Presence Of Naloxone Research Articles

Characteristics and Functional Roles of Opioids Originally Present in Vivo

The characteristics and functional roles of opioids originally present in vivo (endogenous opioids) in guinea-pig ileum were investigated. The release of endogenous opioids was determined by the inhibitory twitch response evoked by 0.1 Hz stimulation after 10 Hz stimulation (post-tetanic twitch inhibition). The effects of peptidase inhibitors increased the post-tetanic twitch inhibition, prevented by β-funaltrexamine and nor-binaltorphimine, which are selective μ- and κ-opioid receptor subtype antagonists, respectively. Dopamine receptor antagonists (haloperidol, sultopride and domperidone) increased the post-tetanic twitch inhibition. These results suggest that dopamine receptors are involved in modulation of the ileal opioid system, so as to diminish endogenous opioid release by tetanic stimulation, and dopamine antagonists increase the opioid action, that might depend more on the increased release of endogenous opioids. The post-tetanic twitch inhibition was inhibited by adrenalectomy, and showed the supersensitivity of the opioid receptors, resulting from a decrease of endogenous opioids by adrenalectomy. These findings suggest that the increase in morphine-analgesia by adrenalectomy was due to this process. In the presence of naloxone, an opioid antagonist, an increase in basal tension after tetanic stimulation (10 Hz stimulation) (post-tetanic contraction) was observed, and was blocked by spantide, a substance P antagonist, and indomethacin, a prostaglandins-biosynthesis inhibitor. This contraction increased with morphine or peptidase inhibitor exposure, depending on the length of time the ileum was exposed to the morphine or peptidase inhibitor. Post-tetanic contraction might be a useful indicator of the formation of physical dependence to morphine or endogenous opioids in the ileum.

Mixed MOP/DOP agonist biphalin elicits anti-transit effect in mouse models mimicking diarrhea-predominant irritable bowel syndrome symptoms.

Opioid receptors play a crucial role in the maintenance of homeostasis in the gastrointestinal (GI) tract. The aim of this study was to characterize the effect of biphalin, a mixed MOP/DOP agonist, on mouse intestinal contractility in vitro and GI motility in vivo and in animal models mimicking symptoms of diarrhea-predominant irritable bowel syndrome (IBS-D). The effect of biphalin on muscle contractility in vitro was characterized in the ileum and colon. The anti-transit activity of biphalin in vivo was assessed in the following tests: whole gastrointestinal transit, colonic bead expulsion, fecal pellet output and castor oil-induced diarrhea, alone and in the presence of naloxone, and MOP and DOP antagonists. In vitro, biphalin (10(-10)-10(-6)M) inhibited colonic and ileal smooth muscle contractions in a concentration-dependent, opioid antagonist-reversible manner. In vivo, biphalin at the dose of 5mg/kg ip prolonged the whole GI transit and inhibited colonic bead expulsion. Biphalin reversed hypermotility and exerted anti-diarrheal effect in mouse models mimicking IBS-D symptoms. Biphalin is an interesting template for novel opioid-based agents to be used in therapy of functional GI diseases.

Involvement of Cholinergic and Opioid System in γ-Terpinene-Mediated Antinociception.

The literature shows that the monoterpenes are great candidates for the development of new drugs for the treatment of various pathological processes, including painful conditions. The gamma terpinene (γ-TPN) is a monoterpene present in plant species that have multiple pharmacological properties and has structural similarity to antinociceptive monoterpenes, such as limonene and alpha-phellandrene. The γ-TPN molecular mass was evaluated by mass spectrometry and showed a pseudomolecular ion with m/z 137.0 Da. The animals did not present any signs of acute toxicity at 2 g/kg, p.o. γ-TPN (1.562 to 50 mg/kg, p.o.) showed an antinociceptive effect in the formalin, capsaicin, and glutamate tests. γ-TPN has antinociceptive action when administered by others routes in glutamate test. To eliminate a possible sedative effect of γ-TPN, the open field and rota-rod test were conducted and the γ-TPN did not show muscle relaxant activity or central depressant effect. To investigate the mechanisms of action, the animals were pretreated with naloxone, glibenclamide, atropine, mecamylamine, or L-arginine in the glutamate test. γ-TPN antinociception was inhibited in the presence of naloxone, glibenclamide, atropine, and mecamylamine. The results suggest that the γ-TPN (p.o.) produced antinociceptive effect in models of chemical nociception through the cholinergic and opioid systems involvement.

