Alpha adrenergic agonists (e.g. vasoconstrictors) represent one of the most commonly used drug classes in dentistry. Although adrenergic agonists have potent vascular effects, recent studies suggest that capsaicin-sensitive nociceptors may express adrenoceptors, suggesting that these drugs may directly modulate the function of an important class of pain-signaling neurons in peripheral tissues. In this study, we tested the hypothesis that adrenergic agonists inhibit activation of peripheral terminals of capsaicin-sensitive fibers innervating dental pulp. Pretreatment with epinephrine or clonidine significantly inhibited capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from superfused bovine dental pulp. These studies suggest that adrenergic agonists may reduce postoperative pain in part via a direct inhibition of capsaicin-sensitive nociceptors. This finding may lead to the development of selective, peripherally acting, adrenergic analgesics. Moreover, because neuropeptide release alters blood flow, it is possible that the vascular effects of these drugs are caused by both vasoconstriction and inhibition of peripheral neuropeptide release.