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Chronic pain is a common neurological disease involving lasting, multifaceted maladaptations ranging from gene modulation to synaptic dysfunction and emotional disorders. Sustained pathological stimuli in many diseases alter the output activities of certain genes through epigenetic modifications, but it is unclear how epigenetic mechanisms operate in the development of chronic pain. We show here that in the rat brainstem nucleus raphe magnus, which is important for central mechanisms of chronic pain, persistent inflammatory and neuropathic pain epigenetically suppresses Gad2 (encoding glutamic acid decarboxylase 65 (GAD65)) transcription through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in impaired g-aminobutyric acid (GABA) synaptic inhibition. Gad2 knockout mice showed sensitized pain behavior and impaired GABA synaptic function in their brainstem neurons. In wild-type but not Gad2 knockout mice, HDAC inhibitors strongly increased GAD65 activity, restored GABA synaptic function and relieved sensitized pain behavior. These findings suggest GAD65 and HDACs as potential therapeutic targets in an epigenetic approach to the treatment of chronic pain., Environmental factors and pathological conditions can result in the alteration of transcription of many genes through modifications of chromatin structure, including DNA methylation and histone acetylation, resulting in stable phenotypes, [...]

Abstract The delta-opioid receptor (DOR) belongs to the superfamily of G-protein-coupled receptors (GPCRs) with seven transmembrane domains, and its membrane trafficking is regulated by intracellular sorting processes involving its C-tail motifs, intracellular sorting proteins, and several intracellular signaling pathways. In the quiescent state, DOR is generally located in the intracellular compartments in central neurons. However, chronic stimulation, such as chronic pain and sustained opioid exposure, may induce membrane trafficking of DOR and its translocation to surface membrane. The emerged functional DOR on cell membrane is actively involved in pain modulation and opioid analgesia. This article reviews current understanding of the mechanisms underlying GPCRs and DOR membrane trafficking, and the analgesic function of emerged DOR through membrane trafficking under certain pathophysiological circumstances.

Abstract Currently, opioid-based drugs are the most effective pain relievers that are widely used in the treatment of pain. However, the analgesic efficacy of opioids is significantly limited by the development of tolerance after repeated opioid administration. Glutamate receptors have been reported to critically participate in the development and maintenance of opioid tolerance, but the underlying mechanisms remain unclear. Using whole-cell voltage-clamp recordings in brainstem slices, the present study investigated chronic morphine-induced adaptations in glutamatergic synaptic transmission in neurons of the nucleus raphe magnus (NRM), a key supraspinal relay for pain modulation and opioid analgesia. Chronic morphine significantly increased glutamate synaptic transmission exclusively in one class of NRM cells that contains μ-opioid receptors in a morphine-tolerant state. The adenylyl cyclase activator forskolin and the cAMP analog 8-bromo-cAMP mimicked the chronic morphine effect in control neurons and their potency in enhancing the glutamate synaptic current was significantly increased in neurons from morphine-tolerant rats. MDL12330a, an adenylyl cyclase inhibitor, and H89, a protein kinase A (PKA) inhibitor, reversed the increase in glutamate synaptic transmission induced by chronic morphine. In addition, PMA, a phorbol ester activator of protein kinase C (PKC), also showed an increased potency in enhancing the glutamate synaptic current in these morphine-tolerant cells. The PKC inhibitor GF109203X attenuated the chronic morphine effect. Taken together, these results suggest that chronic morphine increases presynaptic glutamate release in μ receptor-containing NRM neurons in a morphine-tolerant state, and that the increased glutamate synaptic transmission appears to involve an upregulation of both the cAMP/PKA pathway and the PKC pathway. This glutamate-mediated activation of these NRM neurons that are thought to facilitate spinal pain transmission may contribute to the reduced opioid analgesia during opioid tolerance.

