Sexual Dimorphism of Pain Control: Analgesic Effects of Pioglitazone and Azithromycin in Chronic Spinal Cord Injury.

John C Gensel,Bradley K Taylor,Renée R Donahue,William M Bailey

doi:10.1089/neu.2018.6207

John C Gensel, Bradley K Taylor + Show 2 more

Open Access

https://doi.org/10.1089/neu.2018.6207

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Abstract

Central neuropathic pain develops in greater than 75% of individuals suffering a spinal cord injury (SCI). Increasingly, sex is recognized as an important biological variable in the development and treatment of peripheral neuropathic pain, but much less is known about the role of sex in central neuropathic pain and its pharmacological inhibition. To test the hypothesis that efficacy of analgesic therapies differs between males and females in SCI, we used a mouse model of SCI pain to determine the analgesic efficacy of pioglitazone (PIO), U.S. Food and Drug Administration–approved drug for the treatment of diabetes, and azithromycin (AZM), a commonly prescribed macrolide antibiotic with immunomodulatory properties. Male and female mice received moderate-severe T9 contusion SCI (75-kdyn). A robust heat hyperalgesia developed similarly between male and female mice by 4 weeks post-injury and lasted throughout the duration of the study (14 weeks). Three months after SCI, mice were treated with PIO (10 mg/kg, intraperitoneal) or AZM (160 mg/kg, oral). We observed a sex-specific effect of PIO with significant antihyperalgesic effects in females, but not males. In contrast, AZM was effective in both sexes. Our data support the use of PIO and AZM as novel therapies for SCI pain and highlight the importance of considering sex as a biological variable in clinical and experimental SCI pain research.

Highlights

To begin to address this question, we evaluated the ability of two Food and Drug Administration (FDA)-approved drugs to reduce pain in male and female spinal cord injury (SCI) mice: pioglitazone (PIO), an insulin sensitizer shown to reduce hyperalgesia in models of spinal cord or nerve injury,[9,10,11,12,13] and azithromycin (AZM), an antibiotic that limits SCI macrophage activation, a purported driver of SCI pain.[14,15,16,17]
There is growing experimental evidence that sex is an important biological variable in the pathophysiology of neurotrauma,[20,21] and that development of neuropathic pain may be differentially regulated between males and females.[7]
Whether our results extend to other pain modalities, is unclear