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PERSPECTIVES IN PHARMACOLOGY
Department of Biochemistry, State University of New York, Downstate Medical Center, Brooklyn, New York
Received for publication
January 23, 2008
Accepted
March 18, 2008.
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Abstract |
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It is certainly humbling to recognize that the search for nontolerance-forming potent narcotic analgesics, alone or in combination with adjunctive pharmacotherapy, has been ongoing for at least the past 50 years without notable success. Moreover, this failure has occurred in the face of huge advances in our molecular and cellular knowledge of opioid receptors and the cell signaling pathways that are activated by them. This could indicate that opioid analgesic and tolerance mechanisms are so inextricably intertwined that they cannot be differentially targeted. Alternatively, our conceptual models of tolerance might not be sufficiently inclusive to provide the perspectives needed to develop opioid-based medications with which to treat pain in the absence of tolerance.
This perspective will advance the concept that models of tolerance need to embrace the influence of ongoing physiological state on opioid tolerance mechanisms that are utilized. Because this article is not intended to be a review, aspects of opioid tolerance have been selected that advance the idea that opioid tolerance mechanisms are pliable and context-dependent.
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Cellular Tolerance versus Adaptations Involving Neuronal Networks |
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). This illustrates the important consideration that chronic morphine can induce tolerance adaptations in neurons that do not bear opioid receptors, which might amplify or compensate for the consequences of cellular adaptations that occur within individual neurons. This greatly complicates the generation of tolerance models of translational utility. This notwithstanding, delineation of cellular adaptations to chronic morphine enables the identification of putative pharmacologic cellular targets for the amelioration of tolerance development. It also can facilitate the development of organizing concepts and principals that would apply to chronic morphine-induced adaptations on cellular as well as network organizational levels. |
Translational Utility of Tolerance Models |
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), whereas adaptations involving up-regulation of the adenylyl cyclase (AC) cascade requires hours for full manifestation (Nestler et al., 1994; Nestler and Aghajanian, 1997). Yet another proposed adaptation to chronic morphine that is heterologous and that has a much more delayed onset involves down-regulation of the sodium pump and a reduction in its electrogenic contribution to membrane potential (Fleming, 1999). The existence of i) multiple organizational levels on which opioid tolerance can occur and ii) multiplicity of functions influenced by opioids require that mechanistic models attempting to define tolerance be appropriately constrained and qualified in relationship to the system under study. |
Impairment of Opioid Receptor Functionality |
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), increased opioid receptor internalization (Bohn et al., 2000), decreased opioid receptor density (Chakrabarti et al., 1995), and altered content of G proteins (Ammer and Schulz, 1995). A pivotal aspect of such models is the enhanced phosphorylation of the opioid receptor via G protein receptor kinase that accompanies its activation and is a prelude to it forming a complex with β-arrestin (Pei et al., 1995; Kovoor et al., 1997; Appleyard et al., 1999). This results in its targeting to clathrin-coated pits, G protein uncoupling, and its subsequent internalization and intracellular trafficking to subcellular compartments, e.g., lysozomes where receptor degradation can occur.
These events directly parallel those that have been extensively described for the β2-adrenergic receptor, and they are shared by most, if not all, G protein-coupled receptors (GPCRs). The relevance of these events and models that revolve around them to in vivo pharmacological opioid tolerance is certainly suggested by the coincidence of the temporal characteristics of opioid receptor phosphorylation and G protein uncoupling with the onset of the acute loss of opioid receptor functionality, i.e., receptor desensitization or "acute tolerance" (Zhang et al., 1996; Appleyard et al., 1997). It is important that the above mechanistic formulations of opioid tolerance are invariably thought of as being invariant responses to chronic morphine, independent of ongoing physiological state.