Abstract: Cannabinoid type 2 (CB2) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer''s disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7)—a novel selective CB2 agonist that lacks psychoactivity—on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)1–40 fibrils into the hippocampal CA1 area of rats. In rats injected with Aβ1–40 fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1β, (3) decreased the upsurge of CB2 receptors, (4) promoted Aβ clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer''s disease. [Copyright &y& Elsevier]

Chronic opioid-induced drug dependence and withdrawal syndrome after opioid cessation remain a severe obstacle in clinical treatment of chronic pain and opioid drug addiction. One of the key symptoms during opioid withdrawal is a state of sensitized pain. The most significant molecular adaptation induced by chronic opioids in the brain is upregulation of the cAMP-signaling pathway. Although the cAMP system is known to have multiple effects on central neuron functions, how its upregulation mediates behavioral opioid dependence and withdrawal-induced pain in vivo remains unclear. In this study, we demonstrate that withdrawal from chronic morphine significantly upregulates the mRNA level of adenylyl cyclase (AC) VI and VIII isoforms and immunoreactivity of ACV/VI in the nucleus raphe magnus (NRM), a brainstem site critically involved in opioid modulation of pain. In cellular studies of NRM neurons containing µ-opioid receptors, we show that morphine withdrawal significantly increases glutamate synaptic transmission via a presynaptic mechanism mediated by an upregulated cAMP pathway. Morphine withdrawal also enhances the hyperpolarization-activated current in these neurons by increased intracellular cAMP. Both of the withdrawal-induced cAMP actions increase the excitability of these µ-receptor-containing neurons, which are thought to facilitate spinal pain transmission. Furthermore, in morphine-dependent rats in vivo, blocking the cAMP pathway significantly reduces withdrawal-induced pain sensitization. These results illustrate neurobiological mechanisms for the cAMP-mediated withdrawal pain and provide potential therapeutic targets for the treatment of opioid dependence and withdrawal-related problems. [ABSTRACT FROM AUTHOR]

Examines the ionic basis of the abnormal electrophysiological character of myocytes from the right ventricle of chronic hypoxic guinea pigs. Effect of chronic hypoxia; Role of attenuatement of the outward potassium in the prolongation of the action potential duration; Influence of metabolic changes on phospholyration and dephosphorylation.

Cancer chemotherapy-induced neuropathic pain is a devastating pain syndrome without effective therapies. We previously reported that rats deficient in complement C3, the central component of complement activation cascade, showed a reduced degree of paclitaxel-induced mechanical allodynia (PIMA), suggesting that complement is integrally involved in the pathogenesis of this model. However, the underlying mechanism was unclear. Complement activation leads to the production of C3a, which mediates inflammation through its receptor C3aR1. In this article, we report that the administration of paclitaxel induced a significantly higher expression level of C3aR1 on dorsal root ganglion (DRG) macrophages and expansion of these macrophages in DRGs in wild-type (WT) compared with in C3aR1 knockout (KO) mice. We also found that paclitaxel induced less severe PIMA, along with a reduced DRG expression of transient receptor potential channels of the vanilloid subtype 4 (TRPV4), an essential mediator for PIMA, in C3aR1 KO than in WT mice. Treating WT mice or rats with a C3aR1 antagonist markedly attenuated PIMA in association with downregulated DRG TRPV4 expression, reduced DRG macrophages expansion, suppressed DRG neuron hyperexcitability, and alleviated peripheral intraepidermal nerve fiber loss. Administration of C3aR1 antagonist to TRPV4 KO mice further protected them from PIMA. These results suggest that complement regulates PIMA development through C3aR1 to upregulate TRPV4 on DRG neurons and promote DRG macrophage expansion. Targeting C3aR1 could be a novel therapeutic approach to alleviate this debilitating pain syndrome., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Sorting of intracellular G-protein-coupled receptors (GPCRs) either to lysosomes for degradation or to plasma membrane for surface insertion and functional expression is a key process regulating signaling strength of GPCRs across the plasma membrane in adult mammalian cells. However, little is known about the molecular mechanisms governing the dynamic process of receptor sorting to the plasma membrane for functional expression under normal and pathological conditions. In this study, we demonstrate that delta-opioid receptor (DOPr), a GPCR constitutively targeted to intracellular compartments, is driven to the surface membrane of central synaptic terminals and becomes functional by the neurotrophin nerve growth factor (NGF) in native brainstem neurons. The NGF-triggered DOPr translocation is predominantly mediated by the signaling pathway involving the tyrosine receptor kinase A, Ca(2+)-mobilizing phospholipase C, and Ca(2+)/calmodulin-dependent protein kinase II. Importantly, it requires interactions with the cytoplasmic sorting protein NHERF-1 (Na(+)/H(+) exchange regulatory factor-1) and N-ethyl-maleimide-sensitive factor-regulated exocytosis. In addition, this NGF-mediated mechanism is likely responsible for the emergence of functional DOPr induced by chronic opioids. Thus, NGF may function as a key molecular switch that redirects the sorting of intracellularly targeted DOPr to plasma membrane, resulting in new functional DOPr on central synapses under chronic opioid conditions.

