Involvement Of Opioid Receptors Research Articles

Antinociceptive effect of methanol extract of Celosia cristata Linn. in mice.

Background Celosia cristata Linn. (Amaranthaceae) is used in traditional medicine for the treatment of headache, sores, ulcers, eye inflammations, skin eruption, painful menstruation and carpal tunnel syndrome. This study was performed to evaluate the antinociceptive activity of methanol extract of the whole plant of C. cristata (MECC).MethodsThe evaluation of the antinociceptive effect of MECC was performed using thermal (hot plate, tail immersion test) and chemical (acetic acid, formalin, and glutamate-induced nociception test) pain models in mice at four different doses (50, 100, 200, 400 mg/kg; p.o.). Involvement of opioid receptors mediated central antinociceptive mechanism of MECC was evaluated using naloxone. Furthermore, the association of ATP-sensitive K+ channel and cGMP pathway were evaluated using glibenclamide and methylene blue respectively.ResultsOral treatment of MECC produced significant, strong and dose-dependent central and peripheral antinociceptive effect in experimental pain models. MECC significantly increased the latency time of thermal threshold in both hot plate and tail immersion test. The inhibition of writhing syndrome by the extract in the acetic acid-induced writhing test was remarkable. MECC significantly reduced the formalin-induced neurogenic and inflammatory pain. In addition, the inhibition of glutamate-induced paw licking and edema by MECC was significant. The antinociceptive effect was significantly reversed by naloxone and glibenclamide, suggesting the association of opioid and ATP-sensitive K+ channel system respectively. In addition, MECC also demonstrated the involvement of cGMP pathway in the antinociceptive action.ConclusionThe study suggests that C. cristata possess significant antinociceptive effect which is associated with both central and peripheral mechanisms and provides a rationale for its extensive use at different painful conditions in traditional medicine.

Involvement of delta opioid receptors in alcohol withdrawal-induced mechanical allodynia in male C57BL/6 mice

BackgroundAs a legal drug, alcohol is commonly abused and it is estimated that 17 million adults in the United States suffer from alcohol use disorder. Heavy alcoholics can experience withdrawal symptoms including anxiety and mechanical allodynia that can facilitate relapse. The molecular mechanisms underlying this phenomenon are not well understood, which stifles development of new therapeutics. Here we investigate whether delta opioid receptors (DORs) play an active role in alcohol withdrawal-induced mechanical allodynia (AWiMA) and if DOR agonists may provide analgesic relief from AWiMA. MethodsTo study AWiMA, adult male wild-type and DOR knockout C57BL/6 mice were exposed to alcohol by a voluntary drinking model or oral gavage exposure model, which we developed and validated here. We also used the DOR-selective agonist TAN-67 and antagonist naltrindole to examine the involvement of DORs in AWiMA, which was measured using a von Frey model of mechanical allodynia. ResultsWe created a robust model of alcohol withdrawal-induced anxiety and mechanical allodynia by orally gavaging mice with 3g/kg alcohol for three weeks. AWiMA was exacerbated and prolonged in DOR knockout mice as well as by pharmacological blockade of DORs compared to control mice. However, analgesia induced by TAN-67 was attenuated during withdrawal in alcohol-gavaged mice. ConclusionsDORs appear to play a protective role in the establishment of AWiMA. Our current results indicate that DORs could be targeted to prevent or reduce the development of AWiMA during alcohol use; however, DORs may be a less suitable target to treat AWiMA during active withdrawal.

Analgesic Effect of Melanin from (Nigella sativa L.) in the Hotplate Test in Mice (Possible Opioid Receptor Involvement)

Analgesic Effect of Melanin from (Nigella sativa L.) in the Hotplate Test in Mice (Possible Opioid Receptor Involvement)

A mechanistic approach to anti-nociceptive potential of Artemisia macrocephala Jacquem.

