Are the pharmacology and physiology of a2adrenoceptors determined by a2-heteroreceptors and autoreceptors respectively?

a2-Adrenoceptors are important mediators of physiological responses to the endogenous catecholamines noradrenaline and adrenaline. In addition, a2-adrenoceptors are pharmacological targets for the treatment of hypertension, sympathetic overactivity and glaucoma. a2-Adrenoceptors are also targeted to induce sedation and analgesia in anaesthesia and intensive care. a2-Adrenoceptors were first described as presynaptic receptors inhibiting the release of various transmitters from neurons in the central and peripheral nervous systems. In addition to these presynaptic neuronal receptors, a2-adrenoceptors were also identified in many non-neuronal cell types of the body. Gene-targeting in mice provided a comprehensive assignment of the physiological and pharmacological functions of these receptors to specific a2A-, a2B- and a2C-adrenoceptor subtypes. However, the specific cell types and signalling pathways involved in these subtype-specific a2-adrenoceptor functions were largely unexplored until recently. This review summarizes recent findings from transgenic mouse models, which were generated to define the role of a2-adrenoceptors in adrenergic neurons, that is, a2-autoreceptors, versus a2-adrenoceptors in non-adrenergic neurons, termed a2-heteroreceptors. a2-Autoreceptors are primarily required to limit release of noradrenaline from sympathetic nerves and adrenaline from adrenal chromaffin cells at rest. These receptors are desensitized upon chronic activation as it may for instance occur due to enhanced sympathetic activity during chronic heart failure. In contrast, pharmacological effects of acutely administered a2-adrenoceptor agonist drugs essentially require a2-heteroreceptors in non-adrenergic neurons, including analgesia, sedation, hypothermia and anaesthetic-sparing as well as bradycardia and hypotension. Thus a clear picture has emerged of the significance of auto- versus heteroreceptors in mediating the physiological functions of a2-adrenoceptors and the pharmacological functions of a2-adrenoceptor agonist drugs respectively.