Serotonin 5-HT(3) receptor mediation of pain and anti-nociception: implications for clinical therapeutics.

The involvement of the serotonergic system in pain and anti-nociception has long been recognized. Throughout the nervous system, serotonin (5-HT) exerts effects through heterogeneous populations of receptors that have recently been categorized into distinct "families" based upon their molecular properties. Of these, the 5-HT(3) receptor is distinct in that it is inotropic, mediating a sodium current, and thus is exclusively excitatory, irrespective of the tissue(s) in which it is localized. Widely distributed within the brain, spinal cord, peripheral neurons and extraneural tissues, 5-HT(3) receptors have been localized to several anatomical loci within the peripheral and central neuraxes that subtend the afferent transmission and efferent modulation of pain. This review provides an overview of the anatomy and physiology of 5-HT(3) receptors and focuses upon the work of numerous groups, as well as summarizing our previous and ongoing studies, that have investigated the role of 5-HT(3) receptors in pain and anti-nociception. Data from in vitro studies of pharmacologic function and molecular mechanisms, ex vivo bioassays and animal studies are addressed. Of particular interest are those findings relevant to the possible utility of 5-HT(3)-acting agents in treating human pain and the results of clinical trials employing 5-HT(3) selective drugs for applied therapeutics.