The Ambiguities of Opioid Tolerance Mechanisms: Barriers to Pain Therapeutics or New Pain Therapeutic Possibilities: Fig. 1.

Abstract

Identification of adaptations to chronic morphine that are causally associated with opioid tolerance formation has long been intensely pursued by the opioid research community. There is an impressive array of components of signaling pathways that are influenced by chronic opioid administration. This underscores the importance to tolerance mechanisms of the complex interplay of cellular adaptations that are downstream from the opioid receptor. A major impetus for this research remains the need to develop opioid agonists that are potent and efficacious activators of analgesic mechanisms without triggering opioid tolerance-producing adaptations. Implicit in most models of opioid tolerance is that their underlying mechanisms are invariant and independent of the system in which they have been observed. Reports that prior acute morphine treatment and pain could influence tolerance mechanisms were not understood on mechanistic levels and, consequently, were not incorporated into commonly used models of opioid tolerance. The recent demonstration that adenylyl cyclase/cAMP-related cellular adaptations to chronic morphine depend on cell state demonstrates that ongoing cell physiology is a critical determinant of tolerance mechanisms. The plasticity and pliability of cellular adaptations that mediate tolerance formation indicate that mechanisms underlying opioid analgesic tolerance could be a moving target. Although this might represent a daunting barrier to developing antitolerance pharmacotherapies, appreciation of this complexity could lead to the development of new pharmacotherapeutic approaches.Of the armamentarium of pharmacological agents available to manage postsurgical and neuropathic pain, morphine and its congeners remain among the most widely employed. Nevertheless, the propensity of narcotics to induce analgesic tolerance (operationally defined as a reduction in responsiveness to an agent after repeated exposure) profoundly limits their therapeutic usefulness. It is not surprising that an enormous research effort has been expended over the years toward elucidating the mechanistic underpinnings of opioid tolerance. A major impetus for this research remains the need to develop opioid agonists that are potent and efficacious activators of analgesic mechanisms without triggering opioid tolerance-producing adaptations. Central to this effort is the identification of tolerance substrates, i.e., adaptations causally associated with tolerance formation, on all organizational and functional levels. In this pursuit, conceptual formulations of tolerance become critical, because they determine the contour map guiding the journey as well as the resting stops that are targeted along the way.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...

Recovery from μ-Opioid Receptor Desensitization after Chronic Treatment with Morphine and Methadone

“…The relatively modest effects on opioid signaling measured at the single cell level are surprising given the profound tolerance that can be observed in various physiological and behavioral assays in vivo following chronic treatment with opioids (Christie 2008; Gintzler and Chakrabarti 2008). These observations suggest that the mechanisms that underlie the development of tolerance to opioids involve cellular adaptive changes that may be subtle but lead to systems level adaptations that can vary considerably depending on the system as well as the agonist under study.…”

“…Conversely, there is about a 4 fold shift in the concentration response curve to normorphine in the guinea pig ileum from morphine treated animals (Chavkin and Goldstein, 1984), yet the constipation induced by morphine is generally resistant to the development of tolerance (Ross et al, 2008). It thus appears that no single adaptive process, or cellular adaptation occurring in any single population of neurons, can account for the full range of behavioral measures that are found following chronic opioid treatment (Christie 2008, Gintzler and Chakrabarti 2008, Kieffer and Evans 2002). …”

Gene knockdown with lentiviral vector‐mediated intrathecal RNA interference of protein kinase C gamma reverses chronic morphine tolerance in rats

“…The mechanism behind morphine tolerance is still unclear. Many factors have been reported to relate to morphine tolerance, such as a change of the descending pain modulatory pathway, receptor desensitization and down‐regulation of opioid functional receptors, release of excitatory neurotransmission and other adaptive changes of cell signaling pathways 7, 10. Interestingly, protein kinase C (PKC), especially the PKCγ isoform, has been reported to play a major role in the changes associated with morphine tolerance 11–15.…”

Morphine Desensitization, Internalization, and Down-Regulation of the μ Opioid Receptor Is Facilitated by Serotonin 5-Hydroxytryptamine2AReceptor Coactivation

“…The analgesic effects of morphine are clearly mediated via the opioid peptide (MOP) receptor because they are absent in animals lacking this G protein-coupled receptor (GPCR) (Matthes et al, 1996). However, despite a vast range of studies that have attempted to understand the molecular basis of tolerance to morphine and that have explored why other agonists that also activate the MOP receptor have different functional profiles, this remains a contentious area generating many, apparently conflicting, views (Gintzler and Chakrabarti, 2008). It was assumed initially that the development of tolerance to morphine would reflect MOP receptor desensitization, which would be anticipated to preclude sustained function (Gainetdinov et al, 2004).…”