Abstract Stress is a complex experience that carries both aversive and motivating properties. Chronic stress causes an increase in the risk of depression, is well known to increase relapse of drug ...seeking behavior, and can adversely impact health. Several brain systems have been demonstrated to be critical in mediating the negative affect associated with stress, and recent evidence directly links the actions of the endogenous opioid neuropeptide dynorphin in modulating mood and increasing the rewarding effects of abused drugs. These results suggest that activation of the dynorphin/kappa opioid receptor (KOR) system is likely to play a major role in the pro-addictive effects of stress. This review explores the relationship between dynorphin and corticotropin-releasing factor (CRF) in the induction of dysphoria, the potentiation of drug seeking, and stress-induced reinstatement. We also provide an overview of the signal transduction events responsible for CRF and dynorphin/KOR-dependent behaviors. Understanding the recent work linking activation of CRF and dynorphin/KOR systems and their specific roles in brain stress systems and behavioral models of addiction provides novel insight to neuropeptide systems that regulate affective state.
Endogenous and Exogenous Opioids in Pain Corder, Gregory; Castro, Daniel C; Bruchas, Michael R ...
Annual review of neuroscience,
07/2018, Letnik:
41, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act ...on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.
The nucleus accumbens (NAc) and the dynorphinergic system are widely implicated in motivated behaviors. Prior studies have shown that activation of the dynorphin-kappa opioid receptor (KOR) system ...leads to aversive, dysphoria-like behavior. However, the endogenous sources of dynorphin in these circuits remain unknown. We investigated whether dynorphinergic neuronal firing in the NAc is sufficient to induce aversive behaviors. We found that photostimulation of dynorphinergic cells in the ventral NAc shell elicits robust conditioned and real-time aversive behavior via KOR activation, and in contrast, photostimulation of dorsal NAc shell dynorphin cells induced a KOR-mediated place preference and was positively reinforcing. These results show previously unknown discrete subregions of dynorphin-containing cells in the NAc shell that selectively drive opposing behaviors. Understanding the discrete regional specificity by which NAc dynorphinerigic cells regulate preference and aversion provides insight into motivated behaviors that are dysregulated in stress, reward, and psychiatric disease.
•Optogenetic excitation of nucleus accumbens dynorphin cells elicits dynorphin release•Discrete accumbens shell dynorphinergic populations drive either aversion or reward•These two nucleus accumbens subregions can be bi-directionally controlled•Both aversive and rewarding behaviors require kappa opioid receptors
Al-Hasani et al. show that dynorphin is necessary to drive opposing motivational states within subregions of the nucleus accumbens shell. Dynorphinergic neurons in the ventral shell drive aversion whereas in the dorsal shell they drive preference and reward seeking.
Negative affective states affect quality of life for patients suffering from pain. These maladaptive emotional states can lead to involuntary opioid overdose and many neuropsychiatric comorbidities. ...Uncovering the mechanisms responsible for pain-induced negative affect is critical in addressing these comorbid outcomes. The nucleus accumbens (NAc) shell, which integrates the aversive and rewarding valence of stimuli, exhibits plastic adaptations in the presence of pain. In discrete regions of the NAc, activation of the kappa opioid receptor (KOR) decreases the reinforcing properties of rewards and induces aversive behaviors. Using complementary techniques, we report that in vivo recruitment of NAc shell dynorphin neurons, acting through KOR, is necessary and sufficient to drive pain-induced negative affect. Taken together, our results provide evidence that pain-induced adaptations in the kappa opioid system within the NAc shell represent a functional target for therapeutic intervention that could circumvent pain-induced affective disorders.
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•Pain recruits the dynorphin-kappa opioid receptor system in the nucleus accumbens•Inhibitory inputs onto dynorphin cells are reduced during inflammatory pain•Increase in dynorphin tone mediates inflammatory pain-induced negative affect
Massaly et al. identify a pain-induced enhancement in the kappa opioid system within nucleus accumbens, which drives pain-associated negative emotional states. These results provide a functional substrate for therapies that would circumvent pain-induced affective disorders.
