Bidirectional selection for high and low stress-induced analgesia affects G-protein activity

Mice selected for high (HA) and low (LA) swim stress-induced analgesia (SSIA) are a unique model for studying the genetic background of this phenomenon. HA and LA miceshow substantial differences in the magnitude of the antinociceptive response to stress and when treated with exogenous opioids. However, the direct cause underplaying this distinctive feature has not yet been identified. The current study was designed to investigate the possibility that disturbances in G-protein signaling could explain the divergent response to opioid agonists. Supraspinal and spinal opioid sensitivity was assessed in vivo with intraperitoneal morphine and subsequent thermal stimulus exposure. The level of opioid receptor-mediated G-protein activation was investigated by means of DAMGO and morphine-stimulated [³⁵S]GTPγS assay in the brain and spinal cord homogenates from HA and LA mice. Morphine (3-249 μmol/kg, i.p) was over 6 - and 3 - times more potent in HA than LA mice in the hot plate and tail-flick assays, respectively. Additionally, HA mice showed elevated β - endorphin levels in the brain. Enhanced efficacy of agonist-stimulated [³⁵S]GTPγS binding was detected in opioid receptor-rich limbic regions of HA mice like the hypothalamus and hippocampus. Increased G-protein activity also emerged in the thalamus, periaqueductal gray matter and prefrontal cortex. In conclusion, the magnitude of the antinociceptive response to opioids in HA and LA mice is correlated with alterations in G-protein activation in brain regions responsible for integration and descending modulation of nociceptive information as well as at sites governing the emotional response to stressful stimuli.