Examination of sex and minocycline treatment on acute morphine-induced analgesia and inflammatory gene expression along the pain pathway in Sprague–Dawley rats

Abstract

BackgroundIn addition to its classical effects on opioid receptors, morphine can activate glia and stimulate the production of pro-inflammatory immune molecules which in turn counteract the analgesic properties of morphine. We hypothesized that decreased morphine analgesia in females may be the result of exaggerated microglial activation in brain regions critical for analgesia.MethodsMale and female rats were treated with morphine and/or minocycline and morphine analgesia was examined using the hot plate. We also examined the expression of microglial and astrocyte markers in the pain pathway.ResultsMales treated with minocycline, a microglial inhibitor, exhibited a significant increase in acute morphine analgesia as previously shown; however, morphine analgesia was not affected by minocycline pretreatment in female rats. Minocycline decreased the expression of glial activation markers in the male spinal cord and periaqueductal gray as expected; however, these same molecules were upregulated in the female.ConclusionsThese data describe a significant difference between males and females in the behavioral effects following co-administration of morphine and minocycline.

Binge Ethanol Consumption Increases Inflammatory Pain Responses and Mechanical and Cold Sensitivity: Tigecycline Treatment Efficacy Shows Sex Differences

“…For example, Lenz and colleagues (), showed microglial differences in the female and male brain resulting from developmental maturation and, in particular, that microglia were essential to the masculinization of the brain. In addition, minocycline reduced the ED 50 for morphine‐induced analgesia in males, but not females (Posillico et al., ). However, even taken together, these data do not explain the tigecycline hypersensitivity in females; therefore, additional studies are necessary to assess the female‐specific mechanisms of action.…”

Neuronal and glial factors contributing to sex differences in opioid modulation of pain

“…Preclinical research on opioid modulation of acute or persistent pain in rodents has consistently demonstrated that morphine is more efficacious in males [26,30,[59][60][61][62][63][64][65][66][67]. Sex differences in morphine action are not trivial; in both persistent inflammatory pain [26,29,61,65,[68][69][70][71][72][73] and visceral pain [65,[74][75][76][77], the 50% effective dose (ED 50 ) for females is approximately 2-fold higher than the ED 50 for males.…”

Impact of sex on pain and opioid analgesia: a review

“…Preclinical studies using rodent models are more consistent, with the majority of studies reporting that morphine is more efficacious in modulating persistent pain in males than females. Indeed, using a variety of acute and chronic pain assays, researchers have shown that morphine’s median effective dose in female rodents is approximately twice the concentration of the dose needed for males to achieve comparable levels of pain relief (Kepler et al, 1989; Cicero et al, 2002; Ji et al, 2006; Loyd and Murphy, 2006; Loyd et al, 2008; Posillico et al, 2015). Researchers using other opioids have reported similar results (Barrett et al, 2002; Bai et al, 2015).…”