Oxycodone/Naloxone: role in chronic pain management, opioid-induced constipation, and abuse deterrence.

The use of opioids in the treatment of chronic pain is widespread; the prevalence of specific opioids varies from country to country and depends on product availability, national formulary systems, and provider preferences. Patients often receive opioids for legitimate treatment of pain conditions, but on the opposite side of the spectrum, nonmedical use of opioids is a significant public health concern. Opioids are associated with several side effects, and constipation is the most commonly reported and persistent symptom. Unlike some adverse effects associated with opioid use, tolerance does not develop to constipation. Opioid-induced constipation (OIC) is the most prevalent patient complaint associated with opioid use and has been associated with declines in various quality of life measures. OIC can be extremely difficult for patients to tolerate and may prompt patients to decrease or discontinue opioid treatment. Current management strategies for OIC are often insufficient. A prolonged-release formulation of oxycodone/naloxone (OXN) has been investigated for the treatment of nonmalignant and cancer pain and mitigation of OIC, and evidence is largely favorable. Studies have demonstrated the capability of OXN to alleviate OIC while maintaining pain control comparable to oxycodone-only regimens. There is insufficient evidence for OXN efficacy for patients with mild OIC or patients maintained on high doses of opioids, and use in these populations is controversial. The reduction of costs associated with OIC may provide overall cost effectiveness with OXN. Additionally, the presence of naloxone may deter abuse/misuse by those seeking to misuse the formulation by modes of administration other than oral ingestion. Most studies to date have occurred in European countries, and phase 3 trials continue in the United States. This review will include current therapeutic options for pain and constipation, unique characteristics of OXN, evidence related to use of OXN and its place in therapy, discussion of opioid abuse/misuse, and various abuse-deterrent mechanisms, and areas of continuing research.Electronic supplementary materialThe online version of this article (doi:10.1007/s40122-014-0026-2) contains supplementary material, which is available to authorized users.

Ursolic acid from Agastache mexicana aerial parts produces antinociceptive activity involving TRPV1 receptors, cGMP and a serotonergic synergism

Agastache mexicana is a plant that has long been used in large demands in Mexican folk medicine to treat anxiety, insomnia and pain, among others affections. Chromatographic technique was used to identify ursolic acid (UA), 130.7mg/g and 20.3mg/g, as an antinociceptive active compound identified in ethyl acetate and methanol extracts of A. mexicana aerial parts, respectively. Temporal course curves of the antinociceptive response demonstrated a dose-dependent and significant activity of UA (1 to 100mg/kg, i.p.) with an ED50=2mg/kg in comparison to the efficacy of diclofenac (1 or 30 to 100mg/kg, i.p.), a non-steroidal anti-inflammatory drug, with an ED50=11.56mg/kg. The antinociceptive response consisted in the reduction of abdominal constrictions induced with 1% acetic acid in mice. Similarly, UA at 2mg/kg produced significant antinociception in the intracolonic administration of 0.3% capsaicin (a TRPV1 agonist) in mice. It has been reported the inhibition produced by UA on the calcium‐flux induced by capsaicin on TRPV1 receptor suggesting the antagonistic activity of this receptor. Finally, an ED50=44mg/kg was calculated in the neurogenic and inflammatory nociception induced in the formalin test in rats. The antinociceptive response of UA in the formalin test was not modified in presence of naloxone, flumazenil or l-arginine. Nevertheless, it was reverted in presence of 1-H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, an inhibitor of soluble guanylyl cyclase) and increased in presence of N(G)-l-nitro-arginine methyl ester (l-NAME, inhibitor of nitric oxide synthase), theophylline (inhibitor of phosphodiesterase) and WAY100635 (an antagonist of 5-HT1A receptors). Current results provide evidence that the antinociceptive response of A. mexicana depends in part on the presence of UA. Moreover, this triterpene may exerts its antinociceptive effect mediated by the presence of cGMP and an additive synergism with 5HT1A receptors, but also an antagonistic activity towards TRPV1 receptors may be involved.

