Mol Pain
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ATP and P2X receptors play important roles in the modulation of trigeminal neuropathic pain, while the role of G protein-coupled P2Y₂ receptors and the underlying mechanisms are less clear. The threshold and frequency of action potentials, fast inactivating transient K+ channels (IA) are important regulators of membrane excitability in sensory neurons because of its vital role in the control of the spike onset. In this study, pain behavior tests, QT-RT-PCR, immunohistochemical staining, and patch-clamp recording, were used to investigate the role of P2Y₂ receptors in pain behaviour. ⋯ Our data suggest that inhibition of P2Y₂ receptors leads to down-regulation of ERK-mediated phosphorylation and increase of the expression of I(A)-related Kv channels in trigeminal ganglion neurons, which might contribute to the clinical treatment of trigeminal neuropathic pain.
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Thyroid hormones are essential for the maturation and functions of the central nervous system. Pain sensitivity is related to the thyroid status. However, information on how thyroid hormones affect pain processing and synaptic transmission in the anterior cingulate cortex (ACC) is limited. Nociceptive threshold and synaptic transmission in the ACC were detected in the experimental hypothyroidism (HT) mice. ⋯ These results suggest that HT promotes hypersensitivity to noxious thermal, and that supplementation with T3 or T4 rescues the imbalance between excitatory and inhibitory transmission in the ACC.
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A recent study by Mishra and Hoon identified B-type natriuretic peptide (BNP) as an important peptide for itch transmission and proposed that BNP activates spinal natriuretic peptide receptor-A (NPRA) expressing neurons, which release gastrin releasing peptide (GRP) to activate GRP receptor (GRPR) expressing neurons to relay itch information from the periphery to the brain (Science 340:968-971, 2013). A central premise for the validity of this novel pathway is the absence of GRP in the dorsal root ganglion (DRG) neurons. To this end, they showed that Grp mRNA in DRG neurons is either absent or barely detectable and claimed that BNP but not GRP is a major neurotransmitter for itch in pruriceptors. They showed that NPRA immunostaining is perfectly co-localized with Grp-eGFP in the spinal cord, and a few acute pain behaviors in Nppb-/- mice were tested. They claimed that BNP is an itch-selective peptide that acts as the first station of a dedicated neuronal pathway comprising a GRP-GRPR cascade for itch. However, our studies, along with the others, do not support their claims. ⋯ Accumulating evidence demonstrates that GRP is a key neurotransmitter in pruriceptors for mediating histamine-independent itch. BNP-NPRA signaling is involved in both itch and pain and does not function upstream of the GRP-GRPR dedicated neuronal pathway. The site of BNP action in itch and pain and its relationship with GRP remain to be clarified.
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Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are key players in epigenetic regulation of gene expression. Analgesic activity by HDAC inhibitors has been reported in different pain models including inflammatory and neuropathic pain. These drugs interfere with gene expression through different mechanisms including chromatin remodeling and/or activation of transcription factors. Among other targets, HDAC inhibitors regulate metabotropic glutamate receptors type 2 (mGlu2) expression in central and peripheral central nervous system. However whether inhibition of HAT activity also regulates mGlu2 expression has not been reported. ⋯ Our results demonstrate that systemically injected CUR is able to inhibit H3 and H4 acetylation in the DRG and to down-regulate mGlu2 receptors in the spinal cord. We also demonstrate that long term modification of the mGlu2 expression affects the analgesic properties of the orthosteric mGlu2/3 agonist, LY379268. These data open up the possibility that epigenetic modulators might be given in combination with "traditional" drugs in a context of a multi target approach for a better analgesic efficacy.
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Hydrogen sulfide (H2S), an endogenous gaseotransmitter/modulator, is becoming appreciated that it may be involved in a wide variety of processes including inflammation and nociception. However, the role for H2S in nociceptive processing in trigeminal ganglion (TG) neuron remains unknown. The aim of this study was designed to investigate whether endogenous H2S synthesizing enzyme cystathionine-β-synthetase (CBS) plays a role in inflammatory pain in temporomandibular joint (TMJ). ⋯ These data together with our previous report indicate that endogenous H2S generating enzyme CBS plays an important role in TMJ inflammation, which is likely mediated by inhibition of IK currents, thus identifying a specific molecular mechanism underlying pain and sensitization in TMJ inflammation.