal tissue to Brij 58 ®. The mean permeability coefficients ( K p ) for 2.5, 10 and 25 mg/ml solutions of NTX-HCl (pH 6.8) were 5.0 (×10 −2), 1.8 (×10 −2) and 3.2 (×10 −2) cm/h, respectively, consistent with data from published literature sources. Increase of NTX flux observed with 1% Brij 58 ® solution may be due to the effects of ATP. Increase in flux and the shortening of lag time observed by increasing in solution pH confirmed earlier finding that distribution coefficient (log D) of NTX is significantly affected by small increments in pH value and therefore plays an important role in NTX permeation by allowing faster diffusion across tissue engineered human buccal tissue.

Voltammetry of naltrexone in commercial formulation and human body fluids: Quantification and pharmacokinetic studies

Naltrexone HCl (NAL.HCl) has been reduced at the mercury electrode in Britton–Robinson universal buffer of pH values 2–11 with a mechanism involving the quasi-reversible uptake of the first transferring electron followed by a rate-determining protonation step of its C = O double bond at position C-6. Simple, sensitive, selective and reliable linear-sweep and square-wave adsorptive cathodic stripping voltammetry methods have been described for trace quantitation of NAL.HCl in bulk form, commercial formulation and human body fluids without the necessity for sample pretreatment and/or time-consuming extraction steps prior to the analysis. Limits of quantitation of 6.0 × 10 −9 M and 8.0 × 10 −10 M NAL.HCl in bulk form or commercial formulation and of 9.0 × 10 −9 and 1.0 × 10 −9 M NAL.HCl in spiked human serum samples were achieved by the described linear and square-wave stripping voltammetry methods, respectively. Furthermore, pharmacokinetic parameters of the drug in human plasma samples of healthy volunteers following the administration of an oral single dose of 50 mg NAL.HCl (one Revia ® tablet) were estimated by means of the described square-wave stripping voltammetry method without interferences from the drug's metabolites and/or endogenous human plasma constituents. The estimated pharmacokinetic parameters were favorably compared with those reported in literature.

Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to β‐adrenergic stimulation in cirrhotic rats

It is well known that chronotropic and inotropic responses to beta-adrenergic stimulation are impaired in cirrhosis, but the exact reason is not clear. Considering the inhibitory effect of endogenous opioid peptides and nitric oxide (NO) on beta-adrenergic pathway, we examined their roles in hyporesponsiveness of isolated atria and papillary muscles to isoproterenol stimulation in cirrhotic rats. Cirrhosis was induced by chronic bile duct ligation. Four weeks after ligation or sham operation, the responses of the isolated atria and papillary muscles to isoproterenol stimulation were evaluated in the absence and presence of naltrexone HCl (10(-6) m), N(omega)-nitro-L-arginine methyl ester (L-NAME, 10(-4) m), and naltrexone plus L-NAME in the organ bath. Considering the role of inducible NOS (iNOS) in hemodynamic abnormalities of cirrhotic rats, the chronotropic and inotropic responses of cirrhotic rats to isoproterenol stimulation were also assessed in the presence of aminoguanidine (a selective inhibitor of iNOS, 3 x 10(-4) m). Sham operation had no significant effect on basal atrial beating rate, contractile force, and maximal time derivatives for the development and the dissipation of papillary muscle tension. The basal atrial beating rate of cirrhotic rats did not show any significant difference compared with the sham-operated ones; however, the basal contractile parameters were significantly decreased in cirrhosis. Although the maximum effects of isoproterenol on chronotropic and inotropic responses were significantly reduced in cirrhotic rats, there was no difference in half-maximal effective concentrations of isoproterenol in these concentration-response curves. The basal abnormalities and the attenuated chronotropic and inotropic responses to isoproterenol were completely corrected by the administration of naltrexone, L-NAME and aminoguanidine. Concurrent administration of naltrexone and L-NAME also restored to normal the basal abnormalities and the blunted responses to isoproterenol in cirrhotic rats, and did not show any antagonistic effect. Based on these findings, both the endogenous opioid peptides and NO may be involved in the attenuated chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhosis. It seems that the iNOS activity results in NO-induced hyporesponsiveness to beta-adrenergic stimulation in cirrhosis.

