Induction of G protein-coupled receptor kinases 2 and 3 contributes to the cross-talk between μ and ORL1 receptors following prolonged agonist exposure
Introduction
μ opioid agonists are the drugs of choice in the management of severe and chronic pain. However, the clinical usefulness of these drugs is limited by the development of tolerance upon chronic administration. Tolerance is manifested as a decrease in potency of the drug, so that progressively larger doses are required to obtain the original level of analgesia. Several mechanisms, involving complex compensatory changes in neuronal plasticity and desensitization of signal transduction cascades, contribute to μ opioid tolerance (Nestler, 1996, Nestler and Aghajanian, 1997). Evidence also has mounted for the involvement of orphanin FQ/nociceptin (OFQ/N) in μ receptor tolerance.
OFQ/N is an endogenous peptide that specifically activates the opioid receptor-like 1 receptor (ORL1) and initiates intracellular events including inhibition of adenylyl cyclase and activation of extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) (Harrison and Grandy, 2000). Several studies suggest that chronic exposure to morphine accentuates the endogenous OFQ/N-ORL1 system as a negative feedback mechanism to antagonize the actions of morphine, leading to tolerance (Yuan et al., 1999, Ueda et al., 2000, Gouarderes et al., 1999). In support of this theory, Tian et al. (1998) showed that intracerebroventricular (i.c.v.) injection of an antibody directed against OFQ/N partially reversed the development of morphine tolerance. Similarly, systemic administration of the ORL1 antagonist, J-113397, attenuated morphine tolerance (Ueda et al., 2000). Moreover, morphine tolerance was partially inhibited in mice lacking the ORL1 receptor gene (Ueda et al., 1997). These studies clearly depict a role for OFQ/N in contributing to morphine tolerance. Conversely, chronic activation of the μ receptor also produces cross-tolerance to the analgesic actions of OFQ/N in vivo (Jhamandas et al., 1998). Though the apparent cross-talk between μ and ORL1 receptor systems may be partially explained by complex neuronal circuitry along the descending analgesic pathway (Pan et al., 2000, Heinricher et al., 1997), recent evidence suggests that heterologous desensitization mechanisms may also play a role (Hawes et al., 1998, Mandyam et al., 2000). Data from electrophysiological studies indicate co-localization of μ and ORL1 receptors in a variety of cell populations within the descending analgesic pathway (Connor et al., 1996a, Connor and Christie, 1998, Heinricher et al., 1997, Vaughan et al., 2001, Pan et al., 2000). Therefore, further investigation of the mechanism and result(s) of μ-ORL1 cross-talk at the cellular level is warranted.
While evidence is still emerging to validate the role of GRKs in regulating ORL1 responsiveness (Mandyam et al., 2002), a plethora of data implicate GRKs in the homologous desensitization of the μ receptor following chronic μ agonist treatment. In vitro studies reveal that overexpression of GRK2 or GRK3 potentiates morphine-induced desensitization of the μ receptor (Zhang et al., 1998, Celver et al., 2001, Kovoor et al., 1998); and blockade of GRK2 activity prevents the development of morphine tolerance (Wang, 2000, Li and Wang, 2001). In fact, GRK2 levels are elevated in rat locus coeruleus and cerebral cortex after chronic morphine (Terwilliger et al., 1994) and sufentanil (Hurle, 2001) treatments.
Many of the chronic opioid-induced changes in expression of cellular proteins result from alterations in gene expression (Nestler and Aghajanian, 1997). ERK1/2 are a class of proteins known to translate extracellular signals into alterations of gene expression (Davis, 1993). Opioid receptor coupling to the ERK1/2 pathway has been extensively reported (for review, see Law et al., 2000, Harrison and Grandy, 2000), and ERK1/2 appear to play an important role in the development of chronic opioid tolerance (Pearson et al., 2000, Ortiz et al., 1995). However, the signaling components that bridge the activation of ERK1/2 to the development of chronic opioid tolerance are not clearly understood. Recently, Thelaide et al. (2002) reported that ERK1/2 control expression of GRK2. We have previously demonstrated the functional coupling of μ and ORL1 receptors to ERK1/2 activation in BE(2)-C and SH-SY5Y human neuroblastoma cell lines (Thakker and Standifer, 2002). Both cell lines endogenously express μ (Standifer et al., 1994, Kazmi and Mishra, 1987) and ORL1 receptors (Mandyam et al., 2000, Connor et al., 1996b), and have been shown to be useful model systems to study μ (Prather et al., 1994, Yu and Sadee, 1988) and ORL1 tolerance (Mandyam et al., 2000, Mathis et al., 2001). In the present study, we illustrate a role for ERK1/2 in mediating GRK2 induction following prolonged stimulation of μ or ORL1 receptors, thus contributing to μ-ORL1 cross-talk.
Section snippets
Materials
The following drugs and materials were purchased from, or kindly provided by, the sources indicated: cell culture media (GibcoBRL, Grand Island, NY); fetal bovine sera, penicillin G and streptomycin sulfate (Atlanta Biologicals, Norcross, GA); [D-Ala2, N-methyl-Phe4, Gly-ol5]-enkephalin (DAMGO), OFQ/N, morphine sulfate and [3H]DAMGO (Research Technology Branch of National Institute on Drug Abuse, Rockville, MD); PD98059 (Cell Signaling Technology, Inc., Beverly, MA); [3H]cAMP (Amersham Life
Cross-talk between μ and ORL1 receptors following their prolonged activation
To evaluate the cross-talk between μ and ORL1 receptors, BE(2)-C and SH-SY5Y cells were stimulated with the μ agonists, DAMGO (1 μM) or morphine (10 μM), or the ORL1 agonist, OFQ/N (0.1 nM), for 24 h. The concentrations used for agonist pretreatment produce maximal activation of ERK1/2 (Thakker and Standifer, 2002) and inhibition of forskolin (10 μM)-stimulated cAMP accumulation (Fig. 1). After extensive washing, cells were re-challenged with increasing concentrations of either DAMGO or OFQ/N
Discussion
Chronic opioid administration results in adaptations not only in the neuronal plasticity but also in the regulation of cellular proteins responsible for opioid tolerance. Intracellular adaptations following chronic morphine exposure include upregulation of GRK, β-arrestin (Terwilliger et al., 1994, Hurle, 2001) and dynamin (Noble et al., 2000). These proteins regulate μ receptor signaling and are implicated in chronic morphine tolerance (Zhang et al., 1998, Whistler and von Zastrow, 1998, Bohn
Acknowledgements
This work was supported by grants from the US Public Health Service (DA10738) and the Texas Advanced Research Program (003652-0114-1999 and 003652-0182-2001) to KMS. The authors gratefully acknowledge the many helpful discussions with Drs. Douglas Eikenburg and Lindsay Schwarz, and the excellent technical assistance of Jennifer Christensen and Hatice Ozsoy.
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