Previous experience of chronic pain causes enhanced responses to upcoming noxious events in both humans and animals, but the underlying mechanisms remain unclear. In the present study, we found that rats with complete Freund's adjuvant (CFA)-induced chronic inflammatory pain experience exhibited aggravated pain responses to later formalin test. Enhanced neuronal activation upon formalin assaults and increased phosphorylated cAMP-response element binding protein (CREB) were observed in the prelimbic cortex (PL) of rats with chronic inflammatory pain experience, and inhibiting PL neuronal activities reversed the aggravated pain. Inflammatory pain experience induced persistent p38 mitogen-activated protein kinase (MAPK; p38) but not extracellular regulated protein kinase (ERK) or c-Jun N-terminal kinase (JNK) hyperphosphorylation in the PL. Inhibiting the p38 phosphorylation in PL reversed the aggravated nociceptive responses to formalin test and down-regulated enhanced phosphorylated CREB in the PL. Chemogenetics identified PL-periaqueductal gray (PAG) but not PL-nucleus accumbens (NAc) as a key pathway in inducing the aggravated formalin pain. Our results demonstrate that persistent hyperphosphorylation of p38 in the PL underlies aggravated nociceptive responses in rats with chronic inflammatory pain experience.

When the body is under pathological stress (injury or disease), the status of associated acupoints changes, including decreased pain threshold. Such changes in acupoint from a "silent" to an "active" state are considered "acupoint sensitization," which has become an important indicator of acupoint selection. However, the mechanism of acupoint sensitization remains unclear. In this study, by retrograde tracing, morphological, chemogenetic, and behavioral methods, we found there are some dorsal root ganglion (DRG) neurons innervating the ST36 acupoint and ipsilateral hind paw (IHP) plantar simultaneously. Inhibition of these shared neurons induced analgesia in the complete Freund's adjuvant (CFA) pain model and obstruction of nociceptive sensation in normal mice, and elevated the mechanical pain threshold (MPT) of ST36 acupoint in the CFA model. Excitation of shared neurons induced pain and declined the MPT of ST36 acupoint. Furthermore, most of the shared DRG neurons express TRPV1, a marker of nociceptive neurons. These results indicate that the shared nociceptive DRG neurons participate in ST36 acupoint sensitization in CFA-induced chronic pain. This raised a neural mechanism of acupoint sensitization at the level of primary sensory transmission.

The dorsal root ganglion (DRG) contains heterogeneous populations of sensory neurons including primary nociceptive neurons and C-fibers implicated in pain signaling. Recent studies have demonstrated DRG hyperexcitability associated with downregulation of A-type K(+) channels; however, the molecular correlate of the corresponding A-type K(+) current (I(A)) has remained hypothetical. Kv4 channels may underlie the I(A) in DRG neurons. We combined electrophysiology, molecular biology (Whole-Tissue and Single-Cell RT-PCR) and immunohistochemistry to investigate the molecular basis of the I(A) in acutely dissociated DRG neurons from 7- to 8-day-old rats. Whole-cell recordings demonstrate a robust tetraethylammonium-resistant (20 mM) and 4-aminopyridine-sensitive (5 mM) I(A). Matching Kv4 channel properties, activation and inactivation of this I(A) occur in the subthreshold range of membrane potentials and the rate of recovery from inactivation is rapid and voltage-dependent. Among Kv4 transcripts, the DRG expresses significant levels of Kv4.1 and Kv4.3 mRNAs. Also, single small-medium diameter DRG neurons ( approximately 30 mum) exhibit correlated frequent expression of mRNAs encoding Kv4.1 and Nav1.8, a known nociceptor marker. In contrast, the expressions of Kv1.4 and Kv4.2 mRNAs at the whole-tissue and single-cell levels are relatively low and infrequent. Kv4 protein expression in nociceptive DRG neurons was confirmed by immunohistochemistry, which demonstrates colocalization of Kv4.3 and Nav1.8, and negligible expression of Kv4.2. Furthermore, specific dominant-negative suppression and overexpression strategies confirmed the contribution of Kv4 channels to I(A) in DRG neurons. Contrasting the expression patterns of Kv4 channels in the central and peripheral nervous systems, we discuss possible functional roles of these channels in primary sensory neurons.

Besides the established role of dopamine neurons and projections in nociceptive stimuli, the involvement of ventral tegmental area (VTA) glutamatergic projections to nucleus accumbens (NAc) in pain remains unknown. In the present study, we aimed to examine the role of VTA glutamatergic projections to NAc in painful stimuli and its related behavioral changes.