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Post-Opioid Receptor Adaptations to Chronic Morphine |
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; Nestler and Tallman, 1988; Guitart and Nestler, 1989; Lane-Ladd et al., 1997; Kim et al., 2006) and protein kinase C (PKC) (Mao et al., 1995; Mayer et al., 1995; Narita et al., 1995; Wang et al., 1996; Wei and Roerig, 1998; Zeitz et al., 2001) signaling pathways. More recently, chronic morphine was shown to up-regulate specific AC isoforms (Chakrabarti et al., 1998a; Rivera and Gintzler, 1998), increase phosphorylation of AC (Chakrabarti et al., 1998b) and the Gβ subunit of G proteins (Chakrabarti et al., 2005b), and increase association of the µ-opioid receptor (MOR) with Gs (Chakrabarti et al., 2005a; Chakrabarti and Gintzler, 2007). It is noteworthy that all of these adaptations not only occur concomitantly but also have convergent signaling consequences; in the aggregate, they shift acute MOR-coupled signaling from AC inhibitory to stimulatory (Gintzler and Chakrabarti, 2006). These cellular adaptations to long-term morphine underscores that at least a subset of tolerance mechanisms does not cause the loss of opioid receptor functionality but rather the alteration of the consequences of opioid receptor activation. This is very revealing because it indicates that the protective function served by opioid tolerance formation, i.e., the reinstatement of initial steady-state conditions, does not result solely from unidirectional adaptations, e.g., restricted opioid receptor functionality but from the active assertion of compensatory opioid receptor-coupled cell signaling strategies.
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Opioid Receptor Pleiotropy and Duality of Signaling |
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) and the duality of G protein signaling via the G
and Gβ
subunits (tolerance-associated enhanced AC Gβ stimulatory AC signaling) (Chakrabarti et al., 1998a) are both recruited in response to persistent opioid receptor activation. GPCR pleiotropy and duality of G protein subunit signaling are pillars of cell signaling plasticity and underlie much of the richness and diversity of signaling that is characteristic of GPCRs. Thus, it should not be surprising that they also underlie many of the cellular adaptations that enable cell survival in the face of prolonged opioid exposure. Chronic morphine-induced enhanced opioid receptor pleiotropy and duality of signaling enable opioid tolerance mechanisms to be pliable, as reflected by the shift in MOR-coupled signaling from Gi/Go inhibitory to Gs /Gβ stimulatory AC signaling (Gintzler and Chakrabarti, 2006). This multidimensionality of cellular adaptations to long-term morphine treatment demands the development of mechanistic models of opioid tolerance that include a much broader spectrum of adaptational mechanisms than has thus far been the case if they are to be medicinally relevant. |
Influence of Prior Treatment on Spinal Opioid Tolerance and Addiction |
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). More recently (Lim et al., 2005), it was shown that the rate of onset and the magnitude of antinociceptive tolerance increase with serial intrathecal morphine injections. The authors suggest that repeated cycles of morphine exposure produce sustained changes in the spinal cord that modulate the development of opioid tolerance to subsequent morphine exposure. The demonstration that prior history of morphine-induced plasticity can influence the magnitude of subsequently observed tolerance adaptations can be construed to indicate that at least some of the adaptations to chronic morphine are not set in stone and in fact resonate with evolving physiological state. However, in the absence of any formal direct demonstration of this concept, these phenomena remained an enigma.
Behavioral studies conducted months after opioid withdrawal also support the notion that ongoing physiological state can be a major determinant of addiction predisposition. For example, morphine-dependent rats that had been successfully detoxified and showed no significant signs of morphine dependence consumed significantly larger volumes of morphine solution than opiate naive controls and had recurrence of morphine tolerance and dependence (Dai et al., 1984). Subsequently, it was suggested (Bartoletti et al., 1987) that modification of the neuronal mechanism subserving the excitatory component of the action of opiates by chronic morphine treatment that had occurred months earlier could represent a neurobiological basis for recidivism in addicts. Although the mechanisms responsible for the pliability of opioid responsiveness have remained unidentified, such observations further support the notion of the state dependence of the processes of tolerance and dependence.
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Dependence of Cellular Opioid Tolerance Mechanisms on Cell State |
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).
This notion was directly put to the test by comparing AC/cAMP-related adaptations to long-term morphine treatment among Chinese hamster ovary cells (CHO) stably expressing MOR (MOR-CHO) and MOR-CHO overexpressing either AC2 (AC2-MOR-CHO) or AC1 (AC1-MOR-CHO). These cells manifest qualitatively opposite consequences of acute MOR activation as a result of differences in the relative abundance of specific AC isoforms (Federman et al., 1992; Tsu et al., 1995; Yoshimura et al., 1996) that are differentially regulated by Gβ (Tang and Gilman, 1991).
The qualitative difference in the consequences of acute MOR activation (AC inhibition versus stimulation) has a profound effect on the manifestation of multiple, complementary AC-related adaptations to chronic morphine, many of which are diametrically opposite (Shy et al., 2008). It is striking that none of the AC/cAMP-related adaptations to chronic morphine observed in MOR-CHO and AC1-MOR-CHO (increased AC and Gβ phosphorylation, membrane protein kinase C translocation and MOR Gs association (Chakrabarti et al., 1998b, 2005a,b; Chakrabarti and Gintzler, 2003) is observed in AC2-MOR-CHO. Instead, overexpression of AC2 negates the increment in Gβ phosphorylation and PKC translocation and reverses the increment in AC phosphorylation and MOR Gs association to a decrement (Shy et al., 2008).
