Sub-effective Dose Of Morphine Research Articles

Pharmacological evidence for the involvement of the opioid system in the antidepressant-like effect of simvastatin in mice: Without tolerance and withdrawal syndrome

Statins, 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors, have been shown to be effective in reducing depression in animal models. The present study aimed to investigate the potential antidepressant-like activity of simvastatin and the possible involvement of opioid systems in the mouse forced swimming test (FST). After assessment of locomotor behavior in the open-field test (OFT), FST was applied for evaluation of depressive behavior in mice. Simvastatin (20, 30, and 40 mg/kg, i.p.) or morphine (0.01, 0.1, 1 and 10 mg/kg, i.p.) were administrated 30 min before the OFT or FST. Results showed that simvastatin produced antidepressant effect in a dose-dependent manner. The effect of simvastatin (30 mg/kg) was prevented by the pre-treatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist). In addition, a sub-effective dose of simvastatin (20 mg/kg) produced a synergistic antidepressant-like effect in the FST with a sub-effective dose of morphine (0.1 mg/kg) that it was reversed by naloxone. Moreover, in contrast to morphine, treatment with simvastatin for six days induced neither tolerance to the antidepressant-like effect nor withdrawal signs. In conclusion, these findings demonstrated that simvastatin elicited antidepressant-like action possibly through the stimulation of opioidergic pathways, without inducing tolerance and withdrawal signs.

Anti-allodynic Effect of Mangiferin in Rats With Chronic Post-ischemia Pain: A Model of Complex Regional Pain Syndrome Type I.

The present study reproduces chronic post-ischemia pain (CPIP), a model of complex regional pain syndrome type I (CRPS-I), in rats to examine the possible transient and long-term anti-allodynic effect of mangiferin (MG); as well as its potential beneficial interactions with some standard analgesic drugs and sympathetic-mediated vasoconstriction and vasodilator agents during the earlier stage of the pathology. A single dose of MG (50 and 100 mg/kg, p.o.) decreased mechanical allodynia 72 h post-ischemia-reperfusion (I/R). MG 100 mg/kg, i.p. (pre- vs. post-drug) increased von Frey thresholds in a yohimbine and naloxone-sensitive manner. Sub-effective doses of morphine, amitriptyline, prazosin, clonidine and a NO donor, SIN-1, in the presence of MG were found to be significantly anti-allodynic. A long-term anti-allodynic effect at 7 and 13 days post-I/R after repeated oral doses of MG (50 and 100 mg/kg) was also observed. Further, MG decreased spinal and muscle interleukin-1β concentration and restored muscle redox status. These results indicate that MG has a transient and long-term anti-allodynic effect in CPIP rats that appears to be at least partially attributable to the opioid and α2 adrenergic receptors. Additionally, its anti-inflammatory and antioxidant mechanisms could also be implicated in this effect. The association of MG with sub-effective doses of these drugs enhances the anti-allodynic effect; however, an isobolographic analysis should be performed to define a functional interaction between them. These findings suggest the possible clinical use of MG in the treatment of CRPS-I in both early sympathetically maintained pain and long-term sympathetically independent pain.

Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors.

Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.

Kappa-opioid receptors mediate the antidepressant-like activity of hesperidin in the mouse forced swimming test

The opioid system has been implicated as a contributing factor for major depression and is thought to play a role in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of hesperidin in the mouse forced swimming test. Our results demonstrate that hesperidin (0.1, 0.3 and 1mg/kg; intraperitoneal) decreased the immobility time in the forced swimming test without affecting locomotor activity in the open field test. The antidepressant-like effect of hesperidin (0.3mg/kg) in the forced swimming test was prevented by pretreating mice with naloxone (1mg/kg, a nonselective opioid receptor antagonist) and 2-(3,4-dichlorophenyl)-Nmethyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl)ethyl] acetamide (DIPPA (1mg/kg), a selective κ-opioid receptor antagonist), but not with naloxone methiodide (1mg/kg, a peripherally acting opioid receptor antagonist), naltrindole (3mg/kg, a selective δ-opioid receptor antagonist), clocinnamox (1mg/kg, a selective μ-opioid receptor antagonist) or caffeine (3mg/kg, a nonselective adenosine receptor antagonist). In addition, a sub-effective dose of hesperidin (0.01mg/kg) produced a synergistic antidepressant-like effect in the forced swimming test when combined with a sub-effective dose of morphine (1mg/kg). The antidepressant-like effect of hesperidin in the forced swimming test on mice was dependent on its interaction with the κ-opioid receptor, but not with the δ-opioid, μ-opioid or adenosinergic receptors. Taken together, these results suggest that hesperidin possesses antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.

