Previous studies have shown that tolerance develops to a greater degree in male compared to female rats. The midbrain periaqueductal gray (PAG), and its descending projections to the rostral ventromedial medulla (RVM), provides an essential neural circuit for the antinociceptive effects of opiates and has been implicated in the development of tolerance to morphine. We have previously reported that systemic morphine administration activates a greater proportion of PAG-RVM neurons in male versus female rats; our hypothesis is that if the PAG-RVM pathway is essential for the development of morphine tolerance, then (1) morphine activation of the PAG-RVM pathway should decline as tolerance develops, and (2) sex differences should be reflected as a greater decline in males. These hypotheses were tested using behavioral and neuroanatomical techniques to map the activation of the PAG-RVM pathway during the development of tolerance to repeated morphine administration (4.5 mg/kg; s.c.). We found that as male rats develop tolerance (D50 increased from 3.0 to 6.3 mg/kg), there was no significant decline in the overall activation of the PAG, however, there was a steady decline in the percentage of PAG-RVM output neurons activated by morphine. This reduction occurred in males only; there was no significant decline in the activity of PAG-RVM output neurons in females. These data demonstrate that the greater development of tolerance to morphine administration in male rats corresponds with a significant reduction in the activation of the PAG-RVM circuit. Our results provide additional data demonstrating a central role for the PAG in morphine tolerance.
Loyd, D.R., Morgan, M.M., & Murphy, A.Z. (2008). Sexually dimorphic activation of the periaqueductal gray - rostral ventromedial medullary circuit during the development of morphine tolerance in the rat. European Journal of Neuroscience, 27(6), 1517-1524. doi:10.1111/j.1460-9568.2008.06100.x