Chronic morphine treatment of guinea pigs induces nonspecific sensitivity changes in the nucleus tractus solitarius in vitro

Abstract

Chronic morphine treatment results in the development of an opioid tolerance in guinea pig myenteric S-neurons that is nonspecific among pharmacologically unrelated inhibitory agonists and the concurrent development of a nonspecific super-sensitivity to unrelated excitatory agonists. The purpose of these studies was to extend this model of opioid tolerance in the guinea pig to central neurons, specifically to the medial nucleus tractus solitarius (mnTS), the primary brainstem relay for visceroceptive information. Pharmacological responses of the guinea pig mnTS neurons were examined in an in vitro brainstem slice preparation and compared between chronically morphine-treated animals and untreated controls. The spontaneous activity of guinea pig mnTS neurons was inhibited by gamma-aminobutyric acid (GABA), the GABAA-selective agonist muscimol, 2-chloroadenosine and clonidine and was excited by glutamate and elevations in extracellular potassium. Applied alone, morphine or the GABAA-selective antagonist bicuculline inhibited and excited approximately equal proportions of nucleus tractus solitarius (nTS) neurons. However, when applied in the presence of bicuculline, morphine inhibited most neurons tested. Reduced inhibitory responses to four agonists, i.e., morphine, muscimol, 2-chloroadenosine and clonidine, were observed in mnTS neurons in slices obtained from chronically morphine-treated animals. Increased excitation of these neurons by elevated extracellular potassium was observed. It is concluded that 1) guinea pig nTS neurons respond similarly to nTS neurons from other species in vitro, 2) opioids disinhibit some proportion of guinea pig nTS neurons in vitro through a GABAergic mechanism and 3) the development of opioid tolerance in guinea pig nTS neurons is qualitatively similar to that of guinea pig myenteric S-neurons.