Tramadol induces conditioned place preference in rats: Interactions with morphine and buprenorphine

Surveys and drug surveillance have demonstrated that the abuse liability of tramadol is considerably low in the general population but appears to be higher in opiate addicts, and this difference could attribute to the poly-drug abuse of opioid addicts, although this hypothesis has not been tested in the laboratory. The present study examined the interactions between tramadol and a full μ opioid receptor agonist morphine or a partial μ opioid receptor agonist buprenorphine in a conditioned place preference (CPP) paradigm in rats. Rats were conditioned with tramadol (2–54mg/kg, i.p.), morphine (0.125–8mg/kg, s.c.), buprenorphine (0.01–0.316mg/kg, s.c.) or a combination of a subeffective dose of tramadol (2mg/kg) with a subeffective dose of morphine or buprenorphine and the CPP effect was measured. The retention of CPP effect was also examined. Tramadol, morphine and buprenorphine all produced a dose-dependent and significant CPP. A smaller dose of tramadol (2mg/kg) enhanced morphine- and buprenorphine-induced CPP and shifted the dose-effect curves of both drugs leftward. In addition, the combination of tramadol with morphine or buprenorphine prolonged the retention of CPP. These findings indicate that tramadol potentiates the rewarding effects of morphine or buprenorphine largely in an additive manner and support the general contention that tramadol has relatively low abuse liability.

Pharmacological evidence for the role of nitric oxide in the modulation of stress-induced anxiety by morphine in rats

The present study evaluated the effects of the opioid agonist, morphine on stress induced anxiogenesis and the possible involvement of nitric oxide (NO) in such effects in rats. Acute restraint stress consistently induced an anxiety-like response in the elevated plus maze test, i.e. reduced number of open arm entries and time spent in the open arms as compared to controls. Pretreatment with morphine (1 and 5 mg/kg), attenuated the restraint stress induced anxiogenic response in a dose related manner. Restraint stress induced neurobehavioral suppression was associated with reductions in brain NO oxidation products (NOx) levels, which were also reversed with morphine. Interaction studies showed that sub-effective doses of morphine and l-arginine (a NO precursor) had synergistic effects on stress induced elevated plus maze activity and brain NOx, whereas, l-NAME (a NO synthase inhibitor) neutralized these effects of morphine. Repeated restraint stress (× 5) induced adaptative changes as evidenced by normalization of behavioral suppression and elevations in brain NOx, as compared to acute stress. Pretreatment with morphine in combination with repeated stress (× 5) showed potentiating effects in the induction of behavioral adaptation in the elevatedplus maze and elevations in brain NOx, as compared to repeated stress alone. Further, l-NAME, when administered prior to morphine, blocked this effect of morphine on stress adaptation. These results suggest differential morphine–NO interactions during acute and repeated restraint stress.

Ginger (Zingiber officinale Roscoe) elicits antinociceptive properties and potentiates morphine-induced analgesia in the rat radiant heat tail-flick test.

Ginger (Zingiber officinale Roscoe), a well-known spice plant, has been used traditionally in the treatment of a wide variety of ailments. It has been shown that ginger is a calcium channel blocker; however, its influence on morphine analgesic effects has not been elucidated. We examined the effect of ginger root extract on nociceptive threshold and morphine-induced analgesia in male Wistar rats. To determine the effect of ginger on morphine analgesia, ginger extract (200, 400, and 600 mg/kg i.p.) was injected before a subeffective dose of morphine (2.5 mg/kg i.p.). The radiant heat tail-flick test was used to assess the nociceptive threshold before and at different times after drug administration. Our results showed that ginger extract elicited a significant antinociceptive effect. In addition, in groups that received both morphine and ginger, the observed analgesia was higher than that in groups treated with either morphine or ginger extract alone. Thus, the data indicate that ginger extract has a beneficial influence on morphine analgesia and can be an efficacious adjunct for pain management.

Evidence for the involvement of the opioid system in the antidepressant-like effect of folic acid in the mouse forced swimming test

The opioid system has been implicated in major depression and in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of the water-soluble B-vitamin folic acid in the forced swimming test (FST). The effect of folic acid (10 nmol/site, i.c.v.) was prevented by the pretreatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist), naltrindole (3 mg/kg, i.p., a selective δ-opioid receptor antagonist), naloxonazine (10 mg/kg, i.p., a selective μ 1-opioid receptor antagonist, 24 h before), but not with naloxone methiodide (1 mg/kg, s.c., a peripherally acting opioid receptor antagonist). In addition, a sub-effective dose of folic acid (1 nmol/site, i.c.v.) produced a synergistic antidepressant-like effect in the FST with a sub-effective dose of morphine (1 mg/kg, s.c.). A further approach was designed to investigate the possible relationship between the opioid system and NMDA receptors in the mechanism of action of folic acid in the FST. Pretreatment of the animals with naloxone (1 mg/kg, i.p.) prevented the synergistic antidepressant-like effect of folic acid (1 nmol/site, i.c.v.) and MK-801 (0.001 mg/kg, i.p., a non-competitive NMDA receptor antagonist). Together the results firstly indicate that the anti-immobility effect of folic acid in the FST is mediated by an interaction with the opioid system (μ 1 and δ), likely dependent on the inhibition of NMDA receptors elicited by folic acid.

