Fluoxetine uses in nociceptive pain management: a promising adjuvant to opioid analgesics.

Fluoxetine, a commonly prescribed antidepressant, use in nociceptive pain management represents one of the unsettled issues of fluoxetine therapeutics. By reviewing the literature about fluoxetine's possible roles in this setting, those could be solitary antinociceptive effect, enhancement of acute morphine analgesia, blocking morphine tolerance development, and blocking dependence development and associated abstinence syndrome. In this study, we examined those four alleged roles of fluoxetine. Moreover, as effective alleviation of morphine tolerance, dependence, and abstinence syndrome represents one of the most challenging medical needs, we biochemically analyzed fluoxetine effect on these phenomena. Fluoxetine (10 mg/kg, IP) was examined in hot plate test for assessment of possible analgesic activity and enhancement of morphine acute analgesia (1 and 5 mg/kg, SC). Repeated morphine (5 mg/kg, SC) administration for 9 days developed tolerance and dependence; fluoxetine was co-administered to evaluate its potential to modulate these processes. We also determined concomitant changes in neurotransmitters (glutamate and noradrenaline), inflammatory status, and prooxidant-antioxidant balance. Our results indicated that fluoxetine did not possess significant analgesia solely and did not enhance acute morphine analgesia. However, fluoxetine administration with morphine significantly attenuated tolerance and dependence development and abstinence syndrome with corresponding suppression of morphine-induced changes in neurotransmitters (glutamate and noradrenaline), inflammatory status, and prooxidant-antioxidant balance. These biochemical results may reflect both direct and indirect effects of fluoxetine. Our conclusion is that despite fluoxetine possesses low - if any - analgesic activity, it significantly adds to opioids not via enhancing analgesic activity but through modulation of tolerance and dependence development.

Uses of fluoxetine in nociceptive pain management: A literature overview.

Fluoxetine is one of the top ten prescribed antidepressants. Other therapeutic applications were approved for fluoxetine including, anxiety disorders, bulimia nervosa, and premature ejaculation. However, the role of fluoxetine in nociceptive pain management is still unclear. In this review, we discuss an overview of five possible roles of fluoxetine in pain management: intrinsic antinociceptive effect, enhancement of acute opioid analgesia, attenuation of tolerance development to opioid analgesia, attenuation of dependence development and abstinence syndrome, and attenuation of opioid induced hyperalgesia. Conflicting data were reported about fluoxetine intrinsic anti-nociceptive effect in preclinical and clinical studies except for inflammatory pain. Similar controversy was described in preclinical and clinical studies which explored the possible enhancement of opioid analgesia by fluoxetine co-administration. However, fluoxetine was found to have a promising effect on opioid tolerance and dependence in animal and human studies. Regarding opioid induced hyperalgesia, no studies examined fluoxetine effects in this regard. Our literature review revealed that, the most likely beneficial use of fluoxetine in nociceptive pain management is for alleviation of inflammatory pain and attenuation of opioid tolerance and dependence. Non-steroidal anti-inflammatory and corticosteroids carry many adverse effects and toxicities. Effective alleviation of opioid tolerance and dependence represents a huge health burden and growing unmet medical need. Moreover, most agents used to attenuate these phenomena are either experimental or poorly tolerable drugs which limit their transitional value. Fluoxetine offers an effective, safe, and tolerable alternative for management of both inflammatory pain and opioid tolerance and dependence presently available to clinicians.

Protective effect of citicoline against aluminum-induced cognitive impairments in rats.

The potential protective effect of citicoline on aluminum chloride-induced cognitive deficits was investigated in rats. In a Morris water maze, administration of aluminum chloride to rats for 90 days resulted in increased escape latency to reach the platform and decreased swimming speed in acquisition trials. Similarly, in probe trials, the time required to reach the hidden platform was increased and the time spent in the target quadrant was reduced. Also, administration of aluminum chloride to rats for 90 days increased the reference and working memory errors and time required to end the task in the radial arm maze. In addition, this treatment decreased the step-through latency in the passive avoidance test. Concurrently, treatment of rats with aluminum chloride for 90 days increased hippocampal glutamate, malondialdehyde, and nitrite levels and decreased intracellular reduced glutathione level. In the citicoline-treated group, aluminum chloride-induced learning and memory impairments as assessed by the Morris water maze, radial arm maze, and passive avoidance tests were inhibited. At the same time, treatment of rats with citicoline prevented the biochemical alterations induced by aluminum chloride in the hippocampus. It can be concluded that elevation of hippocampal glutamate level with consequent oxidative stress and nitric oxide (NO) overproduction may play an important role in aluminum-induced cognitive impairments. Also, our results suggest, for the first time, that citicoline can protect against the development of these cognitive deficits through inhibition of aluminum-induced elevation of glutamate level, oxidative stress, and NO overproduction in the hippocampus.