Naloxone increases maturation rate and ratio of inner cell mass to total cells in blastocysts in pigs

The purposes of the present study were to examine the effect of naloxone, a mu-opioid receptor (MOR) antagonist, on porcine oocyte maturation and embryo development. MOR gene was expressed in germinal vesicle (GV) and metaphase II (M-II) porcine oocytes, one-, four-cell stage embryos and blastocysts. In blastocysts, MOR gene was mainly expressed in inner cell mass (ICM) cells. Supplementation of 10(-8) mol/L naloxone in in vitro maturation (IVM) medium increased the maturation rate (P < 0.05). However, 10(-4) mol/L naloxone reduced the maturation rate (P < 0.05) compared with the control. The presence of naloxone during IVM had no effects on fertilization status and subsequent embryonic development after in vitro culture (IVC). The addition of 10(-3) mol/L dibutyryl cyclic adenosine monophosphate (dbcAMP), and 10(-8 ) mol/L naloxone together into IVM medium increased nuclear maturation (P < 0.05) compared with the addition of either dbcAMP or naloxone alone. Supplementation with naloxone in IVC medium did not improve embryonic development. However, at the concentrations of 10(-6) mol/L and 10(-8) mol/L, naloxone increased the ratio of ICM to total cells in blastocysts (P < 0.05). In conclusion, at low concentration, naloxone increases maturation rate and the ratio of ICM to total cells in blastocysts. Naloxone and cAMP have a synergistic effect on oocyte maturation.

Opioid Abuse and Deterrence: Buprenorphine Products

Abuse of opioid based prescription drugs is an ongoing global health concern that affects millions of individuals worldwide. The economic burden from this abuse has led to the development of treatment programs and the use of methadone maintenance in clinics. Yet, methadone itself has abuse liability and is misused in ways such as crushed for nasal insufflation or dissolved for subsequent intravenous injection. Later, a newer synthetic opioid working as a partial agonist at the mu-opioid receptor, buprenorphine (Subutex®), became available for outpatient use.This new opioid produces restricted euphoria, decreases withdrawal symptoms, and can prevent displacement of buprenorphine should the user decide to take illicit opioids. Due to high risk of abuse, the product was discontinued and now only available as a combination (Suboxone®) with the opioid antagonist naloxone.Users who abuse the combination product by parenteral routes will have euphoric effects cancelled by the presence of naloxone. Such novel dosage forms having additional physical and/or pharmacological barriers can provide a safe and effective option for medication-assisted treatment of opioid addiction with increased access to care.

Low dose naloxone attenuates the pruritic but not anorectic response to rimonabant in male rats

Previous research suggests that the acute anorectic effect of cannabinoid CB1 receptor antagonist/inverse agonists may be secondary to response competition from the compulsive scratching and grooming syndrome characteristic of these agents. As the pruritic effect of rimonabant can be attenuated by the opioid receptor antagonist naloxone, these studies test the prediction that naloxone co-treatment should prevent acute rimonabant anorexia. Two experiments comprehensively profiled the behavioural effects of an anorectic dose of rimonabant (1.5mg/kg) in the absence or presence of naloxone (experiment 1: 0.01 or 0.1mg/kg; experiment 2: 0.05mg/kg). In both experiments, rimonabant not only significantly suppressed food intake and time spent eating but also induced compulsive scratching and grooming. In experiment 1, although the lower dose of naloxone seemed to weakly attenuate the effects of rimonabant both on ingestive and compulsive behaviours, the higher dose more strongly suppressed the compulsive elements but did not significantly affect the anorectic response. The results of experiment 2 showed that naloxone at a dose which markedly attenuated rimonabant-induced grooming and scratching did not alter the effects of the compound on food intake or time spent feeding. The apparent independence of the ingestive and compulsive effects of rimonabant was confirmed by the observation that despite a 'normalising' effect of naloxone co-treatment on behavioural structure (BSS), the opioid antagonist did not impact the suppressant effect of rimonabant on peak feeding. The acute anorectic response to rimonabant would not appear to be secondary to compulsive scratching and grooming.

