Clinical studies suggest the comorbidity of functional pain syndromes such as irritable bowel syndrome, painful bladder syndrome, chronic pelvic pain, and somatoform disorders approaches 40% to 60%. The incidence of episodic or persistent visceral pain associated with these “functional” disorders is two to three times higher in women than in men. One of the possible explanations for this phenomenon is estrogen modulation of viscerovisceral cross-sensitization. While a central site of this modulation has been shown previously, our studies suggest a peripheral site, the dorsal root ganglion (DRG). Estrogens have remarkably wide range of functions including modulation of voltage-gated calcium channels (VGCCs) and purinoreceptors (P2Xs). Significantly, inflammation dramatically alters purinoception by causing a several fold increase in ATP-activated current, alters the voltage dependence of P2X receptors, and enhances the expression of P2X receptors increasing neuronal hypersensitivity. Gonadal hormones are thought as indispensable cornerstones of the normal development and function, but it appears that no body region, no neuronal circuit, and virtually no cell is unaffected by them. Thus, increasing awareness toward estrogens appears to be obligatory. 1. DRG Neurons and Visceral Sensitization Sex hormones and 17β-estradiol (E2), in particular, directly influence the functions of primary afferent neurons. However, E2 has a multiplicity of actions: membrane, cytoplasmic, and nuclear: E2 modulates cellular activity by altering ion channel opening, G-protein signaling, and activation of trophic factor-like signal transduction pathways [1]. DRG neurons in culture express receptors of nociceptive signals [2] and retain most, if not all, their intracellular signaling cascades. DRG neurons in vitro are a valuable preparation because adult primary sensory neurons can be studied without the interference of modulation by central or peripheral messengers. Visceral afferents are sensitive to ATP [3], and several indirect pieces of evidence suggest that visceral afferents are E2-sensitive: (i) visceral pain is affected by hormonal level in cycling females [4]; (ii) there are gender differences in the prevalence of functional disorders involving the viscera [5]; (iii) putative visceral afferents [6] fit into the population of DRG neurons that are E2-sensitive. Although it is generally accepted that each primary afferent neuron is a single sensory channel, several studies have challenged that view and demonstrate that a population of DRG neuron can innervate both the
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