Mansouri Mohammad Taghi, Naghizadeh Bahareh, Ghorbanzadeh Behnam, Alboghobeish Soheila, Houshmand Gholamreza, Amirgholami Neda
Department of Pharmacology, School of Pharmacy, Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
Neuroanesthesia Laboratory, Department of Anesthesiology, Emory University School of Medicine, 3B South, Emory University Hospital, 1364 Clifton Road, NE Atlanta, GA 30322, United States.
Endocr Metab Immune Disord Drug Targets. 2018;18(4):362-370. doi: 10.2174/1871530318666171213153920.
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.
严重疼痛会降低患有各种疾病患者的生活质量，这通常是因为慢性吗啡治疗会导致镇痛效果降低或产生耐受性，从而导致剂量不断增加以及令人痛苦的不良反应。一氧化氮（NO）在吗啡耐受性和依赖性中起作用。
已知抗抑郁药文拉法辛可调节神经组织中的一氧化氮（NO）途径。在本研究中，研究了全身性文拉法辛（VLF）对小鼠吗啡耐受性和依赖性发展、急性吗啡诱导的镇痛作用的影响，以及L-精氨酸/NO/cGMP途径在这些作用中可能的参与情况。
动物连续3天对吗啡（50mg/kg，皮下注射，每日一次）的镇痛作用产生耐受性。使用了一氧化氮调节剂，如L-NAME（一氧化氮合酶抑制剂）和L-精氨酸（L-Arg，一氧化氮合酶的底物）、西地那非（cGMP磷酸二酯酶抑制剂）单独或与文拉法辛联合使用。
结果表明，腹腔注射VLF（5-40mg/kg）以剂量依赖性方式产生镇痛作用。L-精氨酸（200mg/kg，腹腔注射）预处理可逆转镇痛作用，而L-NAME（30mg/kg，腹腔注射）和西地那非（10mg/kg，腹腔注射）可增强镇痛作用。此外，将无效剂量（5mg/kg）的VLF与吗啡联合给药，可增强急性吗啡诱导的镇痛作用（5mg/kg，皮下注射）。这种作用被L-精氨酸（200mg/kg，腹腔注射）拮抗，而被L-NAME（30mg/kg，腹腔注射）和西地那非（10mg/kg，腹腔注射）增强。另一方面，VLF可防止吗啡镇痛耐受性和依赖性的发展。这些作用被L-精氨酸（200mg/kg，腹腔注射）拮抗，而被L-NAME（30mg/kg，腹腔注射）和西地那非（10mg/kg，腹腔注射）增强。
我们的数据表明，即使存在对吗啡的耐受性，VLF与吗啡联合使用可能对疼痛管理具有相关的治疗意义。此外，我们的数据证明L-精氨酸/NO/cGMP途径参与了文拉法辛预防吗啡耐受性和依赖性的过程。