Hyptis pectinata: Redox Protection and Orofacial Antinociception

Hyptis pectinata L. Poit, known as 'sambacaitá', is used in Brazil to treat inflammatory and painful disorders. In this study, the antioxidant and orofacial antinociceptive properties of the aqueous extract of H. pectinata leaves (AEPH) were assessed using in vitro and in vivo models. Thus, AEPH reduced the 2,2-diphenyl-1-picrylhydrazyl radical up to 72.10% with an EC₅₀ of 14.56 µg/ml. It also inhibited 40.80% of the lipoperoxidation induced by 2'-azobis (2-amidinopropane) dihydrochloride in the thiobarbituric acid-reactive substances assay. The orofacial antinociceptive activity was evaluated in mice pre-treated with AEPH (100, 200 and 400 mg/kg, p.o.) and morphine (5 mg/kg, i.p.), which received afterwards formalin- (20 µl, 2% solution, s.c.), glutamate- (40 µl, 25 mM, s.c.) and capsaicin- (20 µl, 2.5 µg, s.c.) to induce orofacial nociception. AEPH at all doses reduced (p < 0.001) the nociceptive response in the first (43-62%) and second (47-80%) phases of the formalin test. Besides, the effect of AEPH (400 mg/kg) was not changed in the presence of naloxone (1.5 mg/kg, i.p.), an opioid antagonist. AEPH significantly inhibited mice face rubbing for capsaicin (23-69%, p < 0.05) and glutamate (48-77%, p < 0.001) at all doses. The findings suggested the AEPH has peripheral and central antinociceptive activities, which are not related to opioid receptors.

The putative somatostatin antagonist cyclo-somatostatin has opioid agonist effects in gastrointestinal preparations

AimsSpecificity of receptor antagonists used is crucial for clarifying physiological/pathophysiological roles of the respective endogenous agonist. We studied the effects (somatostatin antagonist and possibly other actions) of cyclo-somatostatin (CSST), a putative somatostatin receptor antagonist on the guinea-pig small intestine, a preparation where somatostatin causes inhibition of nerve-mediated contractions. Main methodsIn isolated organ experiments, half-maximal cholinergic “twitch” contractions of the guinea-pig small intestine were evoked or tonic contractions of the rat stomach fundus strip (in the presence of physostigmine) were elicited by electrical field stimulation. The effects of somatostatin (somatostatin-14), CSST, naloxone, as well as of direct smooth muscle stimulants were examined. Key findingsSomatostatin (10nM–1μM) caused transient inhibition of the twitch contraction, in a naloxone-insensitive manner. Surprisingly, CSST (0.3–1μM) also inhibited twitch contractions (more than 50% reduction at 1μM). This effect was prevented by the opioid receptor antagonist naloxone. Responses to acetylcholine or histamine were not or only minimally inhibited by CSST (up to 3μM). CSST (0.3μM in the absence or 1–10μM in the presence of naloxone) failed to inhibit the effect of somatostatin. The SST2 receptor antagonist CYN-154806 (3μM) attenuated the effect of somatostatin and failed to evoke naloxone-sensitive inhibition of the twitch response. The naloxone-sensitive inhibitory effect of CSST on cholinergic contractions was also confirmed in the rat stomach fundus preparation. SignificanceCyclo-somatostatin exerts opioid agonist activity in the two preparations tested, while it does not behave as a somatostatin-receptor antagonist in the guinea-pig intestine.

Naloxone decreases the inhibitory effect of alprazolam on the release of adrenocorticotropin/cortisol induced by physical exercise in man.