BackgroundArtemisia macrocephala Jacquem (A. macrocephala), locally known as “Tarkha”, is a perennial plant found abundantly in northern areas of Pakistan. It is widely used in traditional medicine to treat fever, pain, gastrointestinal disorders and diabetes. Till date, no published studies are available regarding the in-vivo antinociceptive potential of the crude extract and sub-fractions from the aerial parts of A. macrocephala.MethodsAntinociceptive effects of the crude methanolic extract and its sub-fractions were assessed using experimental pain models, including chemical nociception induced by intraperitoneal acetic acid or subplantar formalin injection and thermal nociception like tail immersion test in-vivo.ResultsThe administration of various doses of crude extract and its fractions showed a dose-dependent indomethacin like antinociceptive effect in acetic acid induced writhing, subplantar formalin injection animal model suggesting the involvement of central mechanism of pain inhibition. Moreover, the crude extract and sub-fractions, on tail flick model (thermal nociception) demonstrated the involvement of central mechanism and significantly increased the latency time to 66.54, 82.94 and 70.53 %. The antagonistic study proposed the possible involvement of opioid receptor using naloxone as non-selective antagonist. The pharmacologically active chloroform and ethyl acetate fractions were further subjected to column chromatography that lead to the isolation four compounds. These isolated compounds were then subjected to various spectroscopic techniques upon which they were confirmed to be one sterol and three flavonoid derivatives. These findings suggest that Artemisia macrocephala possesses peripheral and central analgesic potentials partially associated with opioid system that support its folkloric use for the management of pain. The isolated compounds are currently under investigation in our laboratory for analgesic activity and its possible mechanism of action.ConclusionThe results in this study provide evidences that A. macrocrphala has anticonciceptive effects and can be used for treatment of pain in traditional therapies. This study opens a new channel for isolation of analgesic compounds from the specie that is used traditionally for the management of pain.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-016-1114-0) contains supplementary material, which is available to authorized users.

Antinociceptive and anti-inflammatory effects of Memora nodosa and allantoin in mice

Ethnopharmacological relevanceThe leaves and stems bark of Memora nodosa (Silva Manso) Miers (Bignoniaceae) are used in Brazilian traditional medicine in the treatment of external ulcers and wounds; its roots are used to treat abdominal pain and scabies. Aim of the studyOur aim was to evaluate the antinociceptive and anti-inflammatory activities of Memora nodosa roots ethanolic extract (EMN) and allantoin, a secondary metabolite isolated from this plant. Materials and methodsThe EMN and allantoin antinociceptive activity were evaluated in mice using both chemical and heat-induced pain models such as acetic acid-induced writhing, formalin and tail-flick tests. In the formalin test, a pre-treatment with naloxone was used to verify an involvement of opioid receptor in the antinociceptive effect of EMN and allantoin. Pre-treatment with glibenclemide was used to verity an involvement of ATP-sensitive K+channel in the allantoin antinociceptive effect. EMN and allantoin anti-inflammatory activity were assessed by carrageenan-induced paw edema and pleurisy tests. ResultsThe treatment with EMN (250, 500 and 1000mg/kg, p.o.) inhibit the acetic acid and formalin (both phases)-induced nociception. However, just at doses 500 and 1000mg/kg increased the latency time in tail-flick test. These results suggest the involvement of both peripheral and central antinociceptive mechanisms. The treatment with allantoin (40, 60 and 80mg/kg p.o.) produced a dose-dependent antinociceptive effect in both phases of formalin-induced nociception test; allantoin (60mg/kg) was not able to increase the latency time in tail flick-test. The pre-treatment with naloxone completely reversed the EMN (1000mg/kg) and allantoin (60mg/kg) effect in the first phase of formalin test; and glibenclamide reversed the allantoin effect. The administration of EMN (250, 500 and 1000mg/kg) and allantoin (60mg/kg) showed significant anti-inflammatory activity in the whole carrageenan-induced paw edema. Furthermore, EMN and allantoin reduced the leukocytes migration and pleural exudate to the pleural cavity. ConclusionEMN have significant antinociceptive and anti-inflammatory effects, which appear to be, at least in part, due to the presence of allantoin. However, allantoin is not responsible for the EMN central antinociceptive activity. Allantoin has peripheral antinociceptive activity that involves the opioid receptor and ATP-sensitive K+channels. Opioid receptors are also involved in the EMN antinociceptive activity. These findings support the use of Memora nodosa in popular medicine and demonstrate that this plant has therapeutic potential for the development of antinociceptive and anti-inflammatory phytomedicines.

