The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice

Navani, Dipesh; Sirohi, Smita; Madia, Priyanka A.; Yoburn, Byron C.

doi:10.1016/j.pbb.2011.06.025

Cited by 9 publications

(8 citation statements)

References 18 publications

(57 reference statements)

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“…no effect) when administered by itself (Table 2). Furthermore, as expected for an opioid receptor neutral antagonist, 6β-naltrexol blocks the effects of inverse agonists (Wang et al, 1994, Bilsky et al, 1996, Kenakin, 2001, Wang et al, 2004, Raehal et al, 2005, Wang et al, 2007, Sirohi et al, 2009, Sally et al, 2010, Lam et al, 2011, Navani et al, 2011) (Table 2). As described in more detail below, recent data in models of LS describes similar actions of 6β-naltrexol in vivo , when administered to the whole animal (Corder et al, 2013).…”

Section: Mu Opioid Receptor Constitutive Activity (Morca) Inhibits Lsmentioning

confidence: 69%

“…As illustrated in Table 2, cells obtained from whole animal models of opioid dependence, e.g. animals treated for several days with morphine, exhibit key characteristics of constitutive opioid receptor activity upon challenge with NTX (Wang et al, 2001a, Wang et al, 2004, Raehal et al, 2005, Sirohi et al, 2009, Lam et al, 2011, Navani et al, 2011). These results seem to outweigh the more discrepant results obtained from studies in cell culture lines treated in vitro with opioid receptor agonists for a decidedly shorter treatment (overnight); these studies yield evidence both for (Sally et al, 2010) and against (Divin et al, 2009) intrinsic activity of NTX.…”

Section: Mu Opioid Receptor Constitutive Activity (Morca) Inhibits Lsmentioning

confidence: 99%

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Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Taylor

Corder

2014

Current Topics in Behavioral Neurosciences

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Endogenous activation of μ-opioid receptors (MORs) provides relief from acute pain. Recent studies have established that tissue inflammation produces latent pain sensitization (LS) that is masked by spinal MOR signaling for months, even after complete recovery from injury and re-establishment of normal pain thresholds. Disruption with MOR inverse agonists reinstates pain and precipitates cellular, somatic and aversive signs of physical withdrawal; this phenomenon requires N-methyl-D-aspartate receptor-mediated activation of calcium-sensitive adenylyl cyclase type 1 (AC1). In this review, we present a new conceptual model of the transition from acute to chronic pain, based on the delicate balance between LS and endogenous analgesia that develops after painful tissue injury. First, injury activates pain pathways. Second, the spinal cord establishes MOR constitutive activity (MORCA) as it attempts to control pain. Third, over time, the body becomes dependent on MORCA, which paradoxically sensitizes pain pathways. Stress or injury escalates opposing inhibitory and excitatory influences on nociceptive processing as a pathological consequence of increased endogenous opioid tone. Pain begets MORCA begets pain vulnerability in a vicious cycle. The final result is a silent insidious state characterized by the escalation of two opposing excitatory and inhibitory influences on pain transmission: LS mediated by AC1 (which maintains accelerator), and pain inhibition mediated by MORCA (which maintains the brake). This raises the prospect that opposing homeostatic interactions between MORCA analgesia and latent NMDAR–AC1-mediated pain sensitization create a lasting vulnerability to develop chronic pain. Thus, chronic pain syndromes may result from a failure in constitutive signaling of spinal MORs and a loss of endogenous analgesic control. An overarching long-term therapeutic goal of future research is to alleviate chronic pain by either: a) facilitating endogenous opioid analgesia, thus restricting LS within a state of remission; or b) extinguishing LS altogether.

