Co-Administration of Pioglitazone Improves Fluoxetine’s Antinociceptive, Neuroprotective, and Antidepressant Effects in Chronic Constriction Injury in Rats

Background: Chronic pain may be associated with diabetes mellitus and/or depression. Use of therapies that target both comorbidities is encouraged. Objective: This study was designed to investigate the potential antinociceptive, neuroprotective, and antidepressant effects of combinations of pioglitazone or metformin with fluoxetine in chronic constriction injury (CCI) in rats. Study Design: Experimental trial in rats. Setting: University lab in Saudia Arabia. Methods: Two sets of experiments were performed. In each one, 9 groups of rats (n = 8) were used: sham, CCI, and 7 CCI-treated groups. Treatments were given orally starting on day 7 post-surgery as follows (mg/kg/day): fluoxetine (10, 20, and 40), pioglitazone (20), metformin (50), fluoxetine (20) + pioglitazone, and fluoxetine (20) + metformin. In the first set, on day 14 post-surgery mechanical allodynia, thermal hyperalgesia, and serum cytokines were measured. Moreover, immunoreactivity of glial fibrillary acidic protein (GFAP, a marker for astrocytic activation) in the spinal cord was assessed and histopathological changes in the ipsilateral sciatic nerve were examined. In the second set, on days 14 and 21 post-surgery the forced swimming test was done. Results: In the first set, all treatments significantly decreased mechanical allodynia while all treatments except F10 and F20 significantly decreased thermal hyperalgesia compared to the CCI group. The F20+M group showed the highest decreases, however still significantly lower than those of the sham group. The treatments didn’t impair motor function in the rotarod test. All treatments significantly decreased serum levels of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 while increasing the level of interleukin-10. The CCI-induced marked increase of GFAP immunoexpression has been reduced to moderate with fluoxetine (40) and pioglitazone, and to mild with metformin and the combination groups. The CCI-induced changes in sciatic nerve were less in fluoxetine (40), pioglitazone, and metformin groups, and least in the combination groups. In the second set, the immobility duration was significantly reduced by F20, F40, P, F20+P, and F20+M compared to the CCI group. The F20+P group showed the highest decrease, however still significantly lower than that of the sham group. The treatments didn’t affect locomotor activity in the open field test. Limitations: Measuring the cytokines levels only in blood and not in the spinal cord and sciatic nerve and measuring the outcome measures in the first set of experiments at only one time-point. Conclusions: Co-administration of pioglitazone or metformin with low-dose fluoxetine improved mechanical allodynia, thermal hyperalgesia, and neurohistopathological changes while coadministration of pioglitazone, but not metformin, improved the depressive-like behavior in the peripheral nerve injury model of neuropathic pain in rats. Extrapolation of the current results to clinical reality could be beneficial for pain patients with diabetes and/or depression, however this needs further confirmatory studies. Key words: Antidepressant, antinociceptive, chronic constriction injury, fluoxetine, GFAP, metformin, neuroprotective, pain, pioglitazone, sciatic