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Hyperalgesic priming, a model of pain chronification in the rat, is mediated by ryanodine receptor-dependent calcium release. Although ryanodine induces priming in both sexes, females are 5 orders of magnitude more sensitive, by an estrogen receptor α (EsRα)-dependent mechanism. An inositol 1,4,5-triphosphate (IP 3 ) receptor inhibitor prevented the induction of priming by ryanodine. For IP 3 induced priming, females were also more sensitive. IP 3 -induced priming was prevented by pretreatment with inhibitors of the sarcoendoplasmic reticulum calcium ATPase and ryanodine receptor. Antisense to EsRα prevented the induction of priming by low-dose IP 3 in females. The induction of priming by an EsRα agonist was ryanodine receptor-dependent and prevented by the IP 3 antagonist. Thus, an EsRα-dependent bidirectional interaction between endoplasmic reticulum IP 3 and ryanodine receptor-mediated calcium signaling is present in the induction of hyperalgesic priming, in females. In cultured male DRG neurons, IP 3 (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 IP 3 antagonist, and not observed in the absence of IP 3 IP 3 potentiation was also blocked by ryanodine receptor antagonist. The application of ryanodine (2 nm), instead of IP 3 , also potentiated K20-induced calcium transients in the presence of β-estradiol, in an IP 3 receptor-dependent manner. Our results point to an EsRα-dependent, reciprocal interaction between IP 3 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, IP 3 and ryanodine, in the induction of priming, regulated by estrogen receptor α 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.

Sexual Dimorphism in a Reciprocal Interaction of Ryanodine and IP3Receptors in the Induction of Hyperalgesic Priming

Sexual Dimorphism in a Reciprocal Interaction of Ryanodine and IP₃Receptors in the Induction of Hyperalgesic Priming