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Repository of Research and Investigative Information

Dezful University of Medical Sciences

Venlafaxine Attenuates the Development of Morphine Tolerance and Dependence: Role of L-Arginine/Nitric Oxide/cGMP Pathway

(2018) Venlafaxine Attenuates the Development of Morphine Tolerance and Dependence: Role of L-Arginine/Nitric Oxide/cGMP Pathway. Endocrine Metabolic & Immune Disorders-Drug Targets. pp. 362-370. ISSN 1871-5303

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Abstract

Background: 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. Objective: 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. Methods: 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. Results: 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.). Conclusion: 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.

Item Type: Article
Keywords: Venlafaxine antinociception morphine tolerance physical dependence hot-plate test NO-cGMP ethanol withdrawal syndrome neuropathic pain model rat formalin test nitric-oxide opioid tolerance ellagic acid physical-dependence reuptake inhibitor antidepressant action synthase inhibitors Endocrinology & Metabolism Immunology Pharmacology & Pharmacy
Subjects: QU Biochemistry. Cell Biology and Genetics > QU 100-133 Biochemistry of the Human Body
Divisions: Education Vice-Chancellor Department > Faculty of Pharmacy > Department of Toxicology and Pharmacology
Page Range: pp. 362-370
Journal or Publication Title: Endocrine Metabolic & Immune Disorders-Drug Targets
Journal Index: ISI
Volume: 18
Number: 4
Identification Number: https://doi.org/10.2174/1871530318666171213153920
ISSN: 1871-5303
Depositing User: مهندس مهدی شریفی
URI: http://eprints.dums.ac.ir/id/eprint/181

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