Sex and genotype determine the selective activation of neurochemically-distinct mechanisms of swim stress-induced analgesia

A growing literature documents the important influence of organismic factors such as sex and genotype on pain sensitivity and pain modulation. We recently determined that 3-min forced swims in 15°C water produce non-opioid (i.e., naloxone-insensitive) analgesia in outbred Swiss-Webster mice of both sexes; this form of stress-induced analgesia (SIA) is significantly attenuated by the N-methyl-D-aspartate (NMDA) antagonist, dizocilpine (MK-801) in males, but not females. A pilot study designed to confirm the non-opioid and (in male mice) NMDAergic nature of 15°C swim SIA in the C57BL/6J and DBA/2J inbred strains used widely in gene mapping was conducted, using the hot-plate (54°C) assay of nociception. In female mice of both strains, 15°C swim SIA was insensitive to antagonism by either naloxone (10 mg/kg, IP) or dizocilpine (0.1 mg/kg, IP). In male C57BL/6J mice, the observed SIA was naloxone-insensitive, but was attenuated by dizocilpine. This pattern of results is virtually identical to that obtained using Swiss-Webster mice in this and previous studies. However, male DBA/2J mice displayed SIA that was significantly attenuated by naloxone, but insensitive to dizocilpine antagonism. These findings support the hypothesis that genetic factors and sex, in addition to stressor parameters, can determine the selective recruitment of alternative central mechanisms of pain inhibition.