cyclic-gmp and Morphine-Dependence

Nitric oxide (NO) signalling is at the forefront of intense research interest because its many effects remain controversial and seemingly contradictory. This paper examines its role as a potential mediator of pain and tolerance. Within this context discussion covers endogenous morphine, documenting its ability to be made in animal tissues, including nervous tissue, and in diverse animal phyla. Supporting morphine as an endogenous signalling molecule is the presence of the newly cloned mu3 opiate receptor subtype found in animal (including human) immune, vascular and neural tissues, which is coupled to NO release. Importantly, this mu opiate receptor subtype is morphine-selective and opioid peptide-insensitive, further highlighting the presence of morphinergic signalling coupled to NO release. These findings provide novel insights into pain and tolerance as morphinergic signalling exhibits many similarities with NO actions. Taken together, a select morphinergic signalling system utilising NO opens the gate for the development of novel pharmaceuticals and/or the use of old pharmaceuticals in new ways.

Topics: Analgesics; Analgesics, Opioid; Animals; Base Sequence; Brain; Cyclic AMP; Cyclic GMP; Diabetes Mellitus; Drug Tolerance; Enzyme Inhibitors; Humans; Injections, Intraventricular; Molecular Sequence Data; Morphine; Morphine Dependence; Neurons; Nitric Oxide; Nitric Oxide Synthase; Pain; Receptors, Opioid, mu; Signal Transduction

Severe pain reduces quality of life of patients with various diseases, often because chronic morphine therapy results in reduced analgesic effectiveness, or tolerance, leading to escalating doses and distressing adverse effects. Nitric oxide (NO) plays a role in morphine tolerance and dependence.. Venlafaxine, an antidepressant, is known to modulate nitric oxide (NO) pathway in nervous tissues. In the present study, the effect of systemic venlafaxine (VLF) on the development of morphine tolerance and dependence, acute morphine-induced antinociception, and the probable involvement of the L-arginine/NO/cGMP pathway in these effects were investigated in mice.. Animals developed tolerance to the antinociceptive effect of morphine (50 mg/kg, s.c. daily) for 3 consecutive days. NO modulators like L-NAME (NO synthase inhibitor) and L-Arginine (L-Arg, substrate for NO synthase), sildenafil (cGMP-PDE inhibitor) alone or in combination with venlafaxine were used.. The results showed that i.p. administration of VLF (5-40 mg/kg) produced antinociceptive effect in a dose-dependent way. Pretreatment with L-Arg (200 mg/kg, i.p.) reversed the antinociception and L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.) potentiated the antinociceptive effect. Moreover, co-administration of VLF in non-effective dose (5 mg/kg) with morphine, potentiated acute morphine-induced analgesia (5 mg/kg, s.c.). This effect was antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.). On the other hand, VLF was prevented the development of morphine antinociceptive tolerance and dependence. These effects were antagonized by L-arginine (200 mg/kg, i.p.) and potentiated by L-NAME (30 mg/kg, i.p.) and sildenafil (10 mg/kg, i.p.).. Our data suggest that the combination of VLF with morphine may be a relevant therapeutic implication to manage pain even when tolerance to morphine exists. Moreover, our data demonstrates the involvement of L-Arg/NO/cGMP pathway in the prevention of morphine tolerance and dependence by venlafaxine.

Topics: Analgesics, Opioid; Animals; Arginine; Behavior, Animal; Brain; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mice; Morphine; Morphine Dependence; Nitric Oxide; Nociceptive Pain; Signal Transduction; Time Factors; Venlafaxine Hydrochloride

This study was aimed at evaluating the role of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cascade in mechanisms of morphine dependency formation. Morphine was introduced by intraperitoneal (i.p.) injections in rats twice per day over six days in doses increasing from 10 to 100 mg/kg, For evaluating the role of NO/cGMP cascade, NO synthase inhibitor L-N(G)-Nitroarginine methyl ester (L-NAME) was introduced (10 mg/kg, i.p.) 1 h prior to every injection of morphine. The L-NAME introduction led to enhancement of spontaneous withdrawal syndrome manifestations, which was accompanied by more pronounced decrease in the cGMP levels in midbrain and striatum. It is suggested that the region specific decrease in NO/cGMP cascade signaling activity in the brain can be among mechanisms determining the development of opium dependency.

