Mechanism of morphine addiction by inhibiting the soluble Guanylate Cyclase–Nitric Oxide (sGC–NO) pathway

Abstract

Ample evidence has shown that morphine influences learning and memory and thereby causing addiction. Various studies have shown that it decreases the inhibitory GABAergic synaptic transmission (LTPGABA) via the soluble guanylate cyclase (sGC) and nitric oxide (NO) pathway. But still it is unclear on how does morphine inhibit the sGC–NO pathway. In this study, we show the mechanism of LTPGABA inhibition by morphine with the help of a mathematical model. A two step model of sGC activation is used, where morphine inhibits NO during the first step and consequently blocks sGC activation. Here, morphine binding on μ-opioid receptors blocks the binding of retrogradely travelling NO to sGC and hence its activation. As a result, LTPGABA is not produced which increases the chances of addiction manifold. Alongwith the mechanism, the dependence of morphine inhibition on major parameters such as morphine dissociation, morphine concentration, NO removal & rate of inhibition and its effect on addiction is also shown.