Bradykinin and prostaglandin E₁ regulate calcitonin gene-related peptide expression in cultured rat sensory neurons.

Primary cultures of adult rat dorsal root ganglia (DRG) sensory neurons were used to determine whether bradykinin and prostaglandins E₁ (PGE₁), E₂ (PGE₂) or I₂ (PGI₂) stimulate long-term calcitonin gene-related peptide (CGRP) mRNA accumulation and peptide release. Treatment (24 h) of neurons with either bradykinin or PGE₁, significantly increased CGRP mRNA content and iCGRP release. However, PGE₂ or PGI₂ was without effect. Exposure of the cultured neurons to increasing concentrations of bradykinin or PGE₁ demonstrated that the stimulation of CGRP expression was concentration-dependent, while time-course studies showed that maximal levels of CGRP mRNA accumulation and peptide release were maintained for at least 48 h. Treatment of the neuronal cultures with a bradykinin B₂ receptor antagonist significantly inhibited the bradykinin-induced increase in CGRP expression and release. In addition, preincubation of neuronal cultures with the cyclooxygenase inhibitor indomethacin did not alter the PGE₁-mediated stimulation of CGRP but blocked completely the bradykinin-induced increase in CGRP production. Therefore, these data indicate that bradykinin and PGE₁ can regulate the synthesis and release of CGRP in DRG neurons and that the stimulatory effects of bradykinin on CGRP are mediated by a cyclooxygenase product(s). Thus, these findings suggest a direct relationship between chronic alterations in bradykinin/prostaglandin production that may arise from pathophysiological causes and long-term changes in CGRP expression.