Topics: Animals; Corpus Striatum; Cyclic GMP; Male; Mesencephalon; Morphine; Morphine Dependence; Narcotics; NG-Nitroarginine Methyl Ester; Nitric Oxide; Rats; Rats, Wistar; Substance Withdrawal Syndrome

Peroxizome proliferator-activated receptor gamma (PPARγ) is highly expressed in the central nervous system where it modulates numerous gene transcriptions. Nitric oxide synthase (NOS) expression could be modified by simulation of PPARγ which in turn activates nitric oxide (NO)/soluble guanylyl-cyclase (sGC)/cyclic guanosine mono phosphate (cGMP) pathway. It is well known that NO/cGMP pathway possesses pivotal role in the development of opioid dependence and this study is aimed to investigate the effect of PPARγ stimulation on opioid dependence in mice as well as human glioblastoma cell line. Pioglitazone potentiated naloxone-induced withdrawal syndrome in morphine dependent mice in vivo. While selective inhibition of PPARγ, neuronal NOS or GC could reverse the pioglitazone-induced potentiation of morphine withdrawal signs; sildenafil, a phosphodiesterase-5 inhibitor amplified its effect. We also showed that nitrite levels in the hippocampus were significantly elevated in pioglitazone-treated morphine dependent mice. In the human glioblastoma (U87) cell line, rendered dependent to morphine, cAMP levels did not show any alteration after chronic pioglitazone administration while cGMP measurement revealed a significant rise. We were unable to show a significant alteration in neuronal NOS mRNA expressions by pioglitazone in mice hippocampus or U87 cells. Our results suggest that pioglitazone has the ability to enhance morphine-dependence and to augment morphine withdrawal signs. The possible pathway underlying this effect is through activation of NO/GC/cGMP pathway.

Topics: Animals; Cell Line, Tumor; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Enzyme Inhibitors; Glioblastoma; Hippocampus; Humans; Hypoglycemic Agents; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; Nitric Oxide; Nitric Oxide Synthase; Pioglitazone; PPAR gamma; RNA, Messenger; Signal Transduction; Substance Withdrawal Syndrome; Thiazolidinediones; Transfection

In this study, we investigated whether morphine dependence was inhibited by phosphodiesterase (PDE) 4 inhibitors rolipram and diazepam, since a role for the cyclic AMP systems in the development of morphine dependence was reported. Dependence of morphine was induced by a 7-day s.c. implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone. In order to determine the effect of rolipram or diazepam the animals were injected with these drugs for seven days and 30 min before the administration of naloxone. When opioid withdrawal was precipitated, enhancement of noradrenaline (NA) turnover in the heart was observed 30 min after naloxone administration. Moreover, morphine withdrawal induces Fos expression, increase in cyclic AMP and cyclic GMP levels. Co-administration of rolipram or diazepam with morphine during the pre-treatment period significantly reduces the signs of withdrawal symptoms, the enhancement of NA turnover, the increase in cyclic AMP and the Fos expression. However, these inhibitors did not modify the levels of cyclic GMP. These findings demonstrated that co-administration of rolipram or diazepam with morphine abolish the development of morphine dependence and suggest that these compounds prevent the up-regulation of the cyclic AMP pathway and the associated increase in cyclic AMP level after naloxone administration.

