Constitutive μ-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence

Corder, Gregory; Doolen, Suzanne; Donahue, Renée R.; Winter, Michele K; Jutras, Brandon L.; Hé, Ying; Hu, Xiaoyu; Wieskopf, Joseph S; Mogil, Jeffrey S.; Storm, Daniel R.; Wang, Z J; McCarson, Kenneth E.; Taylor, Bradley K.

doi:10.1126/science.1239403

Cited by 206 publications

(407 citation statements)

References 78 publications

(70 reference statements)

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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: 49%

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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Section: Discussionmentioning

confidence: 49%

Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons

Sullivan

Chavera

Jamshidi

et al. 2016

J Pharmacol Exp Ther

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“…Coadministration of L-THP with LDN prevented the reduction of locomotion produced by L-THP alone; yet LDN alone did not alter locomotor behavior at such a low dose, suggesting that LDN coadministration may block the sedative effects of L-THP. This effect may be mediated through brief opioid receptor antagonism leading to a transient b-endorphin release (Corder et al, 2013). In turn, the b-endorphin induces the release of DA in the nucleus accumbens via activation of m-opioid receptors on GABAergic neurons that inhibits ventral tegmental area GABAergic neurons (Simmons and Self, 2009;Spanagel et al1991), resulting in the overall increase of spontaneous locomotion.…”

Section: Discussionmentioning

confidence: 99%

Combination of Levo-Tetrahydropalmatine and Low Dose Naltrexone: A Promising Treatment for Prevention of Cocaine Relapse

Sushchyk

Wang

2016

Journal of Pharmacology and Experimental Therapeutics

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Relapse to drug use is often cited as the major obstacle in overcoming a drug addiction. Whereas relapse can occur for a myriad of reasons, it is well established that complex neuroadaptations that occur over the course of addiction are major factors. Cocaine, as a potent dopamine transporter blocker, specifically induces alterations in the dopaminergic as well as other monoaminergic neurotransmissions, which lead to cocaine abuse and dependence. Evidence also suggests that adaptations in the endogenous opioids play important roles in pathophysiology of cocaine addiction. Following this evidence, we investigated a combination medication, levotetrahydropalmatine (L-THP) and low dose naltrexone (LDN), targeting primarily dopaminergic and endogenous opioid systems as a cocaine-relapse-prevention treatment. In the present study Wistar rats were used to assess the effects of L-THP and LDN on cocaine self-administration, drug-seeking behavior during cocaine reinstatement, spontaneous locomotion, and effects on the endogenous opioid system. We determined that the combination of L-THP and LDN reduces drug-seeking behavior during reinstatement more potently than L-THP alone. Additionally, the combination of L-THP and LDN attenuates the sedative locomotor effect induced by L-THP. Furthermore, we revealed that treatment with the combination of L-THP and LDN has an upregulatory effect on both plasma b-endorphin and hypothalamic POMC that was not observed in L-THP-treated groups. These results suggest that the combination of L-THP and LDN has great potential as an effective and well-tolerated medication for cocaine relapse prevention.

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“…Infants treated in a neonatal intensive care unit sustain repetitive tissue injuries due to essential medical interventions (Stevens et al, 2003;Carbajal et al, 2008). Emerging clinical evidence suggests that such interventions evoke long-term increases in pain sensitivity in response to prolonged or repeated noxious stimulation (Hermann et al, 2006;Hohmeister et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Emerging clinical evidence suggests that such interventions evoke long-term increases in pain sensitivity in response to prolonged or repeated noxious stimulation (Hermann et al, 2006;Hohmeister et al, 2010). In addition, preclinical studies have demonstrated that tissue damage during a critical period of early life leads to an exacerbated degree of pain hypersensitivity after repeat injury during adulthood (Ren et al, 2004;Hohmann et al, 2005;Chu et al, 2007;Walker et al, 2009;Beggs et al, 2012) provided that the second insult occurs within the same area as the initial trauma (Ren et al, 2004;Chu et al, 2007). Collectively, these findings suggest that neonatal tissue damage causes a localized "priming" of adult spinal pain circuits that contributes to an exaggerated response to future noxious stimulation.…”

Section: Introductionmentioning

confidence: 99%

Neonatal Tissue Damage Promotes Spike Timing-Dependent Synaptic Long-Term Potentiation in Adult Spinal Projection Neurons

Baccei

2016

J. Neurosci.

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Mounting evidence from both humans and rodents suggests that tissue damage during the neonatal period can "prime" developing nociceptive pathways such that a subsequent injury during adulthood causes an exacerbated degree of pain hypersensitivity. However, the cellular and molecular mechanisms that underlie this priming effect remain poorly understood. Here, we demonstrate that neonatal surgical injury relaxes the timing rules governing long-term potentiation (LTP) at mouse primary afferent synapses onto mature lamina I projection neurons, which serve as a major output of the spinal nociceptive network and are essential for pain perception. In addition, whereas LTP in naive mice was only observed if the presynaptic input preceded postsynaptic firing, early tissue injury removed this temporal requirement and LTP was observed regardless of the order in which the inputs were activated. Neonatal tissue damage also reduced the dependence of spike-timing-dependent LTP on NMDAR activation and unmasked a novel contribution of Ca 2ϩ -permeable AMPARs. These results suggest for the first time that transient tissue damage during early life creates a more permissive environment for the production of LTP within adult spinal nociceptive circuits. This persistent metaplasticity may promote the excessive amplification of ascending nociceptive transmission to the mature brain and thereby facilitate the generation of chronic pain after injury, thus representing a novel potential mechanism by which early trauma can prime adult pain pathways in the CNS.

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Constitutive μ-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence

Cited by 206 publications

References 78 publications

Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons

Constitutive Desensitization of Opioid Receptors in Peripheral Sensory Neurons

Combination of Levo-Tetrahydropalmatine and Low Dose Naltrexone: A Promising Treatment for Prevention of Cocaine Relapse

Neonatal Tissue Damage Promotes Spike Timing-Dependent Synaptic Long-Term Potentiation in Adult Spinal Projection Neurons

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