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Section: Mu Opioid Receptor Constitutive Activity (Morca) Inhibits Lsmentioning

confidence: 69%

Section: Mu Opioid Receptor Constitutive Activity (Morca) Inhibits Lsmentioning

confidence: 99%

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Taylor

Corder

2014

Current Topics in Behavioral Neurosciences

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“…If, however, there is constitutive activity of a receptor system in vivo, then it is expected that inverse agonists would produce a greater reduction in a receptor-mediated response (blockade of the endogenous agonist and reduction of constitutive receptor activity) than would a simple antagonist. In opioid-dependent rodents, it has been shown that drugs with inverse agonist properties, such as naloxone and naltrexone, produce greater withdrawal symptoms than do antagonists (e.g., 6b-naltrexol), and the effect of inverse agonists to induce withdrawal is reduced by antagonists (Wang et al, 2001;Raehal et al, 2005;Walker and Sterious, 2005;Sirohi et al, 2009;Navani et al, 2011;Corder et al, 2013). Such results provide strong evidence of functional consequences of opioid receptor constitutive activity in vivo.…”

Section: Discussionmentioning

confidence: 94%

“…Several studies have reported that prolonged exposure to agonists increases MOR and DOR constitutive activity Prather, 2001, 2002;Wang et al, 2007;Divin et al, 2009). This effect has been postulated to play a role in the development of tolerance and dependence that occurs after repeated use of opioids in vivo Prather, 2001, 2002;Raehal et al, 2005;Walker and Sterious, 2005;Divin et al, 2009;Sirohi et al, 2009;Navani et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons

Sullivan

Chavera

Jamshidi

et al. 2016

J Pharmacol Exp Ther

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Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions; however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a nonresponsive state to a functionally competent state. Here we tested the hypothesis that the basal, nonresponsive state of the mu-and delta-opioid receptors (MOR and DOR, respectively) is the result of constitutive receptor activity that activates desensitization mechanisms, resulting in MOR and DOR receptor systems that are constitutively desensitized. ]-enkephalin, inhibited prostaglandin E 2 (PGE 2 )-stimulated cAMP accumulation in peripheral sensory neurons in culture (ex vivo) or inhibited PGE 2 -stimulated thermal allodynia in the rat hind paw in vivo. Prolonged treatment with naloxone induced MOR and DOR responsiveness both in vivo and ex vivo to a similar magnitude as that produced by bradykinin. Also similar to bradykinin, the effect of naloxone persisted for 60 minutes after washout of the ligand. By contrast, prolonged treatment with 6b-naltrexol, did not induce functional competence of MOR or DOR but blocked the effect of naloxone. Treatment with siRNA for b-arrestin-2, but not b-arrestin-1, also induced MOR and DOR functional competence in cultured peripheral sensory neurons. These data suggest that the lack of responsiveness of MOR and DOR to agonist for antinociceptive signaling in peripheral sensory neurons is due to constitutive desensitization that is likely mediated by b-arrestin-2.

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“…As illustrated in Table 2, cells obtained from whole animal models of opioid dependence, e.g., animals treated for several days with morphine, exhibit key characteristics of constitutive opioid receptor activity upon challenge with NTX (Wang et al 2001aRaehal et al 2005;Sirohi et al 2009;Lam et al 2011;Navani et al 2011). As illustrated in Table 2, cells obtained from whole animal models of opioid dependence, e.g., animals treated for several days with morphine, exhibit key characteristics of constitutive opioid receptor activity upon challenge with NTX (Wang et al 2001aRaehal et al 2005;Sirohi et al 2009;Lam et al 2011;Navani et al 2011).…”

Section: Naltrexone As An Inverse Agonistmentioning

confidence: 99%

Behavioral Neurobiology of Chronic Pain

Taylor¹,

Finn²

2014

Current Topics in Behavioral Neurosciences

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Current Topics in Behavioral Neurosciences provides critical and comprehensive discussions of the most significant areas of behavioral neuroscience research, written by leading international authorities. Each volume offers an informative and contemporary account of its subject, making it an unrivalled reference source. Titles in this series are available in both print and electronic formats.With the development of new methodologies for brain imaging, genetic and genomic analyses, molecular engineering of mutant animals, novel routes for drug delivery, and sophisticated cross-species behavioral assessments, it is now possible to study behavior relevant to psychiatric and neurological diseases and disorders on the physiological level. The Behavioral Neurosciences series focuses on ''translational medicine'' and cutting-edge technologies. Preclinical and clinical trials for the development of new diagnostics and therapeutics as well as prevention efforts are covered whenever possible.More information about this series at

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The role of opioid antagonist efficacy and constitutive opioid receptor activity in the opioid withdrawal syndrome in mice

Cited by 9 publications

References 18 publications

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons

Behavioral Neurobiology of Chronic Pain

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