The m, d and K receptors are coupled, via pertussis toxin—sensitive G proteins, to inhibition of adenylyl cyclase activity, activation of receptor-linked K+ currents, and suppression of voltage-gated Ca2+ currents. The hyperpolarization of membrane potential by K+-current activation and the limiting of Ca2+ entry by suppression of Ca2+ currents are tenable but unproven mechanisms for explaining opioid inhibition of neurotransmitter release and pain transmission. Opioid receptors couple to an array of second-messenger systems, including activation of MAP kinases and the phospholipase C (PLC)-mediated cascade. Prolonged exposure to opioids results in adaptations at multiple levels within these signaling cascades that may relate to effects such as tolerance, sensitization, and withdrawal.
RECEPTOR DESENSITIZATION, INTERNALIZATION, AND SEQUESTRATION AFTER CHRONIC EXPOSURE TO OPIOIDS
Tolerance refers to a decrease in effectiveness of a drug with its repeated administration (see Chapter 23). Transient administration of opioids leads to a phenomenon called acute tolerance, whereas sustained administration leads to the development of classical or chronic tolerance. Short-term receptor desensitization, which may underlie the development of tolerance, probably involves phosphorylation of the m and d receptors by PKC. A number of other kinases have been implicated in desensitization, including PKA and p-adrenergic receptor kinase.
Long-term tolerance may be associated with increases in adenylyl cyclase activity—a counter-regulation to the decreased cyclic AMP levels seen after acute opioid administration. Chronic treatment with m-receptor opioids causes superactivation of adenylyl cyclase. This effect is prevented by pretreatment with pertussis toxin, demonstrating involvement of G/o proteins, and also by cotransfection with scavengers of G protein—pgdimers, indicating a role for this complex in superactivation. Recent data, described in the 11th edition of the parent text, argue that opioid tolerance may be related not to receptor desensitization but rather to a lack of desensitization.
Actions and Selectivities of Some Opioids at the Various Opioid Receptor Classes
Receptors m d k
Receptors m d k
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