Evaluation of antinociceptive activity of methanolic extract of leaves of Stephania japonica Linn

Ethnapharmacological relevanceStephania japonica is a common plant, widely distributed in all over Bangladesh. Traditionally, this plant is considered as one of the important ingredients in treatment of a variety of ailments including inflammation, pain, rheumatism, cancer, bone fracture, fever etc. However, the scientific reports regarding the antinociceptive effect of this plant are very limited. This study evaluated the antinociceptive effect of methanolic extract of S. japonica (MESJ) leaves. Materials and methodsThe antinociceptive effect of MESJ was investigated using both heat- and chemical-induced nociceptive models such as hot plate, tail immersion, acetic acid-induced writhing, formalin and glutamate tests at the doses of 50, 100 and 200mg/kg. Morphine (5mg/kg) and diclofenac sodium (10mg/kg) were used as reference drugs in thermal and chemical models, respectively. Moreover, naloxone (2mg/kg) was used in the thermal models to justify the possible role of the opioid receptors. ResultsMESJ produced a significant and dose-dependent increase in the hot plate and tail immersion latencies which were reversed by the treatment with naloxone, suggests the possible involvement of opioid receptors in this activity. Moreover, MESJ inhibited acetic acid-induced writhing, formalin and glutamate-induced lickings in a dose-dependent manner. In parallel, the reference drugs also produced desired antinociceptive effects in this study. ConclusionThese results strongly support the antinociceptive activity of the leaves of Stephania japonica and rationalize the traditional use of the leaves in treatment of different painful conditions.

Involvement of Opioid Receptors in Lipid Rescue of Bupivacaine-Induced Cardiotoxicity

Surv Anesthesiol 2016;60(2):78–79 Lipid rescue, or lipid emulsion (LE), has been shown to resuscitate patients from cardiac-related effects of local anesthetics and from toxicities caused by a wide range of drugs, such as calcium channel blockers, β-blockers, and psychoactive agents. Using nonselective opioid receptor antagonists (ORAs) and highly selective ORAs, the authors of this study examined whether the rescue action of LE is mediated through central or peripheral opioid receptors.

Involvement of opioid receptors in the systemic and peripheral antinociceptive actions of montelukast in the animal models of pain

This study aimed to investigate the involvement of opioid receptors in the systemic and peripheral antinociceptive activities of montelukast in different animal models of pain.Rats and mice were injected with montelukast to produce analgesia. The formalin and acetic acid-induced writhing tests were used to assess the nociceptive activity. The results showed that i.p. administration of montelukast (0.3–10mg/kg) dose-dependently reduced flinching behavior in both the first and second phases of formalin test with mean ED50 of 0.55 and 5.31mg/kg, respectively. Also, intraplantar administration of montelukast (3–30μg/paw) produced antinociception against the two phases of formalin assay in a dose-dependent way with mean ED30 of 2.92 and 8.11μg/paw, respectively. Furthermore, pre-treatment with naloxone (a non-selective opioid receptor antagonist) significantly inhibited both the systemic and also peripheral antinociceptive actions of montelukast in formalin test. In writhing test, the results showed that intraperitoneal administration of montelukast (3–10mg/kg) significantly reduced the writhe number induced by acetic acid in mice. Moreover, co-administration of non-effective doses of montelukast (0.3 and 1mg/kg; i.p.) and morphine (0.25mg/kg; i.p.) significantly decreased the writhes number induced by acetic acid. Also, this effect was naloxone-reversible. These findings suggest that the systemic and peripheral antinociception produced by montelukast were mediated through the opioid receptors in central and peripheral nervous systems. Moreover, combination of montelukast and morphine could be noted as a new strategy for pain relief.

Antinociceptive effect of hydroalcoholic extract and isoflavone isolated from Polygala molluginifolia in mice: evidence for the involvement of opioid receptors and TRPV1 and TRPA1 channels

