The importance of sensory nerve endings as sites of drug action.

The role that sensory nerve endings can play in drug action and the strategy used for its experimental analysis and proof is first exemplified by three effects of nicotine which are seen when the lowest effective doses of the drug are given intravenously in the cat: (1) a vasopressor effect due to arterial chemoreceptor stimulation; (2) a triad of bradycardia, hypotension and apnea, and (3) a depressant effect upon somatic motor activity, both of which are traced to vagal afferent endings in the pulmonary circulation. While receptors in the lung are responsible at least for the initial phase of the reflex responses listed in (2) and (3), sensory endings in heart, aorta, and carotid sinus region may be recruited into action as the drug reaches them. Several of these reflex effects can also be elicited by other sensory stimulant agents such as phenyldiguanide, 5-hydroxytryptamine, and veratrum alkaloids. In the second part, a general outline is given of what may be classified as 'Afferent Pharmacology', dealing with drug action upon sensory receptors and with the resulting remote drug effects. The action upon sensory receptors can either be a direct one ('primary' drug effect) consisting of stimulation, sensitization, desensitization, depression or combinations thereof, or an indirect ('secondary') effect brought about by a variety of drug-induced changes in the tissues surrounding the receptors. Depending on the nature of the primary or secondary action, the remote drug effect can be either an initiation, modification or impairment of those reflexes which have their origin in the sensory endings acted upon. Indeed, the grossly observable pharmacological actions of 'afferent drugs' are generally those relating to the reflex response. To avoid blurring of the boundaries of afferent pharmacology, drugs acting on central synapses of reflex pathways, or on the elaborate efferent control system of afferent input, are not included. A discussion follows of the topics of investigation, the influence of experimental conditions and anesthesia, various approaches and methods, the physiological and pharmacological importance of inquiry in this area, and some of the therapeutic aspects. Finally, brief mention is made of certain features and problems which appear to be characteristic of afferent pharmacology.