• Alprazolam (ALP), a benzodiazepine activating GABAergic receptors, is involved in ACTH secretion. • This study demonstrates a partial opioid influence in the inhibitory effect of ALP on the release of ACTH/cortisol during physical exercise. To establish the possible involvement of alprazolam (ALP) and/or opiates in the mechanism underlying the ACTH/cortisol response to physical exercise. Tests were carried out under basal conditions (exercise control test), exercise plus ALP (50 µg at time -90 min), naloxone (10 mg at time 0) or ALP plus naloxone. Plasma ACTH and serum cortisol concentrations were evaluated in blood samples taken before, during and after the bicycle ergometer tests. ACTH and cortisol concentrations rose significantly after physical exercise. Maximum peak at time 15 min (P ≤ 0.01 vs. baseline) for ACTH and at time 30 min (P ≤ 0.01 vs. baseline) for cortisol. In the presence of naloxone, the ACTH and cortisol responses were significantly increased (maximum peak at time 20 min, P ≤ 0.02 vs. control test for ACTH, and at time 30 min (P ≤ 0.01 vs. baseline) for cortisol) whereas they were abolished by ALP. When ALP and naloxone were given together, the inhibitory effect of ALP was partial. These data demonstrate an inhibitory effect of ALP in the regulation of the ACTH/cortisol response to physical exercise in man and suggest that GABAergic receptor activating benzodiazepines and opioids interact in the neuroendocrine secretion of ACTH/cortisol.

An investigation of the mechanism involved in the cholinergic action of meptazinol.

In concentrations above 20 microM, (+/-)-meptazinol produced a contraction of the guinea-pig isolated ileum and this effect was antagonized by atropine (0.01 to 0.3 microM) in a manner which was not competitive. Cooling the preparation to 15 degrees C blocked the contractile action of meptazinol and of dimethylphenylpiperazinium (DMPP) but did not affect the action of carbachol. Twitch responses of the rat phrenic nerve-diaphragm preparation induced by indirect electrical stimulation in the presence of naloxone (20 nM) were potentiated by meptazinol (1 to 40 microM) which also reversed a partial blockade of the twitch induced by tubocurarine. Neither of these effects was seen in tissues which had been pretreated with the cholinesterase inhibitor BW284C51 (0.2 microM) though tetraethylammonium iodide (40 microM) was still able to enhance the responses to stimulation. In the presence of naloxone (20 nM) electrically induced responses of the rat isolated rectum were abolished by cinchocaine (10 microM), partially blocked by atropine (0.1 to 0.4 microM) and potentiated by meptazinol (1 to 30 microM). The latter action was not seen when meptazinol was administered in the presence of BW284C51. It is concluded that the cholinergic action of meptazinol in these tissues is due to an indirect effect, probably involving inhibition of cholinesterase and that no evidence was seen of any ability to increase the release of acetylcholine itself.

Chemical Composition, Acute Toxicity, and Antinociceptive Activity of the Essential Oil of a Plant Breeding Cultivar of Basil (Ocimum basilicumL.)

Ocimum basilicum L. is an aromatic herb used in Brazil to treat illnesses such as respiratory and rheumatic problems, vomiting, and pain. In the present study, the chemical composition, acute toxicity, and antinociceptive effects of the essential oil (EO) of the cultivar "Maria Bonita" obtained from O. basilicum L. PI 197442 genotype were evaluated in Swiss mice (20-35 g each). Lethal dose to cause 50 % death (LD50) was calculated from a dose-response curve (100-5000 mg/kg body wt.; n = 6) as 532 mg/kg body wt. In the acetic acid-induced writhing test (0.6 % i. p.), EO (50, 100, and 200 mg/kg body wt., n = 8, s. c.) was effective in reducing the abdominal contractions at all doses (48-78 %). In the hot-plate test, EO significantly increased the latency at 50 mg/kg body wt. at all times (37-52 %, n = 8, s. c.). However, the effects of morphine and EO at 50 mg/kg were reverted in the presence of naloxone, an opioid antagonist. In the formalin test, EO significantly reduced paw licking time in the first and second phases of pain at 200 mg/kg body wt. (38 and 75 %, respectively, n = 8, s. c.). The results suggested that the peripheral and central antinociceptive effects of EO are related to the inhibition of the biosynthesis of pain mediators, such as prostaglandins and prostacyclins, and its ability to interact with opioid receptors.