PurposeThe plants of the genus Polygala (Polygalaceae) have been used for a long time in folk medicine to treat pain and inflammation. The species Polygala molluginifolia is native to southern Brazil and is popularly known as “cânfora”. The presented study analyzes the antinociceptive effect of hydroalcoholic extract from Polygala molluginifolia (HEPm) and an isoflavone (ISO) isolated from the extract, in behavioral models of pain in mice, as well as the mechanism underlying this effect. Materials and methodsThe phytochemical analysis of HEPm was performed through a capillary electrophoresis analysis and colorimetric test. The antinociceptive effects of HEPm and ISO (10–1000mg/kg, i.g.) were evaluated by applying the formalin test; mechanical and thermal hyperalgesia to postoperative pain in mice. The possible involvement of opioid receptors, TRPV1 and TRPA1 channels in the antinociceptive effect of HEPm and ISO were also evaluated. Finally, the nonspecific effects of HEPm and ISO were evaluated by measuring locomotor activity (Open-field Test) and corporal temperature. ResultsThe 5,3′,4′-trihydroxy-6″,6″-dimethylpyrano[2″,3″:7,6] isoflavone (ISO) was identified in HEPm by capillary electrophoresis analysis and selected for the experimental tests. The oral administration of HEPm or of ISO significantly inhibited the neurogenic and inflammatory phases of formalin-induced pain, edema formation and local hyperemia, without causing any change to locomotor activity. Acute and repeated treatment of animals with HEPm reduced mechanical and thermal (heat and cold) hyperalgesia in the postoperative pain. In addition, administering HEPm or ISO markedly reduced nociceptive behavior induced by the peripheral and central injection of TRPV1 and TRPA1 channels activators. Finally, the antinociception provided by the administration of HEPm or ISO was reversed by the preadministration of naloxone. ConclusionsTaken together, these results provide the first experimental evidence of the significant antinociceptive effect of HEPm and ISO in animal models of acute pain without causing sedation or locomotor dysfunction. This effect appears to be mediated, at least in part, by the activation of opioid receptors and/or by the inhibition of TRPV1 and TRPA1 channels. Moreover, this study adds new scientific evidence and highlights the therapeutic potential of the medicinal plant Polygala molluginifolia in the development of phytomedicines with analgesic properties.

Stress-Induced Enhancement of Ethanol Intake in C57BL/6J Mice with a History of Chronic Ethanol Exposure: Involvement of Kappa Opioid Receptors.

Our laboratory has previously demonstrated that daily forced swim stress (FSS) prior to ethanol drinking sessions facilitates enhanced ethanol consumption in mice with a history of chronic intermittent ethanol (CIE) vapor exposure without altering ethanol intake in air-exposed controls. Because both stress and chronic ethanol exposure have been shown to activate the dynorphin/kappa opioid receptor (KOR) system, the present study was designed to explore a potential role for KORs in modulating stress effects on ethanol consumption in the CIE model of dependence and relapse drinking. After stable baseline ethanol intake was established in adult male C57BL/6J mice, subjects received chronic intermittent exposure (16 h/day × 4 days/week) to ethanol vapor (CIE group) or air (CTL group). Weekly cycles of inhalation exposure were alternated with 5-day limited access drinking tests (1 h access to 15% ethanol). Experiment 1 compared effects of daily FSS and KOR activation on ethanol consumption. CIE and CTL mice were either exposed to FSS (10 min), the KOR agonist U50,488 (5 mg/kg), or a vehicle injection (non-stressed condition) prior to each daily drinking session during test weeks. FSS selectively increased drinking in CIE mice. U50,488 mimicked this effect in CIE mice, but also increased drinking in CTL mice. Experiment 2 assessed effects of KOR blockade on stress-induced drinking in CIE and CTL mice. Stressed and non-stressed mice were administered the short-acting KOR antagonist LY2444296 (0 or 5 mg/kg) 30 min prior to each drinking session during test weeks. FSS selectively increased ethanol consumption in CIE mice, an effect that was abolished by LY2444296 pretreatment. In Experiment 3, CIE and CTL mice were administered one of four doses of U50,488 (0, 1.25, 2.5, 5.0 mg/kg) 1 h prior to each daily drinking test (in lieu of FSS). All doses of U50,488 increased ethanol consumption in both CIE and CTL mice. The U50,488-induced increase in drinking was blocked by LY2444296. Our results demonstrate that the KOR system contributes to the stress enhancement of ethanol intake in mice with a history of chronic ethanol exposure.