Topics: Animals; Cyclic AMP; Cyclic GMP; Diazepam; Male; Morphine Dependence; Myocardium; Norepinephrine; Normetanephrine; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Rolipram; Substance Withdrawal Syndrome

To explore the effects of long-term morphine exposure on cAMP and cGMP levels in primary cultured tuberomammillary nucleus (TM) neurons of neonatal rats and the effects of sinomenine on morphine-dependent TM cells.. TM neurons after a 7-day primary culture were further cultured in the medium containing 100 micromol/L morphine for 48 h to prepare the cell model of morphine dependence. Serial doses of histamine or sinomenine were administered 30 min naloxone treatment, the cAMP and cGMP levels of the TM cells were determined by enzyme immunoassay. cAMP and cGMP levels were also determined in normal TM cells treated by histamine or sinomenine.. After treatment with 100 micromol/L morphine for 48 h, cAMP and cGMP levels in the TM neurons were increased markedly. Treatment with 100 micromol/L naloxone added in the culture media caused an overshoot of cellular cAMP and a marked declination of cGMP, resulting in significantly increased cAMP/cGMP ratio. Sinomenine at 30 and 100 micromol/L and histamine at 40 micromol/L failed to obviously affect cAMP and cGMP levels in normal TM neurons, but sinomenine at 300 micromol/L and histamine at 80 micromol/L significantly increased the intracellular cAMP level. After pre-treatment with sinomenine at the above 3 doses or histamine at 40 micromol/L, the TM neurons with morphine dependence exhibited significant reduction in intracellular cAMP level but increment in cGMP level after naloxone treatment, with significantly reduced cAMP/cGMP ratio.. Long-term morphine (100 micromol/L) exposure for 48 h can induce marked changes of cAMP and cGMP levels in the TM neurons. The central histaminergic nervous system may be responsible for the development of morphine dependence and withdrawal. Sinomenine can significantly reduce the cAMP level and enhance cGMP level of morphine-dependent TM neurons precipitated by naloxone, which results in a near-normal ratio of cAMP and cGMP.

Topics: Animals; Animals, Newborn; Cells, Cultured; Cyclic AMP; Cyclic GMP; Female; Histamine; Hypothalamus; Morphinans; Morphine; Morphine Dependence; Neurons; Rats; Rats, Sprague-Dawley

Although the phenomenon of opioid tolerance and dependence has been widely investigated, neither opioid nor non-opioid mechanisms are completely understood. In view of the modulation of 5-HT transport into presynaptic terminals in the brain by nitric oxide (NO) via cGMP, and the existence of a tonic 5-HTergic inhibition of dopamine release, the present study investigated the effect of fluoxetine, a selective serotonin reuptake inhibitor, and NO modulators L-N(G)-nitroarginine methyl ester (L-NAME; NO synthase inhibitor) and L-Arginine (substrate for nitric oxide synthase) alone or in combination against morphine tolerance and dependence. Animals developed tolerance to the antinociceptive effect of morphine (10 mg/kg s.c. twice daily) on day 3 and the degree of tolerance was further enhanced on days 9 and 10. The development of tolerance to the antinociceptive effect of morphine was delayed by prior administration of fluoxetine (10 mg/kg i.p, twice daily for 9 days) and L-NAME (10 mg/kg i.p. twice daily for 9 days) alone or in combination. It was accentuated by L-Arginine (50 mg/kg i.p. twice daily for 9 days) alone or in combination with fluoxetine (10 mg/kg i.p. twice daily for 9 days). Similarly, fluoxetine (10 mg/kg i.p.) or L-NAME (10 mg/kg i.p.), when administered acutely on day 10, reversed morphine-induced tolerance. L-Arginine (50 mg/kg i.p.) however, when administered acutely on day 10, accentuated morphine tolerance. Fluoxetine (10 mg/kg i.p. twice daily for 9 days) suppressed the development of morphine dependence as assessed by naloxone (2 mg/kg i.p.)-precipitated withdrawal jumps. This suppression of dependence was potentiated by L-NAME (10 mg/kg i.p. twice daily for 9 days) and reversed by L-Arginine (50 mg/kg i.p. twice daily for 9 days), respectively. Acute administration of the respective drugs on day 10 modulated morphine dependence in a similar fashion. L-Arginine also reversed fluoxetine-induced weight loss in morphine-dependent animals. The present study demonstrated that fluoxetine suppressed the dependence and development of tolerance to the antinociceptive effect of morphine. Fluoxetine-induced suppression was potentiated by L-NAME and accentuated by L-Arginine. The results therefore suggest that a complex phenomenon such as morphine tolerance and dependence might involve close interplay of the NO-c GMP/5-HT/DA receptor system. To the best of the authors' knowledge, this is the first report to suggest targeting this cascade for ame