Cannabinoid CB1 receptors of the dorsal hippocampus are important for induction of conditioned place preference (CPP) but do not change morphine CPP

Interactions between cannabinoid and opioid systems have been reported in many studies. In the present study, we have investigated influence of cannabinoid CB1 receptor mechanism on the acquisition of conditioned place preference (CPP) induced by morphine in male Wistar rats. The cannabinoid CB1 receptor agonist (WIN55,212-2) and antagonist (AM251) were injected bilaterally into the dorsal hippocampus. Morphine and naloxone were injected subcutaneously (s.c.). The conditioning treatments with injections of morphine (6 and 9 mg/kg) induced a CPP for the drug-associated place. When administered into the dorsal hippocampus, WIN55,212-2 (1 μg/rat) induced CPP, but significantly did not alter CPP induced by a sub-effective dose of morphine (3 mg/kg). Moreover, administration of different doses of AM251 (50 and 100 ng/rat) into the dorsal hippocampus induced CPP, while did not change CPP by the sub-effective dose of morphine. Naloxone alone (1 mg/kg) induced conditioned place aversion (CPA). The drug (0.5 and 1 mg/kg) also caused CPA when co-administered with WIN55,212-2 (1 μg/rat). These results suggest that endocannabinoid system in the dorsal hippocampus is important for the CPP paradigm. However, agents did not alter morphine-induced CPP.

Melatonin enhances the rewarding properties of morphine: involvement of the nitric oxidergic pathway

Melatonin has different interactions with opioids including the enhancement of the analgesic effects of morphine and also reversal of tolerance and dependence to morphine. The present study assessed the effect of melatonin on morphine reward in mice using a conditioned place preference (CPP) paradigm. Our data showed that subcutaneous administration of morphine (1-7.5 mg/kg) significantly increased the time spent in the drug-paired compartment in a dose-dependent manner. Intraperitoneal (i.p.) administration of melatonin (1-40 mg/kg) alone did not induce either CPP or conditioned place aversion (CPA), while the combination of melatonin (5-20 mg/kg) and sub-effective dose of morphine (0.5 mg/kg) led to rewarding effect. We further investigated the involvement of the nitric oxidergic pathway in the enhancing effect of melatonin on morphine CPP, by a general nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). L-NAME (1 and 5 mg/kg, i.p.) alone or in combination with morphine (0.5 mg/kg) did not show any significant CPP or CPA. Co-administration of L-NAME (5 mg/kg) with an ineffective combination of melatonin (1 mg/kg) plus morphine (0.5 mg/kg) produced significant CPP that may imply the similarity of action of melatonin and L-NAME and involvement of the nitric oxidergic pathway in this regard. Our results indicate that pretreatment of animals with melatonin enhances the rewarding properties of morphine via a mechanism which may involve the nitric oxidergic pathway.

Nifedipine potentiates antinociceptive effects of morphine in rats by decreasing hypothalamic pituitary adrenal axis activity

It has been shown that nifedipine, as a calcium channel blocker can potentiate the antinociceptive effect of morphine; however, the role of Hypothalamic–Pituitary–Adrenal (HPA) axis on this action has not been elucidated. We examined the effect of nifedipine on morphine-induced analgesia in intact and adrenalectomized (ADX) rats and on HPA activity induced by morphine. To determine the effect of nifedipine on morphine analgesia, nifedipine (2 mg/kg i.p.) that had no antinociceptive effect, was injected concomitant with sub-effective dose of morphine (1 and 2 mg/kg). The tail-flick test was used to assess the nociceptive threshold, before and 15, 30, 60, 90, 120 and 180 min after drug administration. Our results showed that, nifedipine could potentiate the antinociceptive effect of morphine and this effect of nifedipine in ADX was greater than sham operated rats which, was reversed by corticosterone replacement. Nifedipine has an inhibitory effect on morphine -induced corticosterone secretion. Thus, the data indicate that the mechanism underlying the potentiation of morphine analgesia by nifedipine involves mediation, at least in part, by attenuating the effect of morphine on HPA axis.

