Sexual Dimorphism in a Reciprocal Interaction of Ryanodine and IP3 Receptors in the Induction of Hyperalgesic Priming

Hyperalgesic priming, a model of pain chronification in the rat is mediated by ryanodine receptor-dependent calcium release. While ryanodine induces priming in both sexes, females are 5-orders of magnitude more sensitive, by an estrogen receptor alpha (EsRα)-dependent mechanism. An inositol 1,4,5-triphosphate (IP3) receptor inhibitor prevented the induction of priming by ryanodine. For IP3 induced priming, females were also more sensitive. IP3-induced priming was prevented by pre-treatment with inhibitors of the sarco-endoplasmic reticulum calcium ATPase and ryanodine receptor. Antisense to EsRα prevented the induction of priming by low dose IP3 in females. The induction of priming by an EsRα agonist was ryanodine receptor-dependent and prevented by the IP3 antagonist. Thus, an EsRα-dependent bi-directional interaction between ER IP3 and ryanodine receptor-mediated calcium signaling is present in the induction of hyperalgesic priming, in females. In cultured male dorsal root ganglion neurons, IP3 (100 μM) potentiated depolarization-induced transients produced by extracellular application of high-potassium solution (20 mM, K20), in nociceptors incubated with β-estradiol. This potentiation of depolarization-induced calcium transients was blocked by the IP3 antagonist, and not observed in the absence of IP3. IP3 potentiation was also blocked by ryanodine receptor antagonist. The application of ryanodine (2 nM), instead of IP3, also potentiated K20-induced calcium transients in the presence of β-estradiol, in an IP3 receptor-dependent manner. Our results point to an EsRα-dependent, reciprocal interaction between IP3 and ryanodine receptors that contributes to sex differences in hyperalgesic priming. SIGNIFICANCE STATEMENT The present study demonstrates a mechanism that plays a role in the marked sexual dimorphism observed in a model of the transition to chronic pain, hyperalgesic priming. This mechanism involves a reciprocal interaction between the endoplasmic reticulum receptors, IP3 and ryanodine, in the induction of priming, regulated by estrogen receptor alpha in the nociceptor of female rats. The presence of this signaling pathway modulating the susceptibility of nociceptors to develop plasticity may contribute to our understanding of sex differences observed clinically in chronic pain syndromes.