Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons

Abstract

Agonists acting on µ-opioid receptors (MOR) are very effective analgesics but cause tolerance during long-term or repeated exposure. Intensive efforts have been made to find novel opioid agonists that are efficacious analgesics but can elude the signalling events that cause tolerance. µ-Opioid agonists differentially couple to downstream signalling mechanisms. Some agonists, such as enkephalins, D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), methadone and sufentanyl are efficacious at mediating G-protein and effector coupling, as well as triggering MOR regulatory events that include MOR phosphorylation, β-arrestin binding, receptor endocytosis and recycling. By contrast, morphine and closely related alkaloids can mediate efficacious MOR-effector coupling but poorly trigger receptor regulation. Several models have been proposed to relate differential MOR regulation by different opioids with their propensity to cause tolerance. Most are based on dogma that β-arrestin-2 (βarr-2) binding causes MOR desensitization and/or that MOR endocytosis and recycling are required for receptor resensitization. This review will examine some of these notions in light of recent evidence establishing that MOR dephosphorylation and resensitization do not require endocytosis. Recent evidence from opioid-treated animals also suggests that impaired MOR-effector coupling is driven, at least in part, by enhanced desensitization, as well as impaired resensitization that appears to be βarr-2 dependent. Better understanding of how chronic exposure to opioids alters receptor regulatory mechanisms may facilitate the development of effective analgesics that produce limited tolerance.

Figure 1

Previous models to explain how strongly internalizing opioid agonists can proiduc less tolerance than weakly internalizing agonists. (A) Strongly internalizing agonists induce rapid desenisitization of MOR coupling. GRK2-mediated phosphorylation is pivotal for βarr-2 binding and endocytosis, both process that were considered ireversible at the cell surface, so MOR slowly resensitizes over the time course of endocytosis and recycling. (B) With weakly internalizing agonists, MOR desensitizes slowly (accelerated by PKC activity) but accumulates in a phosphorylated desensitized state at the cell surface because it stimulates GRK2 and βarr-2 binding very weakly, so cannot resensitize causing tolerance. As discussed in the text, the crucial assumption that endocytosis (and recycling) is necessary for resensitization is incorrect.

Figure 2

Summary of current evidence for mechanisms of MOR regulation in resensitization and tolerance. (A) Desensitized MOR efficiently resensitizes when GRK2, βarr-2 (k.o.) or dynamin (to block endocytosis directly) are blocked, suggesting that resensitization is very efficient in the absence of endocytosis. Directly blocking endocytosis with concanavalin-A (ConA) does not affect resensitization or dephosphorylation of MOR. (B) After chronic morphine treatment, desensitization is enhanced, and resensitization is blocked. This does not appear to involve changes in endocytosis, but impaired resesnitization is restored to control rates by inhibiting GRK2, βarr-2 or dynamin.