Antinociceptive and anti-inflammatory activities of flavonoids isolated from Pistacia integerrima galls

The present study deals with the anti-hyperalgesic and anti-inflammtory effects of flavonoids (1–4) isolated from the chloroform fraction of Pistacia integerrima galls. The structure of isolated compounds was elucidated by using advance spectroscopy analysis and comparing their physical spectral data with reported one. The pretreatment of compounds (1–4) caused significant anti-hyperalgesic effects in acetic acid induced writhing test in a dose dependent manner. The compounds strongly complimented the effects in both phases of formalin test. However, the administration of naloxone did not abolish the induced antinociceptive effects and therefore suggested the absence of opioid receptor involvement. The pretreatment of flavonoids (1–4) elicited marked anti-inflammtory effects in carrageenan induced paw edema test in mice during various assessment times (1–5h). The effects were dose dependent and maximum results were observed after 3rd h of treatments which remained significant up to 5th hour. It is concluded that the isolated flavonoids (1–4) possessed strong anti-hyperalgesic and anti-inflammtory activity and thus are strong candidates for further detail studies.

Analgesic and anti-inflammatory potential of aerial parts of the Daphne mucronata Royle extract in mice: Opioid-independent action

ObjectiveTo investigate the analgesic and anti-inflammatory property and possible involvement of opioid receptors of ethyl acetate extract from aerial parts of Daphne mucronata (D. mucronata) in mice by formalin test. MethodsSingle doses of 2.5, 5.0 and 10.0 mg/kg of body weight of ethyl acetate extract of D. mucronata were intraperitoneally administered to the mice 30 min before analgesic test. The anti-nociceptive effect of preparations was evaluated based on the formalin in mice. ResultsThe results indicated that the extract (2.5, 5.0 and 10.0 mg/kg) increased the pain threshold of mice and induced analgesia in both phases of formalin test. Like morphine sulfate (5.0 mg/kg, i.p.), the extract also showed more effective analgesic effect on the late phase of formalin test. Pre-treatment of animals with naloxone (5.0 mg/kg i.p.) did not inhibit the effects of the extract. ConclusionsOur findings suggest that D. mucronata contains potential analgesic and anti-inflammatory compounds which support its traditional use. Moreover, it seems that the analgesic and anti-inflammatory effects of the extract is mediated by non-opioid mechanisms. Further pharmacological studies are required to determine whether the analgesic mechanisms are actually responsible for such properties.

Involvement of Opioid Receptors in the Lipid Rescue of Bupivacaine-Induced Cardiotoxicity

Involvement of Opioid Receptors in the Lipid Rescue of Bupivacaine-Induced Cardiotoxicity

Antinociceptive and neuropharmacological activities of methanol extract of Phoenix sylvestris fruit pulp.

Fruits of Phoenix sylvestris Roxb. (Arecaceae) are used to treat back pain, toothache, headache, arthritis, nervous debility and as sedative. The aim of this study was to evaluate the antinociceptive and neuropharmacological activities of methanol extract of P. sylvestris fruit pulp (MEPS). The antinociceptive activity of MEPS was evaluated by heat-induced (hot plate, tail immersion test) and chemical-induced pain models (acetic acid-induced writhing, formalin-induced nociception, glutamate-induced nociception and paw edema test). The effect of MEPS on central nervous system (CNS) was studied using hole cross test, open field test, sodium thiopental-induced sleeping time and elevated plus maze test. MEPS showed strong, significant and dose-dependent antinociceptive activity in all heat-induced and chemical-induced pain models at all experimental doses. Involvement of opioid receptor mediated analgesia was evident from the reversal of analgesic effect by naloxone. MEPS also showed reduced locomotor activity in both hole cross and open field tests. The increase in sleeping time in sodium thiopental-induced sleeping test and anxiolytic activity in elevated plus maze test were also significant. So, it is evident that MEPS possesses strong central and peripheral antinociceptive activity as well as CNS depressant, sedative and anxiolytic activity. The results justify the ethnomedicinal use of P. sylvestris fruit in different painful conditions and CNS disorders.

