Sex differences in MAP kinase activation in the periaqueductal gray after morphine treatment

Abstract

Morphine is a potent opioid analgesic, but its long term use can lead to negative side effects, including tolerance, which is a decrease in the effectiveness of the opioid. An area of active interest is looking into the molecular effects of chronic morphine treatment in the Periaqueductal gray (PAG), a brain region that controls descending pain modulation. One such molecular target within the PAG is extracellular‐signal regulated kinase 1/2 (ERK). Previous studies have shown that pharmacological inhibition of ERK enhanced morphine tolerance, indicating that ERK activity is associated with better responsiveness to morphine. The PAG is known to contain a heterogenous population of neurons including GABA and glutamate subtypes. However, which neurons ERK is activated in within the PAG following morphine tolerance is unknown. Further, there are known differences in PAG activity between male and female mice. These sex‐differences have not been well studied after morphine tolerance using acute pain tests. The purpose of this research is to investigate differences in ERK activation following morphine tolerance in male and female mice. We treated wild‐type male and female mice with morphine (10 mg/kg, i.p.) or saline for 5 days to induce morphine tolerance, following which both behavior and protein immunofluorescence were assessed. We observe sex‐specific differences in ERK activation levels and morphine antinociceptive tolerance in mice. We also assessed co‐localization of ERK with GABA and glutamate neurons after morphine tolerance. The study will help us understand the cell‐type specificity of kinase activation following morphine tolerance. Further this will give us more information about the nature of neurons that are contributing to sex‐differences in opioid functions within the PAG.