These experiments formally tested the inter-relatedness of tolerance adaptations and cell state. Results directly demonstrate that adaptational strategies in the AC/cAMP signaling pathway elicited by chronic morphine are not hard-wired but instead are conditional on cell state. In this particular case, the default acute responsiveness of cells to MOR activation is a determinant of the mechanisms harnessed by cells to cope with the persistent activation of MOR. In cells in which acute MOR activation inhibits AC activity (MOR-CHO, AC1-MOR-CHO; Fig. 1, left), chronic morphine elicits adaptations that augment a stimulatory arm of MOR-G protein coupling. In contrast, in cells manifesting acute stimulatory AC responsiveness to MOR (AC2-MOR-CHO; Fig. 1, right), the same treatment with morphine elicits adaptations that enhance AC inhibitory responsiveness. It is noteworthy that the substrates for tolerance formation remain the same but are differentially modulated. This underscores the plasticity of the cellular adaptations that mediate tolerance formation and provide a cellular basis for inferences to that effect drawn from much earlier behavioral studies.
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Relevance to CNS |
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; Glatt and Snyder, 1993; Mons et al., 1993; Cali et al., 1994; Mons and Cooper, 1994). Consequently, nuanced differences in the state of cells present would probably occur, particularly after chronic morphine, because many of the AC isoforms are differentially regulated by chronic opioid administration (Avidor-Reiss et al., 1997). Thus, the plasticity of adaptations related to AC/cAMP signaling in cells maintained in culture would seem to be applicable to the CNS. |
Translational Utility of Pliability of Tolerance Mechanisms |
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), altered association/activity of regulators of G protein signaling proteins] needs to be determined on all organizational and functional levels. This notwithstanding, a picture is emerging that suggests that opioid tolerance mechanisms represent a moving target. In the end, attempts to define a complete set of tolerance substrates may be successful. However, the nature of their modulation as well as altered interactions and functionality would seem to define a continuum of multidirectional changes rather than a rigid predetermined grid. |
Future Challenges and Clinical Implications |
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). Likewise, intrathecal opioid therapy was found to be effective in the management of chronic noncancer pain, which was not inhibited by the development of tolerance (Roberts et al., 2001). Analogous results had been obtained in preclinical rat studies in which the analgesic action of the continuous systemic application of morphine on chronic thermal hyperalgesia due to sciatic constriction injury was unabated after 7 days, which is considered long-term for animal models (Backonja et al., 1995). It is noteworthy that studies using mice and a chronic inflammatory pain model demonstrated an opposite effect on tolerance development and that tolerance development could be modulated by an interaction between chronic inflammatory pain and genetics (Liang et al., 2006). At present, there is no mechanistic understanding of attenuated opioid tolerance development in some pain states. A complete understanding of the ways in which ongoing physiological state can influence opioid tolerance mechanisms could prove to be useful in identifying unique physiological parameters of painful states that are causally associated with diminished tolerance and a biochemical basis for this interaction. Validation of the generality of the perspective that opioid tolerance mechanisms are plastic certainly would represent a major paradigm shift that, on the surface, would make even more daunting attempts to develop pharmacological strategies that would eliminate or at least markedly attenuate opioid tolerance formation. However, realization of the pliability of opioid tolerance mechanisms could also open new possibilities. It could suggest the utility of developing antitolerance pharmacotherapies that target a very restricted CNS region, which is essential for opioid antinociception and contains cells using a homogeneous set of tolerance adaptations. The unfolding increasing complexity of opioid tolerance represents a panoply of pharmacologic possibilities with which to play.
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Footnotes |
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ABBREVIATIONS: AC, adenylyl cyclase; GPCR, G protein-coupled receptor; MOR, µ-opioid receptor; MOR-CHO, Chinese hamster ovary cells stably expressing µ-opioid receptor; AC1-MOR-CHO, MOR-CHO overexpressing AC1; AC2-MOR-CHO, MOR-CHO overexpressing AC2; PKC, protein kinase C; CNS, central nervous system.
Address correspondence to: Dr. Alan Gintzler, Dept. of Biochemistry, SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203. E-mail: alan.gintzler{at}downstate.edu
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Abstract
Cellular Tolerance versus...