Dexmedetomidine induces conditioned place preference in rats: Involvement of opioid receptors

Dexmedetomidine (DEX) is an alpha-2 adrenergic agonist drug recently introduced to anesthesia practice. Certain agents used in anesthesia practice have been associated with abuse and addiction problems; however, few studies have investigated the role of DEX on addictive processes. Here, the effects and possible mechanisms of action of DEX on conditioned place preference (CPP), a model used for measuring the rewarding effects of drug abuse in rats, was investigated. The CPP apparatus was considered “biased” as the animals preferred the grid side to the mesh side. Male Wistar albino rats weighing 250–300g were divided into several groups, including control (saline), morphine (10mg/kg), DEX (2.5–20μg/kg), naloxone alone (0.5mg/kg) and a combination (0.5mg/kg naloxone plus 20μg/kg DEX) (n=7–8 for each group). The CPP effects of morphine, DEX, saline and the combination were evaluated. All the drug and saline administrations except naloxone were performed by intraperitoneal (ip) injections. Naloxone was injected subcutaneously (sc) when given alone or in combination with DEX. Morphine (10mg/kg) and DEX (5–20μg/kg) produced CPP that were statistically significant relative to saline-injected rats. DEX-induced CPP was significantly reversed by pretreatment with naloxone, an opioid antagonist. Naloxone alone treatment did not cause any significant effect on CPP. Our results suggest that DEX produces CPP effects similar to morphine in rats and that opioidergic mechanism may be responsible for DEX-induced CPP. Thus, DEX might have the potential to be addictive, and this possibility should be considered during clinical application of this drug.

Involvement of Opioid Receptors in the Lipid Rescue of Bupivacaine-Induced Cardiotoxicity.

Lipid emulsion (LE) has been successfully used for resuscitation of local anesthetic cardiotoxicity caused by bupivacaine overdose. Opioid receptors have been shown to play a key role in cardio protection. We explored whether this rescue action of LE is mediated through opioid receptors. Asystole was induced by bupivacaine (10 mg/kg over 20 seconds, IV) in young male Sprague-Dawley rats, and resuscitation with LE (intralipid 20%; 5 mL/kg bolus and 0.5 mL/kg/min maintenance) was started immediately. The rats were pretreated 2 minutes before inducing asystole with nonselective opioid receptor antagonists such as naloxone and naloxone methiodide, as well as highly selective opioid receptor antagonists for subtype κ, δ, and µ or phosphate buffer solution as a control. Heart rates and ejection fractions were measured using echocardiography. LE rescue of bupivacaine cardiotoxicity was prevented by high-dose (1 mg/kg) naloxone but not by lower doses of naloxone (1, 5, and 10 µg/kg), by naloxone methiodide (which does not cross the blood-brain barrier), and by a selective δ- and κ-opioid receptor antagonists at a higher (10 mg/kg) dose. Successful LE rescue was not affected by highly selective µ-opioid receptor antagonists. δ-Opioid receptor antagonist (10 mg/kg) pretreatment also resulted in reduced phosphorylation level of cardiac glycogen synthase kinase-3β in rats that were not resuscitated by LE compared with control. Our data highlight the involvement of peripheral δ- and κ-opioid receptors in the rescue action of LE.

Mechanisms of the Analgesic Action of Corticotrophin-Releasing Factor on Somatic Pain Sensitivity in Rats

This review provides an analysis of data on the mechanisms of the analgesic action of corticotropin-releasing factor (CRF) on somatic pain sensitivity. Experiments on rats addressed the involvement of opioid and glucocorticoid receptors and type 2 CRF receptors in mediating the analgesic effect induced by systemic administration of CRF. The results showed that the analgesic action of CRF may involve type 2 CRF receptors; CRF analgesia can appear in two forms: opioid-dependent and opioid-independent, whose development appears to be determined by the nature of the pain stimulus and the use of anesthesia. The opioid-dependent form of analgesia may be supported by glucocorticoid hormones.

Involvement of the NO/cGMP/KATP pathway in the antinociceptive effect of the new pyrazole 5-(1-(3-fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021)