Topics: Animals; Arginine; Body Weight; Cyclic GMP; Depression, Chemical; Diarrhea; Dopamine; Drug Interactions; Drug Tolerance; Female; Fluoxetine; Male; Mice; Morphine Dependence; Naloxone; Narcotic Antagonists; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Selective Serotonin Reuptake Inhibitors; Serotonin; Substance Withdrawal Syndrome

By inducing morphine dependence in mice, the changes of cGMP contents, phosphodiesterase (PDE) and soluble guanylate cyclase (sGC) activities and their phosphorylation regulated by protein kinase A (PKA) were observed. It was found that: (1) cGMP contents in cerebellum, striatum, hippocampus and cerebral cortex were significantly lower. (2) The sGC activities were apparently decreased in cerebellum and striatum. In the striatum and cerebral cortex the sGC activities and phosphorylation levels in vitro were significantly increased and were inhibited by PKA inhibitor. (3) The PDE activities showed no change in cerebellum and hippocampus, but in striatum and cerebral cortex PDE activities and phosphorylation levels in vitro were significantly increased and were inhibited by PKA inhibitor. (4) These changes described above were not observed in mice treated with naloxone 30 min prior to daily morphine injection. Our data indicate that the decrease of cGMP contents occurred generally in brain regions of morphine-dependent mice. The decrease of cGMP contents in cerebellum and hippocampus may be due to the decrease of sGC activities, but the decrease of cGMP contents in striatum and cerebral cortex may be mainly due to the increase of PDE activity. Both sGC and PDE activities were regulated by PKA.

Topics: Animals; Brain; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Guanylate Cyclase; Male; Mice; Morphine Dependence; Phosphoric Diester Hydrolases; Random Allocation

Topics: Aminooxyacetic Acid; Animals; Bucladesine; Cyclic GMP; Drug Tolerance; Humans; Male; Mice; Morphine; Morphine Dependence; Pain; Tryptophan

Topics: Animals; Brain; Central Nervous System Depressants; Cyclazocine; Cyclic GMP; Dextrorphan; Dose-Response Relationship, Drug; Humans; Levorphanol; Male; Morphine Dependence; Narcotics; Pentazocine; Rats; Stress, Psychological; Time Factors

Topics: Animals; Caudate Nucleus; Cyclic AMP; Cyclic GMP; Humans; Male; Morphine Dependence; Narcotics; Nucleotides, Cyclic; Phosphoproteins; Rats; Time Factors; Tyrosine 3-Monooxygenase

Topics: Adrenocorticotropic Hormone; Animals; Behavior, Animal; Corticosterone; Cyclic AMP; Cyclic GMP; Humans; Male; Morphine Dependence; Naloxone; Nucleotides, Cyclic; Rats; Reflex; Time Factors

Topics: Aminobutyrates; Animals; Apomorphine; Brain Chemistry; Cerebellum; Corpus Striatum; Cyclic GMP; gamma-Aminobutyric Acid; Humans; Male; Morphine Dependence; Rats; Rats, Inbred Strains; Substance Withdrawal Syndrome

An increase in mouse cerebellar C-GMP levels during acute morphine treatment was observed, which was possibly related to the decrease in C-GMP phosphodiesterase levels also observed in acute treatment. Chronic treatment lowered C-GMP levels as did abrupt withdrawal without naloxone.

Topics: Animals; Cerebellum; Cyclic GMP; Guanylate Cyclase; Humans; Male; Mice; Morphine; Morphine Dependence; Naloxone; Phosphoric Diester Hydrolases; Substance Withdrawal Syndrome

Topics: Animals; Brain; Brain Chemistry; Bucladesine; Cyclic AMP; Cyclic GMP; Depression, Chemical; Disease Models, Animal; Drug Implants; Humans; Male; Morphine; Morphine Dependence; Motor Activity; Naloxone; Phosphoric Diester Hydrolases; Rats; Stimulation, Chemical; Substance Withdrawal Syndrome