Scheme illustrating possible mechanisms of opiate tolerance in the LC. Chronic opiate administration produces tolerance--a relative decrease in the ability of m opiate agonists to regulate K⁺ channels and a Na⁺-dependent inward current in LC neurons.  Although the mechanisms underlying tolerance have not yet been established, three types of mechanisms are proposed.  Arrow 1:  The up-regulated cAMP system in the LC would contribute to tolerance by making it more difficult for opiates to acutely inhibit the Na⁺-dependent inward current via inhibition of the cAMP system.  Arrow 2:  It is possible that the up-regulated cAMP system also contributes to tolerance in LC neurons by enhancing desensitization of the m-opioid receptor.  This is based on the observation that the cAMP pathway promotes desensitization of the receptor (possibly via receptor phosphorylation) induced by short-term enkephalin exposure under control conditions.  This mechanism is consistent with the ability of cAMP-dependent protein kinase to phosphorylate and desensitize other G-protein-linked receptors.  Arrow 3:  Based on the evidence that several G-protein-linked receptors are also phosphorylated and desensitized by bARK and associated proteins (e.g., b-arrestin), it is possible that the chronic morphine-induced increase in bARK levels in LC neurons contributes to opiate tolerance.  From 40.