Drug dependent sex-differences in periaqueducatal gray mediated antinociception in the rat

Abstract

Mu-opioid receptor (MOPr) agonists, such as morphine, produce greater antinociception in male compared to female rats. The ventolateral periaqueductal gray (vlPAG) appears to contribute to this sex difference despite fewer vlPAG output neurons projecting to the rostral ventromedial medulla in male compared to female rats. This greater projection in female rats suggests that non-opioid activation of vlPAG output neurons should produce greater antinociception in female compared to male rats. This hypothesis was tested by comparing the time course and antinociceptive potency of microinjecting MOPr agonists (morphine, DAMGO, fentanyl) and non-opioid compounds (bicuculline, kainic acid) into the vlPAG of female and male rats. Microinjection of morphine or DAMGO produced antinociception that had a slow onset (peak from 15–30 min) and long duration (60 min) compared to the antinociception produced following microinjection of fentanyl, bicuculline, or kainic acid (peak effect at 3 min; duration less than 30 min). No sex-differences in the time courses were evident. All five compounds caused a dose-dependent antinociception when microinjected into the vlPAG. Antinociceptive potency was significantly greater in male compared to female rats following microinjection of morphine, DAMGO, and bicuculline, but not following microinjection of fentanyl or kainic acid. In no case did activation of the vlPAG produce greater antinocicepiton in female compared to male rats. These findings demonstrate that the vlPAG can produce comparable antinociception in female and male rats, but antinociception produced by inhibition of GABAergic neurons (whether by morphine or the GABAA receptor antagonist bicuculline) produces greater antinociception in males.

Ligand-biased activation of extracellular signal-regulated kinase 1/2 leads to differences in opioid induced antinociception and tolerance

“…The hot plate test was conducted 2 min after each injection. Our previous data show clear dose-dependent antinociception using this procedure (Bobeck et al, 2009). …”

Sex Associated Differential Expressions of the Alternatively Spliced Variants mRNA of OPRM1 in Brain Regions of C57BL/6 Mouse

“…To our knowledge, Compared with female WT mice, male WT mice exhibited higher pain thresholds and enhanced opioid receptor-induced antinociception [6,[22][23][24], in contrast, mixed KOPR/MOPR ligands have been found to produce greater analgesia in women than men [25]. There were numerous mechanisms and pathways explaining the sex differences between antinociception, tolerance, physical dependence, addiction and withdrawal, for example, the GIRK2-null mutation reduced the ''pain'' threshold in male but not in female mice, effectively eliminating the sex differences in pain threshold [22].…”

“…All mice were housed in groups of 3-5, separated based on sex and litter, maintained on a 12-hour light / 12-hour dark cycle, and given ad libitum access to food and water in a temperature-controlled room. Estrous phase was not measured in order to prevent heightened stress in female mice [23,37]. All procedures were approved by Nanjing University of Chinese Medicine Animal Care and Use Committee.…”

“…Previous studies investigating sex differences of μ opioid agonist analgesia were always focusing on the expression of μ opioid receptor (probably only a matter of MOR1) in Periaqueducatal Gray (PAG) by ethology, pharmacology, neuroanatomy, immunohistochemistry and immunofluorescence [6,23,30,36,37]. Aiming to demonstrate the relationship between OPRM1 splice variant and sex differences and using the established RT-SYBR green qPCR assays, we examined the expression levels of OPRM1 splice variants mRNA in six brain regions and spinal cord of male and female C57BL/6 Mice.…”

“…There were numerous mechanisms and pathways explaining the sex differences between antinociception, tolerance, physical dependence, addiction and withdrawal, for example, the GIRK2-null mutation reduced the ''pain'' threshold in male but not in female mice, effectively eliminating the sex differences in pain threshold [22]. On one hand, it had been demonstrated that the ventolateral periaqueductal gray (vlPAG) produced comparable antinociception in female and male rats despite fewer vlPAG output neurons projecting to the rostral ventromedial medulla in male compared to female rats, but antinociception produced by inhibition of GABAergic neurons could produce greater antinociception in males [23]. On the other hand, Scott proposed that only estrus females' response to morphine was lower than that of males and females have fewer ventral periaqueductal gray (vPAG) mu opioid receptors than males, suggesting that ovarian hormones and PAG mu opioid receptor density contribute to sex differences in antinociception produced by morphine [6].…”