Role of oxidative stress and inducible nitric oxide synthase in morphine-induced tolerance and dependence in mice. Effect of alpha-lipoic acid.

In this study, the possible role of oxidative stress and nitric oxide (NO) synthase isoforms in the development of morphine tolerance and dependence, and effect of alpha-lipoic acid on these parameters were investigated in mice. The development of morphine tolerance as measured by the hot plate test and dependence, as assessed by naloxone-precipitated withdrawal manifestations, produced an increase in brain glutamate and malondialdehyde (MDA) levels and NO production as well as a decrease in brain intracellular reduced glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity. Also, the development of these syndromes increased inducible but not neuronal NO synthase mRNA and protein expressions in mice brain. Co-administration of alpha-lipoic acid (α-LA) inhibited the development of morphine tolerance and dependence, their associated biochemical alterations, except elevation of brain glutamate level, and their associated increase in brain inducible NO synthase mRNA and protein expressions. The inhibitory effect of α-LA on morphine-induced tolerance and dependence and on naloxone-induced biochemical alterations in morphine-dependent mice was enhanced by concurrent administration of the NMDA receptor antagonist, dizocilpine, the antioxidant, N-acetylcysteine or the selective inducible NO synthase inhibitor, aminoguanidine. On the other hand, this inhibitory effect of α-LA was not changed by concurrent administration of the selective neuronal NO synthase inhibitor, 7-nitroindazole but antagonized by concurrent administration of the NO precursor, L-arginine. These results suggest that α-LA through inhibition of morphine-induced oxidative stress and increase in the expression and activity of inducible NO synthase in the brain can attenuate the development of morphine tolerance and dependence.

Inhibition of brain oxidative stress and inducible nitric oxide synthase expression by thymoquinone attenuates the development of morphine tolerance and dependence in mice.

In this study, the effect of thymoquinone on morphine-induced tolerance and dependence in mice was investigated. Repeated administration of thymoquinone along with morphine attenuated the development of morphine tolerance, as measured by the hot plate test, and dependence, as assessed by naloxone-precipitated withdrawal manifestations. Concurrently, morphine-induced progressive increase in brain malondialdehyde (MDA) level and nitric oxide (NO) production as well as progressive decrease in brain intracellular reduced glutathione (GSH) level and glutathione peroxidase (GSH-Px) activity were inhibited by co-administration of thymoquinone. Morphine-induced progressive increase in brain glutamate level was not inhibited by concomitant administration of thymoquinone. Similarly, co-administration of thymoquinone inhibited naloxone-induced increase in brain MDA level, NO overproduction and decrease in brain intracellular GSH level and GSH-Px activities but it did not inhibit naloxone-induced elevation of brain glutamate level in morphine-dependent mice. The inhibitory effect of thymoquinone on morphine-induced tolerance and dependence on naloxone-induced biochemical alterations in morphine-dependent mice was enhanced by concurrent i.p. administration of the NMDA receptor antagonist, dizocilpine, the antioxidant, N-acetylcysteine or the NO synthase inhibitor, L-N (G)-nitroarginine methyl ester. On the other hand, this inhibitory effect of thymoquinone was antagonized by concurrent i.p. administration of NO precursor, L-arginine. In addition, concomitant administration of thymoquinone inhibited morphine tolerance and dependence-induced increase in inducible but not in neuronal NO synthase mRNA expression in mice brain. These results demonstrate that inhibition of morphine-induced oxidative stress, increase in the expression of brain inducible NO synthase and NO overproduction by thymoquinone can attenuate the development of morphine tolerance and dependence.