Noradrenergic and corticosteroid receptors regulate somatic and motivational symptoms of morphine withdrawal

Abstract Somatic and motivational symptoms accompanying opiate withdrawal are considered one of the major reasons for relapse to opiate-seeking and opiate-taking behaviors. These symptoms are accompanied by the activation of stress-related processes including hypothalamic-pituitary-adrenal axis activity and noradrenergic (NA) signaling. In particular, the NA system plays an important role in the expression of somatic signs of opiate withdrawal, whereas glucocorticoid (GR) and mineralocorticoid receptors (MR) are activated during opiate abstinence. The purpose of our study was to examine the roles of α 1 -, α 2 -, and β-adrenoceptors (ARs) as well as GR and MR, in the formation and expression of physiological and motivational symptoms of morphine withdrawal. We showed that systemic pretreatment with the selective α 1 -AR antagonist prazosin (0–1 mg/kg), the selective α 2 -AR antagonist RX821002 (0–2 mg/kg), the selective β-adrenergic antagonist, propranolol (0–10 mg/kg), or the selective MR antagonist spironolactone (0–50 mg/kg), but not the selective GR antagonist mifepristone (0–40 mg/kg), decreased somatic symptoms of naloxone-precipitated morphine withdrawal in mice chronically treated with morphine. In contrast, only propranolol pretreatment attenuated the dysphoric affective state accompanying naloxone-precipitated morphine withdrawal as assessed in the conditioned place aversion (N-CPA) paradigm. Together, our results demonstrate the important roles of noradrenergic receptors in the modulation of somatic, but not motivational/affective, symptoms of morphine withdrawal. In addition MR but not GR regulates the expression of only somatic symptoms of morphine withdrawal.