Tolerance of locus coeruleus neurones to morphine and suppression of withdrawal response by clonidine

Abstract

NORADRENERGIC neurones of the locus coeruleus (LC; A6 of ref. 1) are inhibited by the systemic or local administration of adrenergic agonists^2–5, opiates^6,7 and enkephalins^8,9. The adrenergic receptors of the LC, which are of the presynaptic or α₂ type⁵, seem to mediate inhibitory responses to recurrent LC collaterals¹⁰ and adrenaline inputs from the lower brain stem^4,11. In addition to adrenergic receptors, there are opiate receptors located in the LC^12,13 which presumably mediate the actions of endogenous opiate-like substances (enkephalins and β-endorphin) located in nerve terminals within the LC^14–16. Recently, clonidine, which is the most powerful of the α₂ agonists known to inhibit the firing of LC neurones^3,5, has been reported to suppress the symptoms of opiate withdrawal in humans¹⁷. On this basis, the latter authors suggested that the opiate-withdrawal syndrome may be due in part to increased noradrenergic neuronal activity in areas such as the LC which are regulated by both α₂ adrenoceptors and opiate receptors. In this connection, it is interesting that the drug piperoxane, which blocks α₂ adrenoceptors and accelerates the firing of LC neurones^4,5 produces many of the symptoms (such as anxiety and hypertension) seen in opiate withdrawal¹⁸. In the present study, single-cell recording and microiontophoretic techniques were used to establish the development of tolerance of LC cells to the depressant effects of morphine, naloxone-induced withdrawal activations of LC neuronal firing in morphine-dependent animals, and the ability of clonidine to suppress the withdrawal of LC neurones through a non-opiate receptor.