The process that causes a cell to produce a particular response after binding of an agonist to its receptor is called signal transduction. Of particular interest to anesthesiologists is the transmembrane signaling that follows agonist binding to ligand-gated ion channels (e.g., gamma-aminobutyric acidAreceptors) or G protein-coupled receptors (e.g., adrenergic and opiate receptors). In the former case, the receptor and the channel that translocate chloride anions are on the same protein, whereas in the case of the opiate receptors at least three separate proteins participate in the signal transduction; i.e., the receptor, the G protein, and the effector. With that many “moving parts,” the opportunity to modulate such a system abounds. When one considers that each family of receptors has many subtypes (e.g., there are nine adrenergic receptor subtypes), which can couple to more than 20 different G proteins and nearly 100 effector mechanisms, it becomes easy to understand how a single species of agonist can give rise to a plethora of diverse biologic responses.

In this issue of Anesthesiology, Gutstein et al. [1] tested the hypothesis that opiate receptors are coupled to mitogen-activated protein kinase cascades, which induce changes in cellular function by phosphorylation of cytoplasmic and nuclear proteins. Until a few years ago, such a notion would have seemed farfetched because the hyperpolarization effects of opioids in neuronal cells could be easily explained by a well-characterized activation of potassium channel (promoting escape of intracellular cations), inhibition of calcium channels (preventing calcium from entering into the cell), or both. Although these transduction mechanisms can explain the inhibitory effect of opioids on neuronal excitability, they do not provide an answer for the multitude of excitatory effects (e.g., tolerance, dependence/addiction, muscle rigidity) that opioids also exhibit at the cellular level.

The authors have developed cDNAs for each of the rat opiate receptors, which, when spliced into an appropriate vector, can be introduced into cells, which then express “pure” populations of these receptor subtypes. The fidelity of transfection and protein expression ensures that only one species of receptor is present and is a useful technique for defining the transduction pathways used by specific receptor subtypes. In two mammalian cell types they demonstrated that the micro- and delta-receptor subtypes activate extracellular signal-related kinase, one of the three defined mitogen-activated protein kinase species.

These findings have novel implications at the fundamental and clinical levels. At the fundamental level, it will be important to define which are the “downstream” effects of extracellular signal-related kinase activation and to determine if these can explain some of the excitatory effects of opioids. Such information may lead to therapeutic strategies that can interrupt the development of tolerance, dependence, and addiction. In addition, the fact that kappa-agonists cannot stimulate extracellular signal-related kinase may provide insights into the different pharmacologic actions exhibited by drugs acting exclusively at the kappa-receptor subtype.

I have one final thought: Even though nature is parsimonious in having but two endogenous opiate ligands and three opiate receptor subtypes, it can still introduce remarkable specificity by discriminating which molecular component in transduction pathways can “match” with one other component.

Mervyn Maze, M.B., Ch.B., F.R.C.P.

Professor and Director of Research; Department of Anesthesia; Stanford University; Staff Physician, Anesthesiology Service VAPAHCS; Palo Alto, California 94304

Gutstein HB, Rubie EA, Mansour A, Akil H, Woodgett JR: Opioid effects on mitogen-activated protein kinase signaling cascades. Anesthesiology 1997; 87:1118-26.