Pharmacological Basis for the Medicinal Use of Black Pepper and Piperine in Gastrointestinal Disorders

Dried fruits of Piper nigrum (black pepper) are commonly used in gastrointestinal disorders. The aim of this study was to rationalize the medicinal use of pepper and its principal alkaloid, piperine, in constipation and diarrhea using in vitro and in vivo assays. When tested in isolated guinea pig ileum, the crude extract of pepper (Pn.Cr) (1–10 mg/mL) and piperine (3–300 μM) caused a concentration-dependent and atropine-sensitive stimulant effect. In rabbit jejunum, Pn.Cr (0.01–3.0 mg/mL) and piperine (30–1,000 μM) relaxed spontaneous contractions, similar to loperamide and nifedipine. The relaxant effect of Pn.Cr and piperine was partially inhibited in the presence of naloxone (1 μM) similar to that of loperamide, suggesting the naloxone-sensitive effect in addition to the Ca(2+) channel blocking (CCB)-like activity, which was evident by its relaxant effect on K+ (80 mM)-induced contractions. The CCB activity was confirmed when pretreatment of the tissue with Pn.Cr (0.03–0.3 mg/mL) or piperine (10–100 μM) caused a rightward shift in the concentration–response curves of Ca(2+), similar to loperamide and nifedipine. In mice, Pn.Cr and piperine exhibited a partially atropine-sensitive laxative effect at lower doses, whereas at higher doses it caused antisecretory and antidiarrheal activities that were partially inhibited in mice pretreated with naloxone (1.5 mg/kg), similar to loperamide. This study illustrates the presence of spasmodic (cholinergic) and antispasmodic (opioid agonist and Ca(2+) antagonist) effects, thus providing the possible explanation for the medicinal use of pepper and piperine in gastrointestinal motility disorders.

Opioid Blockade and Inflammation Reveal Estrous Cycle Effects on Visceromotor Reflexes Evoked by Bladder Distention

Painful bladder disorders vary in intensity with the menstrual cycle in women. We evaluated the influence of the correlate in rats (the estrous cycle) on the nociceptive visceromotor reflex to bladder distention in the presence/absence of inflammation and of spinal opioid blockade. We recorded visceromotor reflexes as electromyogram responses of the abdominal musculature to graded (10 to 60 mm Hg) bladder distention in anesthetized female rats in the presence of intrathecal saline or naloxone (10 μg) 1 day after receiving intravesical zymosan or anesthesia alone. In saline treated rats visceromotor reflexes to bladder distention were significantly greater in those with an inflamed vs a noninflamed bladder when examined together. When separated into phases, rats with bladder inflammation showed complex estrous cycle effects with significantly greater visceromotor reflexes to bladder distention during metestrus and proestrus than diestrus. In naloxone treated rats visceromotor reflexes to bladder distention were significantly greater in those with an inflamed vs a noninflamed bladder when examined together. Naloxone enhanced the overall magnitude of visceromotor reflexes to bladder distention in the inflamed and noninflamed conditions. The magnitude of visceromotor reflexes to bladder distention in noninflamed and inflamed conditions in the presence of naloxone was estrous phase dependent in the order, estrus >metestrus >diestrus >proestrus. Similar findings were apparent on analysis of data on responses at threshold intensity (30 mm Hg). Data suggest that circulating hormones present during the estrous cycle alter bladder reactivity and opioid modulatory systems to maintain constancy of input from the bladder to the central nervous system.

