Effects of extrasynaptic GABA‐A signaling in the PAG on morphine antinociception.

Abstract

Mu‐opioid receptors (MOPrs) reduce GABA‐mediated inhibition of ventrolateral periaqueductal gray (vlPAG) output neurons to activate the descending pain modulatory system and induce antinociception. Both tonic and phasic GABAA‐mediated currents are observed in the vlPAG. Tonic GABAA currents are reduced in vlPAG neurons from female rats pretreated with Complete Freud's Adjuvant (CFA) for 5‐7 days to induce chronic inflammatory pain (2‐way ANOVA; F (1, 45) = 15.24, p = 0.0003). The mRNA and protein levels of the GABAA delta subunit, known to mediate tonic currents in other brain areas, are increased in the vlPAG of female, but not male rats, pretreated with CFA. The decrease in current in females may be due to the rapid clearance of GABA because of upregulation of GABA transporters. Neuronal GAT1 transcripts were increased in female vlPAG pretreated with CFA (Two‐way ANOVA, F (1, 16) = 25.63, p < 0.0001). Glial GAT3 transcripts were decreased in males and increased in female vlPAG pretreated with CFA (Two way ANOVA, F (1, 16) = 32.93). Finally, we explored the role of the GABAA delta subunit in morphine‐induced antinociception with the novel selective allosteric agonist (DS2). DS2 (3 µg) was injected in to the vlPAG of male and female rats prior to cumulative morphine doses and testing of thermal nociceptive thresholds using the hot plate test. DS2 significantly decreased the ED50 of morphine in male rats (vehicle = 4.8 µg vs. DS2 = 10.8 µg, F(1,61) = 6.57, p = 0.013). Interestingly, female rats exhibited a leftward shift of the morphine dose response following DS2 microinjection (vehicle = 15.5 µg vs. DS2 = 5.1 µg, p < 0.05). These data support a role for the GABAA receptors containing the delta subunit in pain modulation in vivo.