Ligand-directed signaling has been suggested as a basis for the differences in responses evoked by otherwise receptor-selective agonists. The underlying mechanisms are not understood, yet clearer ...definition of this concept may be helpful in the development of novel, pathway-selective therapeutic agents. We previously showed that κ-opioid receptor activation of JNK by one class of ligand, but not another, caused persistent receptor inactivation. In the current study, we found that the μ-opioid receptor (MOR) could be similarly inactivated by a specific ligand class including the prototypical opioid, morphine. Acute analgesic tolerance to morphine and related opioids (morphine-6-glucuronide and buprenorphine) was blocked by JNK inhibition, but not by G protein receptor kinase 3 knockout. In contrast, a second class of μ-opioids including fentanyl, methadone, and oxycodone produced acute analgesic tolerance that was blocked by G protein receptor kinase 3 knockout, but not by JNK inhibition. Acute MOR desensitization, demonstrated by reduced D-Ala²-Met⁵-Glyol-enkephalin—stimulated ³⁵SGTPγS binding to spinal cord membranes from morphine-pretreated mice, was also blocked by JNK inhibition; however, desensitization of D-Ala²-Met⁵-Glyol-enkephalin—stimulated ³⁵SGTPγS binding following fentanyl pretreatment was not blocked by JNK inhibition. JNK-mediated receptor inactivation of the κ-opioid receptor was evident in both agonist-stimulated ³⁵SGTPγS binding and opioid analgesic assays; however, gene knockout of JNK 1 selectively blocked κ-receptor inactivation, whereas deletion of JNK 2 selectively blocked MOR inactivation. These findings suggest that ligand-directed activation of JNK kinases may generally provides an alternate mode of G protein—coupled receptor regulation.
Food palatability is one of many factors that drives food consumption, and the hedonic drive to feed is a key contributor to obesity and binge eating. In this study, we identified a population of ...prepronociceptin-expressing cells in the central amygdala (PnocCeA) that are activated by palatable food consumption. Ablation or chemogenetic inhibition of these cells reduces palatable food consumption. Additionally, ablation of PnocCeA cells reduces high-fat-diet-driven increases in bodyweight and adiposity. PnocCeA neurons project to the ventral bed nucleus of the stria terminalis (vBNST), parabrachial nucleus (PBN), and nucleus of the solitary tract (NTS), and activation of cell bodies in the central amygdala (CeA) or axons in the vBNST, PBN, and NTS produces reward behavior but did not promote feeding of palatable food. These data suggest that the PnocCeA network is necessary for promoting the reinforcing and rewarding properties of palatable food, but activation of this network itself is not sufficient to promote feeding.
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•PnocCeA neurons are activated following palatable food consumption•PnocCeA neurons promote palatable food consumption specifically•PnocCeA neuronal projections in the CeA, vBNST, PBN, and NTS promote reward
Eating calorically dense, palatable foods is a major contributor to obesity and binge eating. In this article, Hardaway et al. identify a central amygdala brain circuit expressing the neuropeptide prepronociceptin in mice that promotes palatable food consumption and reward.