The pyrazol compounds are known to possess antipyretic, analgesic and anti-inflammatory activities. This study was conducted to investigate the peripheral antinociceptive effect of the pyrazole compound 5-(1-(3-Fluorophenyl)-1H-pyrazol-4-yl)-2H-tetrazole (LQFM-021) and involvement of opioid receptors and of the NO/cGMP/KATP pathway. The oral treatments in mice with LQFM-021 (17, 75 or 300 mg/kg) decreased the number of writhing. In the formalin test, the treatments with LQFM-021 at doses of 15, 30 and 60 mg/kg reduced the licking time at both neurogenic and inflammatory phases of this test. The treatment of the animals with LQFM-021 (30 mg/kg) did not have antinociceptive effects in the tail-flick and hot plate tests. Furthermore, pre-treatment with naloxone (3 mg/kg i.p.), L-name (10 mg/kg i.p.), ODQ (10 mg/kg i.p.) or glibenclamide (3 mg/kg i.p.) antagonized the antinociceptive effect of LQFM-021 in both phases of the formalin test. In addition, it was also demonstrated that the treatments of mice with LQFM-021(15, 30 and 60 mg/kg) did not compromise the motor activity of the animals in the chimney test. Only the highest dose used in the antinociceptive study promoted changes in the open field test and pentobarbital-induced sleep test, thus ruling out possible false positive effects on nociception tests. Our data suggest that the peripheral antinociception effects of the LQFM-021 were mediated through the peripheral opioid receptors with activation of the NO/cGMP/KATP pathway.

Modulation of opioid-induced feeding behavior by endogenous nitric oxide in neonatal layer-type chicks.

The current study was designed to evaluate the effects of central administration of L-arginine (The precursor of nitric oxide), N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, selective opioid receptor agonists and involvement of central nitrergic/opioidergic systems on feeding behavior in neonatal layer-type chicks. The results of this study showed that the intracerebroventricular (ICV) injection of L-arginine (400 and 800 nmol) significantly decreased food intake (P < 0.001) but the injection of 200 nmol L-arginine had no effect on cumulative food intake in FD3 chickens (P > 0.05). The ICV injection of L-NAME (200 and 400 nmol) increased food intake (P < 0.001) but 100 nmol of L-NAME had no significant effect (P > 0.05). On the other hand, the co-injection of 100 nmol L-NAME significantly attenuated the anorexigenic effect of 800 nmol L-arginine (P < 0.001). Moreover, the food intake of chicks was significantly decreased by ICV injection of DAMGO (μ-opioid receptor agonist, 125 pmol) (P < 0.001) while both DPDPE (δ-opioid receptor agonist, 40 pmol) and U-50488H (κ-opioid receptor agonist, 30 nmol) significantly stimulated food intake (P < 0.001). In addition, the hypophagic effect of DAMGO was significantly amplified by administration of L-arginine (P < 0.001) while the administration of L-NAME attenuated the hypophagic effect of DAMGO (P < 0.001). In contrast, co-injection of L-arginine or L-NAME with DPDPE had no effect on the hyperphagia induced by DPDPE as well as the hyperphagic effect of U-50488H on food intake was not affected by concurrent injection of L-arginine or L-NAME (P > 0.05). These results suggest that nitrergic and opioidergic systems have an important role on feeding behavior in the CNS of neonatal layer-type chicks and it seems that interaction between them is mediated by μ-opioid receptor.

Discriminative stimulus properties of mitragynine (kratom) in rats.

Mitragynine (MG) is the primary active alkaloid extracted from the leaves of Mitragyna speciosa or kratom and exhibits pharmacological activities mediated by opioid receptors. The plant has been traditionally used for its opium and psychostimulant-like effects to increase work efficiency or as a substitute in the self-treatment of opiate addiction. The present study was performed to investigate the discriminative stimulus effects of MG in rats. The pharmacological mechanism of MG action and its derivative, 7-hydroxymitragynine (7-HMG) with a specific focus on opioid receptor involvement was examined in rats trained to discriminate morphine from vehicle. In order to study the dual actions of MG, the effect of cocaine substitution to the MG discriminative stimulus was also performed in MG-trained rats. Male Sprague Dawley rats were trained to discriminate MG from vehicle in a two-lever drug discrimination procedure under a tandem variable-interval (VI 60') fixed-ratio (FR 10) schedule of food reinforcement. Rats acquired the MG discrimination (15.0mg/kg, i.p.) which was similar to the acquisition of morphine discrimination (5.0mg/kg, i.p.) in another group of rats. MG substituted fully to the morphine discriminative stimulus in a dose-dependent manner, suggesting pharmacological similarities between the two drugs. The administration of 7-HMG derivative in 3.0mg/kg (i.p.) dose engendered full generalisation to the morphine discriminative stimulus. In addition, the MG stimulus also partially generalised to cocaine (10.0mg/kg, i.p.) stimulus. The present study demonstrates that the discriminative stimulus effect of MG possesses both opioid- and psychostimulant-like subjective effects.