Effect of morphine on ischemia-reperfusion injury: Experimental study in testicular torsion rat model

ObjectivesTo investigate the effects of morphine on reperfusion injury due to testicular torsion-detorsion (T/D). MethodsWe divided 36 adult male Sprague-Dawley rats into six groups. Testicular ischemia was achieved by twisting the right testis 720° counterclockwise for 1 hour, and reperfusion was allowed for 4 hours after detorsion. The baseline group was for basal normal values. The sham-operated group served as the control group. The T/D group underwent 1 hour of testicular torsion and 4 hours of detorsion. The morphine group received pretreatment with intravenous morphine sulfate (10 mg/kg) just before detorsion. The naltrexone group received an intravenous injection of naltrexone HCl (20 mg/kg) 15 minutes before detorsion. The naltrexone/morphine group received intravenous administration of naltrexone HCl (20 mg/kg) 15 minutes before detorsion and morphine sulfate (10 mg/kg) just before detorsion. ResultsThe ipsilateral malondialdehyde levels in the T/D group were significantly greater than in the control and baseline groups. Moreover, the ipsilateral testicular malondialdehyde values in the morphine group were significantly lower than in the T/D and naltrexone/morphine groups. Also, significant decreases occurred in catalase and superoxide dismutase activities in the T/D group compared with the control and baseline groups. These values were significantly greater in the morphine group than in the T/D and naltrexone/morphine groups. The ipsilateral testes of all groups that underwent testicular torsion showed similar histopathologic changes. ConclusionsMorphine increased the ipsilateral intratesticular antioxidant markers during the reperfusion phase after unilateral testicular torsion, which was eventually reflected in lower testicular malondialdehyde levels. Furthermore, this effect was mediated through the opioid receptors.

Suspected Secondary Thiafentanil Intoxication in a Captive Mountain Lion (Puma concolor)

Inadvertent ingestion of thiafentanil oxalate by a captive adult female mountain lion (Puma concolor) caused a prolonged clinical syndrome that included sedation and depression, muscle tension, and myopathy that was incompletely antagonized by naltrexone HCl. A serum chemistry profile revealed markedly elevated creatinine phosphokinase (CK; 490,450 IU/l), alanine aminotransferase (ALT; 1,896 IU/l), and aspartate aminotransferase (AST; 4,321 IU/l) 2 days after onset. The affected animal's condition gradually improved over the next 15 days in response to supportive therapy that included diazepam (5 mg as needed), Normasol R (3 l/day), dexamethasone (tapering dose starting at 1 mg/kg), and ketoprofen (1 mg/kg). She eventually recovered completely. Based on these observations, carcasses of animals immobilized with thiafentanil should be marked and disposed of properly to preclude opportunities for secondary exposure and potential intoxication in scavenging species. In addition, caution is advised when using thiafentanil in animals that could be preyed upon before full metabolism of the drug.

Effect of surfactant HLB and different formulation variables on the properties of poly-D,L-lactide microspheres of naltrexone prepared by double emulsion technique

The aim of this work was to investigate the role of HLB of emulsifier as well as volume of the internal aqueous phase (W1) and presence of salt in the external aqueous phase (W2) on the morphology, size and encapsulation efficiency of poly(D,L-lactide) microspheres containing naltrexone HCl. PLA microparticles containing naltrexone HCl, an effective opiate antagonist, were prepared by a water-in-oil-in-water emulsification–solvent evaporation procedure. One of the five different emulsifiers: span 80, span 20, tween 85, tween 80 and tween 20, with HLB values from 4–17 were added to W1. Presence of emulsifier in W1 resulted in smaller particles with a more dense and uniform internal structure. Incorporation of span 80 (HLB 4.3, suitable for W/O emulsions) yield the highest encapsulation efficiency. Increasing the HLB value to 8 or 11 (span 20 or tween 85) decreased the efficiency of naltrexone HCl-loading. HLB values higher than 15 (tween 80 or tween 20) increased encapsulation efficiency unexpectedly, which could be attributed to migration of these emulsifiers to the O/W2 interface and modifying the surface properties of microparticles. Increasing the internal water phase volume from 0.2–1.8 ml resulted in larger particle size with poor encapsulation efficiency. Addition of 10% w/w NaCl to the W2 changed the surface morphology of microspheres from a porous form to a smooth surface. It was shown that, by selecting the appropriate HLB value of emulsifier in W1, addition of salt to W2 and controlling the volume of W1, one can control the encapsulation efficiency, size and morphology of microspheres.

Effect of cold acclimation and repeated swimming on opioid and nonopioid swim stress-induced analgesia in selectively bred mice