Naloxone decreases the inhibitory effect of ethanol on the release of arginine-vasopressin induced by physical exercise in man

To establish whether ethanol and/or endogenous opioids play a role in the control of arginine-vasopressin (AVP) response to physical exercise, six healthy men underwent six bicycle-ergometer tests until exhaustion [exercise control test; exercise plus ethanol (50 of 110 ml proof whiskey orally), exercise plus naloxone (2 mg injected plus 5 mg infused or 4 mg injected plus 10 mg infused intravenously] or exercise plus ethanol plus naloxone). Plasma AVP levels, physiological and biochemical variables were measured during tests. Physiological and biochemical variables were similar in all tests. During the control test, exercise significantly increased plasma AVP levels, with a peak value five times higher than baseline. The AVP response to exercise was similar in the presence of naloxone, whereas it was abolished by ethanol. When ethanol tests were repeated in the presence of naloxone, at both lower and higher dose, ethanol inhibition on AVP secretion was only partial, with mean peak responses 2.5 times higher than basal values. Results indicate an ethanol involvement in regulation of the AVP response to physical exercise. Furthermore, naloxone-sensitive endogenous opioids appear to play a role in the mechanism underlying ethanol inhibitory action, but not in mediation of the AVP response to physical exercise.

Effects of curcumin, morphine and naloxone on the experimentally-induced paw edema in rats

In this study, effects of curcumin (active substance of turmeric), morphine (an opioid receptor agonist) and naloxone (an opioid receptor antagonist) in separate and combined treatments have been investigated on the paw edema induced by formalin in rats. Subcutaneous injection of formalin (50μl, 2.5%) in the ventral surface of the hind paw induced a considerable edema in the paw that lasted up to 24h after formalin injection. Chronic oral administration of curcumin (30 and 60mg/kg, 15 days) and subcutaneous injection of morphine (1mg/kg) significantly (p<0.05) decreased the paw edema induced by formalin. Naloxone (1mg/kg) used alone was without effect, whereas pretreatment with naloxone (1mg/kg) before morphine (1mg/kg) significantly (p<0.05) prevented the suppressive effect of morphine on the paw edema. The reducing effect of curcumin on the paw edema was potentiated by morphine, whereas naloxone did not change the anti-edematous effect of curcumin. Curcumin (30mg/kg, 15 days) in the presence of naloxone (1mg/kg) plus morphine (1mg/kg) treatment, produced an anti- edematous effect, which resembled the one following administration of curcumin (30 mg/kg, 15 days) alone. Present findings indicate that curcumin may produce an anti-edematous effect. The endogenous opioid system may involve in modulation of local edema. In addition, morphine may potentiate the anti-edematous effect of curcumin.

Cross-Reactivity of Naloxone with Oxycodone Immunoassays: Implications for Individuals Taking Suboxone®

In 2002, the US Food and Drug Administration approved the use of the sublingual tablet, Suboxone® (Reckitt Benckiser Pharmaceuticals), to treat opioid dependence. The formulation is available at 2 doses, 2 or 8 mg (free base) buprenorphine hydrochloride and 0.5 or 2 mg (free base) naloxone hydrochloride dihydrate (1). The combination product is designed to decrease the potential for intravenous abuse, since parenteral administration may precipitate opioid withdrawal(2). To monitor compliance, physicians request urine testing of buprenorphine and often additional testing to ensure no illicit drug use. A client recently requested multianalyte testing of patients taking Suboxone. Initial testing suggested a response with the oxycodone assay. We hypothesized this response was due to the presence of naloxone. To test this hypothesis, we ( a ) assayed a 40-μg/L buprenorphine calibrator with the oxycodone assay and ( b ) assayed drug-free urine samples that had been supplemented with increasing concentrations (100–10 000 μg/L of naloxone (Cerilliant Corporation) and naloxone glucuronide (Sigma–Aldrich). We evaluated 2 enzyme immunoassays: the homogeneous enzyme immunoassay (HEIA) oxycodone (Immunalysis Corporation) and the DRI® …

Morphine Reduces the Threshold of Helium Preconditioning Against Myocardial Infarction: The Role of Opioid Receptors in Rabbits

