Functional interaction between α2-adrenoceptors, μ- and κ-opioid receptors in the guinea pig myenteric plexus: Effect of chronic desipramine treatment

The existence of a functional interplay between α2-adrenoceptor and opioid receptor inhibitory pathways modulating neurotransmitter release has been demonstrated in the enteric nervous system by development of sensitivity changes to α2-adrenoceptor, μ- and κ-opioid receptor agents on enteric cholinergic neurons after chronic sympathetic denervation. In the present study, to further examine this hypothesis we evaluated whether manipulation of α2-adrenoceptor pathways by chronic treatment with the antidepressant drug, desipramine (10 mg/kg i.p. daily, for 21 days), could entail changes in enteric μ- and κ-opioid receptor pathways in the myenteric plexus of the guinea pig distal colon. In this region, subsensitivity to the inhibitory effect of both UK14,304 and U69,593, respectively α2A-adrenoceptor and κ-opioid receptor agonist, on the peristaltic reflex developed after chronic desipramine treatment. On opposite, in these experimental conditions, supersensitivity developed to the inhibitory effect of [D-Ala, N-Me-Phe4-Gly-ol5]-enkephalin (DAMGO), μ-opioid receptor agonist, on propulsion velocity. Immunoreactive expression levels of α2A-adrenoceptors, μ- and κ-opioid receptors significantly decreased in the myenteric plexus of the guinea pig colon after chronic desipramine treatment. In these experimental conditions, mRNA levels of α2A-adrenoceptors, μ- and κ-opioid receptors significantly increased, excluding a direct involvement of transcription mechanisms in the regulation of receptor expression. Levels of G protein-coupled receptor kinase 2/3 and of inhibitory Gi/o proteins were significantly reduced in the myenteric plexus after chronic treatment with desipramine. Such changes might represent possible molecular mechanisms involved in the development of subsensitivity to UK14,304 and U69,593 on the efficiency of peristalsis. Alternative molecular mechanisms, including a higher efficiency in the coupling between receptor activation and downstream intracellular effector systems, possibly independent from inhibitory Gi/o proteins, may be accounted for the development of supersensitivity to DAMGO. Increased sensitivity to the μ-opioid agonist might compensate for the development of α2A-adrenoceptor and κ-opioid receptor subsensitivity. On the whole, the present data further strengthen the concept that, manipulation of α2-adrenergic inhibitory receptor pathways in the enteric nervous system entails changes in opioid inhibitory receptor pathways, which might be involved in maintaining homeostasis as suggested for μ-opioid, but not for κ-opioid receptors.