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

Author(s): Mohammad Taghi Mansouri*, Bahareh Naghizadeh, Behnam Ghorbanzadeh, Soheila Alboghobeish, Gholamreza Houshmand, Neda Amirgholami.

Journal Name: Endocrine, Metabolic & Immune Disorders - Drug Targets
(Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders)

Volume 18 , Issue 4 , 2018

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Graphical 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.

Keywords: Venlafaxine, antinociception, morphine, tolerance, physical dependence, hot-plate test, NO-cGMP.

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Article Details

Year: 2018
Page: [362 - 370]
Pages: 9
DOI: 10.2174/1871530318666171213153920
Price: $65

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