Making sense out of antisense for the study of drug receptors.

Editorial In recent years various classes of drugs have been studied as agents to aid in anesthesia and analgesia that were not originally designed for these therapeutic uses. One example is the use of ␣ 2-adrenergic agonists as analgesic/anesthetic adjuvants (1). Since these drugs (e.g., clonidine) were primarily developed for the treatment of cardiovascular disorders, it is not surprising that cardiovascular effects can limit their use. Molecular cloning studies have indicated the existence of three ␣ 2-adrenergic receptor subtypes (␣ 2A , ␣ 2B , and ␣ 2C), although the precise physiologic role of each of these subtypes has not yet been defined. Therefore, it is plausible to speculate that not all of the receptor subtypes will be involved in analgesic actions. More importantly, the subtypes mediating these actions might be distinct from those involved in the cardiovascular effects, and thus it might be possible to develop drugs with an improved efficacy/toxicity profile compared with presently available non–subtype-selective drugs. Classically, the identification of receptor subtypes mediating a physiological response has relied on the use of subtype-selective antagonists and, to a lesser degree, agonists. Other information (radioligand binding, immunohistochemistry, or in situ hybridization) can provide evidence regarding the presence of a receptor subtype in a tissue or cell type of interest. However, such results are incomplete and potentially misleading in the absence of functional data. In the case of ␣ 2-adrener-gic receptors (and for that matter, many other classes of G pro-tein–linked receptors for which multiple subtypes have been cloned) highly subtype-selective agents are not available and this has limited insight into the functional role of each subtype. The cloning of G protein–linked receptors and components of their signal transduction machinery provides a number of alternative approaches to define the functional role of receptor subtypes and signaling components. Such approaches include " chronic methods, " such as the generation of transgenic animals , which overexpress or lack a certain receptor or signaling component, and " acute methods, " whereby receptor expression is inhibited by antisense techniques. Recombinant DNA– based techniques have the potential to achieve a degree of specificity greater than that achieved by classical pharmacological methods, but this advantage can be offset by various limitations. For example, in the case of transgenic animals, factors such as gene dosage effects, inappropriate tissue targeting, in-ducibility versus constitutive expression, developmental effects of transgenes, and compensatory changes all may influence observed results. In this …