Agonists of the nociceptin/orphanin FQ opioid peptide (NOP) receptor, a member of the opioid receptor family, are under active investigation as novel analgesics, but their modes of signaling are less ...well characterized than those of other members of the opioid receptor family. Therefore, we investigated whether different NOP receptor ligands showed differential signaling or functional selectivity at the NOP receptor. Using newly developed phosphosite-specific antibodies to the NOP receptor, we found that agonist-induced NOP receptor phosphorylation occurred primarily at four carboxyl-terminal serine (Ser) and threonine (Thr) residues, namely, Ser
, Ser
, Thr
, and Ser
, and proceeded with a temporal hierarchy, with Ser
as the first site of phosphorylation. G protein-coupled receptor kinases 2 and 3 (GRK2/3) cooperated during agonist-induced phosphorylation, which, in turn, facilitated NOP receptor desensitization and internalization. A comparison of structurally distinct NOP receptor agonists revealed dissociation in functional efficacies between G protein-dependent signaling and receptor phosphorylation. Furthermore, in NOP-eGFP and NOP-eYFP mice, NOP receptor agonists induced multisite phosphorylation and internalization in a dose-dependent and agonist-selective manner that could be blocked by specific antagonists. Our study provides new tools to study ligand-activated NOP receptor signaling in vitro and in vivo. Differential agonist-selective NOP receptor phosphorylation by chemically diverse NOP receptor agonists suggests that differential signaling by NOP receptor agonists may play a role in NOP receptor ligand pharmacology.
Abstract Phosphorylation of specific sites in the second intracellular loop and in the C-terminal domain have previously been suggested to cause desensitization and internalization of the mu-opioid ...receptor (MOP-R). To assess sites of MOP-R phosphorylation in vivo , affinity-purified, phosphoselective antibodies were raised against either phosphothreonine-180 in the second intracellular loop (MOR-P1) or the C-terminal domain of MOP-R containing phosphothreonine-370 and phosphoserine-375 (MOR-P2). We found that MOR-P2-immunoreactivity (IR) was significantly increased within the striatum of wild-type C57BL/6 mice after injection of the agonist fentanyl. Pretreatment with the antagonist naloxone blocked the fentanyl-induced increase. Furthermore, mutant mice lacking MOP-R showed only non-specific nuclear MOR-P2-IR before or after fentanyl treatment, confirming the specificity of the MOR-P2 antibodies. To assess whether MOP-R phosphorylation occurs following endogenous opioid release, we induced chronic neuropathic pain by partial sciatic nerve ligation (pSNL), which caused a significant increase in MOR-P2-IR in the striatum. pSNL also induced signs of mu opioid receptor tolerance demonstrated by a rightward shift in the morphine dose response in the tail withdrawal assay and by a reduction in morphine conditioned place preference (CPP). Mutant mice selectively lacking all forms of the β-endorphin peptides derived from the proopiomelanocortin ( Pomc ) gene did not show increased MOR-P2-IR, decreased morphine antinociception, or reduced morphine CPP following pSNL. In contrast gene deletion of either proenkephalin or prodynorphin opioids did not block the effects of pSNL. These results suggest that neuropathic pain caused by pSNL in wild-type mice activates the release of the endogenous opioid β-endorphin, which subsequently induces MOP-R phosphorylation and opiate tolerance.
Effective and safe doses of opiate painkillers, like morphine, can be limited by respiratory depression. Schmid et al. (2017) now present a quantitative method to design ligands and correlate GPCR ...signaling bias to the dose separation between therapeutic and adverse effects in animals.
Effective and safe doses of opiate painkillers, like morphine, can be limited by respiratory depression. Schmid et al. (2017) now present a quantitative method to design ligands and correlate GPCR signaling bias to the dose separation between therapeutic and adverse effects in animals.
Pain Wars: A New Hope Parker, Kyle E.; Bruchas, Michael R.
Neuron,
12/2018, Letnik:
100, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Nociceptin opioid peptide receptor agonists interact with mu-opioid receptor agonists for pain relief. A new study by Ding et al. (2018) examines a bifunctional nociceptin- and mu-opioid receptor ...agonist, AT-121, that provides analgesia without physiological side effects or abuse liability, offering a promising new hope toward better analgesics.
Nociceptin opioid peptide receptor agonists interact with mu-opioid receptor agonists for pain relief. A new study by Ding et al. (2018) examines a bifunctional nociceptin- and mu-opioid receptor agonist, AT-121, that provides analgesia without physiological side effects or abuse liability, offering a promising new hope toward better analgesics.