Figure 2

Diagram of the postulated cross-talk between estrogen and opioid receptors. Upon binding of the opioids, opioid receptors (OR) activate different intracellular signaling pathways through the G protein (composed of α, β and γ subunits). The activation of phospholipase C (PLC) catalyzes the hydrolysis of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP₂) into inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ induces calcium release from the endoplasmic reticulum that activates calcium-dependent signaling. DAG activates protein kinase C (PKC). PKC activates adenylate cyclase (AC), which increases cAMP production, and subsequently stimulates protein kinase A (PKA). PKA can phosphorylate various proteins including ion channels (L-type voltage-gated Ca²⁺ channels [L-VGCC], G protein-coupled inwardly rectifying K⁺ channels [GIRK], and small conductance Ca²⁺-dependent K⁺ channels [SK]) and cAMP-responsive element binding protein (CREB). The activation of the mitogen-activated protein kinase (MAPK) transduction cascades can stimulate multiple targets, including nuclear transcription factors (such as CREB), cytoplasmic enzymes (including tyrosine hydroxylase), cytoskeletal proteins, and ion channels. Estradiol (E2) can activate the membrane-bound estrogen receptor (mER) and modulate the ionic conductance through phosphorylation of ionotropic receptors or uncoupling of OR from their ionic channels or intracellular effectors. E2 can also bind to nuclear ER dimers and thereby bind to the estrogen-responsive element (ERE) on the DNA, resulting in the activation of specific gene transcription. Additionally, rapid effects of E2 mediated by mER can lead to CREB phosphorylation, altering gene transcription through the interaction with the cAMP responsive element (CRE). Modified from [181].