Brief, repetitive administration of helium before prolonged coronary artery occlusion and reperfusion protects myocardium against infarction. Opioid receptors mediate the cardioprotective effects of ischemic pre- and postconditioning, but whether these receptors also play a role in helium preconditioning is unknown. The authors tested the hypotheses that opioid receptors mediate helium preconditioning and that morphine (a mu(1)-opioid receptor agonist with delta(1)-opioid agonist properties) lowers the threshold of cardioprotection produced by helium in vivo. A randomized, prospective study. A university research laboratory. Male New Zealand white rabbits. Rabbits (n = 56) were instrumented for the measurement of systemic hemodynamics and subjected to a 30-minute left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. In separate experimental groups, rabbits (n = 6 or 7 per group) received 0.9% saline (control), 1 or 3 cycles of 70% helium-30% oxygen administered for 5 minutes interspersed with 5 minutes of an air-oxygen mixture, morphine (0.1 mg/kg intravenously), or the nonselective opioid antagonist naloxone (6 mg/kg intravenously) before LAD occlusion. Other groups of rabbits received 3 cycles of helium or 1 cycle of helium plus morphine (0.1 mg/kg) in the absence or presence of naloxone (6 mg/kg) before ischemia and reperfusion. Statistical analysis of data was performed with analysis of variance for repeated measures followed by Bonferroni modification of the Student t test. Myocardial infarct size was determined by using triphenyltetrazolium chloride staining and presented as a percentage of the left ventricular area at risk. Helium reduced myocardial infarct size in an exposure-related manner (36 +/- 6 [p > 0.05] and 25% +/- 4% [p < 0.05 v control] for 1 and 3 cycles of helium, respectively; data are mean +/- standard deviation) compared with control (44% +/- 7%). Morphine and naloxone alone did not affect infarct size (45 +/- 2 and 40% +/- 8%, respectively). The combination of 1 cycle of helium and morphine reduced infarct size (24% +/- 5%, p < 0.05 v control) to an equivalent degree as 3 cycles of helium. Naloxone pretreatment abolished cardioprotection produced by 3 cycles of helium (47% +/- 2%) and the combination of 1 cycle of helium plus morphine (45% +/- 4%). The results indicate that morphine lowers the threshold of helium preconditioning. Opioid receptors mediate helium preconditioning and its augmentation by morphine in vivo.

Electroacupuncture improves impaired gastric motility and slow waves induced by rectal distension in dogs

Rectal distension (RD) is known to induce upper gastrointestinal (GI) symptoms. The aim of this study was to investigate the effects and underlying mechanisms of RD on gastric slow waves (GSW) and motor activity and furthermore to investigate the effects and mechanisms of electroacupuncture (EA) on GSW and motor activity. Eight female hound dogs chronically implanted with gastric serosal electrodes and a gastric fistula were studied in six separate sessions. Antral motility, GSW, heart rate variability, and rectal pressure were evaluated for the above purposes. 1) RD at a volume of 120 ml suppressed antral motility significantly. Guanethidine blocked the inhibitory effect of RD. EA at ST36 was able to restore the suppressed antral contractions induced by RD (16.6+/-1.7 vs. 8.0+/-1.4, P<0.001). Naloxone partially blocked the effect of EA on antral contractions. 2) RD reduced the percentage of normal GSW from 98.8+/-0.8% at baseline to 76.1+/-8.6% (P<0.05) that was increased to 91.8+/-3.0% with EA. The effects of EA on the GSW were nullified by the presence of naloxone. 3) EA did not show any significant effect on rectal pressure, suggesting that the ameliorating effects of EA on RD-induced impaired gastric motility were not due to a decrease in rectal pressure. 4) EA increased the vagal activity suppressed by RD. In conclusion, RD inhibits postprandial gastric motility and impairs GSW in dogs, and the inhibitory effects are mediated via the adrenergic pathways. EA at ST36 is able to restore the RD-induced impaired GSW and motor activities, possibly by enhancing vagal activity, and is partially mediated via the opioid pathway. EA may have therapeutic potential for functional gastrointestinal disorders.