Swiss–Webster mice selectively bred for high swim stress-induced analgesia (SSIA) were exposed to continuous ambient cold (5 °C) for 6 weeks or to daily 3-min swims for 14 consecutive days either in 20 or 32 °C water. Thereafter, mice subjected to the particular procedure were injected intraperitoneally with 10 mg/kg of naltrexone HCl and were tested for modification of the opioid and nonopioid component of SSIA. SSIA was reduced following swims at either water temperature and was antagonized by naltrexone to greater extent than in nonswimming mice. Thus, the nonopioid (i.e. naltrexone-resistant) portion of the overall SSIA was significantly reduced, whereas the opioid (naltrexone-sensitive) portion became relatively augmented. In contrast, SSIA differed neither in magnitude nor in sensitivity to naltrexone between cold-acclimated and unacclimated mice. Swim hypothermia as well as the nonopioid component of SSIA were decreased after repeated swimming at 32 and 20 °C, but remained unchanged after cold acclimation. This argues for the essential role of an extrathermal, probably emotional in nature, factor not only in the elicitation of nonopioid SSIA, but also in the modulation of thermoregulatory processes during swimming. We suggest that the emergency component of swim stress, together with initial moderate hypothermic challenge, first produces the opioid form of SSIA, and subsequently, as the swim continues, also affects the thermoregulatory processes maintaining thermal homeostasis. This causes further increase in swim hypothermia and raises its stressing property to induce the nonopioid form of SSIA.

Analgesia in Selectively Bred Mice Exposed to Cold in Helium/Oxygen Atmosphere

In order to evaluate the stressing role of swim hypothermia in producing swim stress-induced analgesia (SSIA), we examined whether a mere decrease in the animals’ core temperature without swimming would be sufficient to elicit analgesia. The subjects were Swiss–Webster mice selectively bred for 37 and 40 generations for divergent magnitudes of SSIA. High (HA) and low analgesia (LA) mice were exposed for 15 min to temperatures in the range between −5 and +20°C in 79% He/21% O 2 (Heliox) atmosphere. The Heliox exposure produced ambient temperature-dependent hypothermia and analgesia, as assessed with a hot-plate test (56°C). The post-Heliox analgesia was of much higher magnitude in HA than in LA mice. The steeper slope of regression of the magnitude of analgesia upon hypothermia in HA mice indicates that these mice are far more sensitive to the analgesic effect of hypothermia than LA mice. Naltrexone HCl (10 mg/kg i.p.) attenuated analgesia in ambient temperature-dependent manner in HA, but not in LA mice. In view of the apparent similarity of Heliox-induced analgesia and SSIA we suggest that hypothermia is a powerful component of swim stress to induce SSIA in the mouse.

Naltrexone: a controversial therapy for alcohol dependence.

1. Naltrexone HCL (ReVia) may be an effective adjunct in the treatment of alcohol dependence in motivated individuals. 2. Naltrexone therapy is controversial because its use conflicts with the view of abstinence held by Alcoholics Anonymous and most medical treatment programs. 3. Knowledge of the controversy can help nurses advocate for their patients, and may help nurses acknowledge the need to define their care according to a nursing paradigm.

Conditional hypoalgesia is attenuated by Naltrexone applied to the periaqueductal gray

The ventrolateral periaqueductal gray (vPAG) is an important component in a brainstem system involves in the endogenous modulation of nociception and defensive behavior. The present study was conducted to determine if opioid receptors within the vPAG contribute to the hypoalgesia seen in rats during presentation of a Pavlovian CS for footshock. Independent groups of animals received microinjections of either 5.0 μg naltrexone HCl or vehicle into the vPAG prior to being placed in an observation chamber in which shock had been delivered 24 h earlier. Nociceptive reactivity was measured with the formalin test. Naltrezone treatment attenuated conditional hypoalgesia but did not affect formalin-induced behavior in non-shocked rats. Naltrexone had no effect on the amount of defensive freezing behavior observed during the test session. These results indicate that conditional hypoalgesia as measured by the formalin test involved the activation of documented brainstem antinociceptive systems.

The beta-carboline DMCM produces hypoalgesia after central administration

DMCM (Methyl 6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate), an “inverse agonist” at benzodiazepine receptors, produced a dose-related (0.5-20 μ/rat) elevation in the latency of rats to respond to a noxious thermal stimulus 20 min after i.c.v. administration. By 50 min after administration, no hypoalgesia could be detected. In animals given 5.0 μg of DMCM centrally, systemic injection of the opioid antagonist naltrexone HCl (0.75-7.0 mg/ml/kg) resulted in significant attenuation of hypoalgesia only at the highest dose tested. These results are discussed in terms of the role played by GABAergic central mechanisms in the activation of endogenous pain control systems.

Naltrexone potentiates 4-aminopyridine seizures in the rat

The effects of a pharmacological blockade of the mu opiate receptors on the manifestation of tonic-clonic seizures were investigated in freely moving animals. 4-aminopyridine, a specific blocker of the neuronal K+ channels was used to produce generalized convulsions. After pretreatment of adult rats with 1 mg/kg naltrexone HCl, 3, 5, 7, 9, 14 mg/kg 4-aminopyridine was injected intraperitoneally, and the latencies of the symptoms generated by 4-aminopyridine were measured. Naltrexone HCl decreased these latencies and enhanced the seizures significantly. The experiments provided further evidence for the existence of a tonic anticonvulsant opioid system in the brain.