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
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
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