The central nucleus of the amygdala (CeA) plays a critical role in positive emotional responses that involve stimulus-reward learning and are induced by the reinforcing effects of many drugs of abuse, including alcohol. Behavioral studies have implicated CeA as a key brain structure in alcohol reward, but the underlying mechanisms are still poorly understood. Recent studies have demonstrated that both NMDA and non-NMDA receptors in CeA neurons are targets of acute and chronic alcohol in naive and alcohol-dependent animals. However, little is known about the role of CeA non-NMDA receptors in synaptic actions of alcohol and, particularly, in the behavior of alcohol reward. In the present study with both whole-cell voltage-clamp recordings in CeA slices in vitro and analysis of an animal model of conditioned place preference (CPP) in vivo, we investigated the synaptic mechanisms for actions of acute and chronic ethanol on CeA non-NMDA receptor functions and their contribution to ethanol-induced reward behavior. Acute ethanol significantly inhibited evoked and miniature synaptic currents mediated by non-NMDA receptors through inhibitions of both postsynaptic non-NMDA receptors and presynaptic glutamate release involving N-type Ca2+ channels. CeA neurons from rats exhibiting the ethanol-induced CPP behavior showed a significant increase in non-NMDA synaptic transmission. Blockade of this increased synaptic transmission through CeA microinjection abolished the CPP behavior. These results suggest that acute alcohol inhibits CeA non-NMDA synaptic transmission through both presynaptic and postsynaptic mechanisms, and chronic alcohol upregulates this synaptic activity, which is required for the alcohol-induced reward behavior.

Glutamate neurotransmission plays an important role in the processing of pain and in chronic opioid-induced neural and behavioral plasticity, such as opioid withdrawal and opioid dependence. Kappa-opioid receptors also have been implicated in acute opioid modulation of pain and chronic opioid-induced plasticity, both of which are primarily mediated by mu-opioid receptors. Using whole-cell patch clamp recordings in brain slices in vitro and system analysis of pain behaviors in rats in vivo, this study investigated the functional role of glutamate synaptic transmission and kappa-opioid receptors in two behavioral pain conditions: m-opioid-induced analgesia (decreased pain) and mu-opioid withdrawal-induced hyperalgesia (increased pain). In the nucleus raphe magnus (NRM), a brainstem structure that controls spinal pain transmission, we found that kappa-receptor agonists presynaptically inhibited glutamate synaptic currents in both of the two cell types that are thought to respectively inhibit or facilitate spinal pain transmission. In rats, both glutamate receptor antagonists and the kappa agonist microinjected into the NRM attenuated mu-opioid-induced analgesia, which is most likely mediated through activation of such pain-inhibiting neurons. However, during opioid abstinence-induced withdrawal, the same doses of glutamate receptor antagonists and the kappa agonist administered in the NRM suppressed the withdrawal-induced hyperalgesia, which is thought to be mediated by activation of those pain-facilitating neurons during opioid withdrawal. These results demonstrate that kappa-opioid receptors antagonize mu-receptor-induced effects in both analgesic and hyperalgesic states, and suggest inhibition of glutamate synaptic transmission as a presynaptic mechanism for the kappa antagonism of these two mu receptor-mediated actions.