P.2.130 Efficacy of ziprasidone in dysphoric mania

The opioid system has been implicated in major depression and in the mechanism of action of antidepressants. This study investigated the involvement of the opioid system in the antidepressant-like effect of the water-soluble B-vitamin folic acid in the forced swimming test (FST). The effect of folic acid (10 nmol/site, i.c.v.) was prevented by the pretreatment of mice with naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist), naltrindole (3 mg/kg, i.p., a selective δ-opioid receptor antagonist), naloxonazine (10 mg/kg, i.p., a selective μ1-opioid receptor antagonist, 24 h before), but not with naloxone methiodide (1 mg/kg, s.c., a peripherally acting opioid receptor antagonist). In addition, a sub-effective dose of folic acid (1 nmol/site, i.c.v.) produced a synergistic antidepressant-like effect in the FST with a sub-effective dose of morphine (1 mg/kg, s.c.). A further approach was designed to investigate the possible relationship between the opioid system and NMDA receptors in the mechanism of action of folic acid in the FST. Pretreatment of the animals with naloxone (1 mg/kg, i.p.) prevented the synergistic antidepressant-like effect of folic acid (1 nmol/site, i.c.v.) and MK-801 (0.001 mg/kg, i.p., a non-competitive NMDA receptor antagonist). Together the results firstly indicate that the anti-immobility effect of folic acid in the FST is mediated by an interaction with the opioid system (μ1 and δ), likely dependent on the inhibition of NMDA receptors elicited by folic acid.

Involvement of opioid receptors in electroacupuncture-produced anti-hyperalgesia in rats with peripheral inflammation

Our previous study showed that electroacupuncture (EA) significantly attenuated inflammatory hyperalgesia. It has also been reported that EA analgesia in uninjured animals is mediated by μ and δ opioid receptors at 2–15 Hz and by κ opioid receptor at 100 Hz. Because persistent pain changes neural response to external stimulation, we hypothesized that (1) the mechanisms of EA anti-hyperalgesia may be different under conditions of persistent pain and that (2) combining EA with a sub-effective dose of morphine could enhance EA anti-hyperalgesia. Hyperalgesia, decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the hind paws of rats. Selective antagonists against μ (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, CTOP), δ (naltrinodole, NTI) and κ (nor-binaltorphimine, BNI) opioid receptors were administered intrathecally 10 min before each of two EA treatments at acupoint Huantiao (GB30), one immediately post and the other 2 h post-CFA. Morphine was given (i.p.) 40 min before the second EA treatment. PWL was measured before and 2.5 and 5 h post-CFA. Both 10 and 100 Hz EA-produced anti-hyperalgesia were blocked spinally by μ- and δ- but not κ-receptor antagonists. EA combined with a sub-threshold dose of morphine (2.5 mg/kg) enhanced anti-hyperalgesia additively (10 Hz EA) or synergistically (100 Hz EA) compared to that produced by each component alone. These results suggest selective involvement of μ and δ, but not κ, receptors in EA-produced anti-hyperalgesia in rats. A combined EA and opioid drug protocol may provide an improved treatment strategy for inflammatory pain.

BOC-CCK-4, CCKBreceptor agonist, antagonizes anxiolytic-like action of morphine in elevated plus-maze

This study investigated a role of cholecystokinin (CCK) in the anxiolytic-like action of morphine, an agonist of μ-opioid receptors, in the rat plus-maze model of anxiety. The acute administration of morphine (1 mg/kg) induced a significant increase of exploratory activity in the plus-maze, but did not affect the locomotor activity in the motility test. The higher dose of morphine (2.5 mg/kg) tended to decrease the locomotor activity and, therefore, did not cause the anxiolytic-like action in the plus-maze. The other drugs (naloxone, BOC-CCK-4, L-365,260) and their combinations with morphine (0.5–1 mg/kg) did not affect the locomotor activity of rats. The opioid antagonist naloxone itself (0.5 mg/kg) did not change the exploratory activity in the plus-maze, but potently antagonized the anxiolytic-like action of morphine (1 mg/kg). An agonist of CCKBreceptors BOC-CCK-4 (1–50 μg/kg) induced a dose-dependent anxiogenic-like action in the plus-maze. Nevertheless, only one dose of BOC-CCK-4 (10 μg/kg) completely reversed the action of morphine. Also, one dose of CCKBreceptor antagonist L-365,260 (10 μg/kg) was effective to modify the behaviour of rats in the elevated plus-maze. Namely, this dose of L-365,260 increased the ratio between open and total arm entries, a behavioural measure believed to reflect the anxiolytic-like action in the elevated plus-maze. The combination of L-365,260 (100 μg/kg) with the sub-effective dose of morphine (0.5 mg/kg) caused the anxiolytic-like action in the plus-maze not seen if the drugs were given alone. In conclusion, morphine induces a potent anxiolytic-like action in the elevated plus-maze and CCK is acting as an endogenous antagonist of this effect of morphine.