Are the pharmacology and physiology of α₂adrenoceptors determined by α₂‐heteroreceptors and autoreceptors respectively?

<jats:p>α<jats:sub>2</jats:sub>‐Adrenoceptors are important mediators of physiological responses to the endogenous catecholamines noradrenaline and adrenaline. In addition, α<jats:sub>2</jats:sub>‐adrenoceptors are pharmacological targets for the treatment of hypertension, sympathetic overactivity and glaucoma. α<jats:sub>2</jats:sub>‐Adrenoceptors are also targeted to induce sedation and analgesia in anaesthesia and intensive care. α<jats:sub>2</jats:sub>‐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, α<jats:sub>2</jats:sub>‐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 α<jats:sub>2A</jats:sub>‐, α<jats:sub>2B</jats:sub>‐ and α<jats:sub>2C</jats:sub>‐adrenoceptor subtypes. However, the specific cell types and signalling pathways involved in these subtype‐specific α<jats:sub>2</jats:sub>‐adrenoceptor functions were largely unexplored until recently. This review summarizes recent findings from transgenic mouse models, which were generated to define the role of α<jats:sub>2</jats:sub>‐adrenoceptors in adrenergic neurons, that is, α<jats:sub>2</jats:sub>‐autoreceptors, versus α<jats:sub>2</jats:sub>‐adrenoceptors in non‐adrenergic neurons, termed α<jats:sub>2</jats:sub>‐heteroreceptors. α<jats:sub>2</jats:sub>‐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 α<jats:sub>2</jats:sub>‐adrenoceptor agonist drugs essentially require α<jats:sub>2</jats:sub>‐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 α<jats:sub>2</jats:sub>‐adrenoceptors and the pharmacological functions of α<jats:sub>2</jats:sub>‐adrenoceptor agonist drugs respectively.</jats:p>