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

Abstract

Agonists acting on m-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. m-Opioid agonists differentially couple to downstream signalling mechanisms. Some agonists, such as enkephalins, ,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, b-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 b-arrestin-2 (barr-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 barr-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. LINKED ARTICLESThis IntroductionOpioids are potent and effective analgesics. It is well established that nearly all clinically used opioids mediate their analgesic effects by activating the m-opioid receptor (MOR; Kieffer and Gaveriaux-Ruff, 2002). However, long-term use of m-opioid agonists produces adverse effects that include the development of tolerance and addiction, limiting their clinical utility (Williams et al., 2001;Christie, 2008;Morgan and Christie, 2011). Qualitatively, all MOR agonists produce tolerance in vivo although there are differences in the extent of tolerance (Morgan and Christie, 2011), suggesting that opioid analgesics resistant to tolerance could be developed. Recent promising approaches to limit tolerance have been extensively reviewed and include simultaneous activation of more than one opioid receptor type (e.g. MOR and DOR receptors), selective targeting of heteromultimers or opioids that differentially activate distinct intracellular signalling cascades, possibly involving differential activation of Ga subtypes (Pineyro and Archer-Lahlou, 2007), and particularly differential G-protein activation versus endocytosis (e.g. Martini and Whistler, 2007;Christie, 2008;Koch and Hollt, 2008;Berger and Whistler, 2010;von Zastrow, 2010). BJPBritish Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 1704 British Journal of Pharmac...

GRK2 Protein-mediated Transphosphorylation Contributes to Loss of Function of μ-Opioid Receptors Induced by Neuropeptide FF (NPFF2) Receptors

“…However, in contrast to morphine-induced modification of Ser-375 and desensitization, which were shown to be persistent (37), the Ser-377 phosphorylation and MOP receptor desensitization induced by 1DMe were transient (return to basal after 1 h, Fig. 2, B and D), confirming the recent observation that MOP receptor endocytosis and recycling are not necessary for dephosphorylation and resensitization (3,38). This also suggests that, while sharing a common initial step, 1DMe effect on opioid signaling is of short duration, whereas morphine can induce prolonged alterations in receptor signaling and trafficking likely to contribute to tolerance (3).…”

“…The absence of co-internalization suggests that the interaction between the two receptors is transient or, in contrast, that the dimer is resistant to internalization, as recently observed for angiotensin AT1-AT2 receptor complexes, specifically visualized by BiFC (70). ␤-Arrestin is a major partner for desensitization and internalization (3,44). Its interaction with GPCRs is regulated by receptor phosphorylation, but it also highly depends on receptor-active conformation (71).…”

Endocytic Profiles ofδ-Opioid Receptor Ligands Determine the Duration of Rapid but Not Sustained cAMP Responses

“…This is not altogether surprising given that the further downstream in the signaling pathway modulatory factors that are independent of receptorligand interaction are progressively recruited. As a consequence, downstream readouts such as cAMP levels are expected to be weaker predictors of the regulation that takes place at the receptor level (Dang and Christie, 2012).…”

Agonist Binding and Desensitization of the μ-Opioid Receptor Is Modulated by Phosphorylation of the C-Terminal Tail Domain

“…Canonically, phosphorylation of the C-terminal tail of MOPr leads to recruitment of the b-arrestin protein to the receptors, interrupting G protein-mediated signaling and promoting receptor internalization (Gainetdinov et al, 2004). Loss of b-arrestin-2, however, does not abolish desensitization of G protein signaling, suggesting that perhaps other mechanisms exist to induce acute desensitization (Dang et al, 2009;Quillinan et al, 2011;Dang and Christie, 2012). Additionally, there are multiple possible phosphorylation sites in the C-terminal tail of MOPr, many of which are not directly involved in b-arrestin recruitment.…”