Chronic pain is one of the most burdensome health issues facing the planet (as costly as diabetes and cancer combined), and in desperate need for new diagnostic targets leading to better therapies. The bioactive lipid sphingosine 1-phosphate (S1P) and its receptors have recently been shown to modulate nociceptive signaling at the level of peripheral nociceptors and central neurons. However, the exact role of S1P generating enzymes, in particular sphingosine kinase 2 (Sphk2), in nociception remains unknown. We found that both sphingosine kinases, Sphk1 and Sphk2, were expressed in spinal cord (SC) with higher levels of Sphk2 mRNA compared to Sphk1. All three Sphk2 mRNA-isoforms were present with the Sphk2.1 mRNA showing the highest relative expression. Mice deficient in Sphk2 (Sphk2(-/-)) showed in contrast to mice deficient in Sphk1 (Sphk1(-/-)) substantially lower spinal S1P levels compared to wild-type C57BL/6 mice. In the formalin model of acute peripheral inflammatory pain, Sphk2(-/-) mice showed facilitation of nociceptive transmission during the late response, whereas responses to early acute pain, and the number of c-Fos immunoreactive dorsal horn neurons were not different between Sphk2(-/-) and wild-type mice. Chronic peripheral inflammation (CPI) caused a bilateral increase in mechanical sensitivity in Sphk2(-/-) mice. Additionally, CPI increased the relative mRNA expression of P2X4 receptor, brain-derived neurotrophic factor and inducible nitric oxide synthase in the ipsilateral SC of wild-type but not Sphk2(-/-) mice. Similarly, Sphk2(-/-) mice showed in contrast to wild-type no CPI-dependent increase in areas of the dorsal horn immunoreactive for the microglia marker Iba-1 and the astrocyte marker Glial fibrillary acidic protein (GFAP). Our results suggest that the tightly regulated cell signaling enzyme Sphk2 may be a key component for facilitation of nociceptive circuits in the CNS leading to central sensitization and pain memory formation.

Cinnabarinic acid (CA) is a trace kynurenine metabolite, which activates both type-4 metabotropic glutamate (mGlu4) and arylic hydrocarbon (Ah) receptors. We examined the action of CA in models of inflammatory and neuropathic pain moving from the evidence that mGlu4 receptors are involved in the regulation of pain thresholds. Systemic administration of low doses of CA (0.125 and 0.25 mg/kg, i.p.) reduced nocifensive behaviour in the second phase of the formalin test. CA-induced analgesia was abrogated in mGlu4 receptor knockout mice, but was unaffected by treatment with the Ah receptor antagonist, CH223191 (1 mg/Kg, s.c.). Acute injection of low doses of CA (0.25 mg/kg, i.p.) also caused analgesia in mice subjected to Chronic Constriction Injury (CCI) of the sciatic nerve. Electrophysiological recording showed no effect of CA on spinal cord nociceptive neurons and a trend to a lowering effect on the frequency and duration of excitation of the rostral ventromedial medulla (RVM) ON cells in CCI mice. However, local application of CH223191 or the group-III mGlu receptor antagonist, MSOP disclosed a substantial lowering and enhancing effect of CA on both populations of neurons, respectively. When repeatedly administered to CCI mice, CA retained the analgesic activity only when combined with CH223191. Repeated administration of CA plus CH223191 restrained the activity of both spinal nociceptive neurons and RVM ON cells, in full agreement with the analgesic activity. These findings suggest that CA is involved in the regulation of pain transmission, and its overall effect depends on the recruitment of mGlu4 and Ah receptors.

Neuropathic pain is a kind of chronic pain that remains difficult to treat due to its complicated underlying mechanisms. Accumulating evidence has indicated that enhanced synaptic plasticity of nociceptive interneurons in the superficial spinal dorsal horn contributes to the development of neuropathic pain. Neuroligin1 (NL1) is a type of excitatory postsynaptic adhesion molecule, which can mediate excitatory synaptic activity, hence promoting neuronal activation. Vglut2 is the most common marker of excitatory glutamatergic neurons. To explore the role of NL1 in excitatory neurons in nociceptive regulation, we used transgenic mice with cre recombinase expression driven by the Vglut2 promoter combined with viral vectors to knockdown the expression of NL1 in excitatory neurons in the spinal dorsal horn. We found that NL1 was upregulated in the L4-L6 spinal dorsal horn in Vglut2-cre+/- mouse subjected to spared nerve injury (SNI). Meanwhile, the expression of phosphorylated cofilin (p-cofilin) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 1 (GluR1) was also increased. Spinal microinjection of a cre-dependent NL1-targeting RNAi in Vglut2-cre+/- mouse alleviated the neuropathic pain-induced mechanical hypersensitivity and reduced the increase in p-cofilin and GluR1 caused by SNI. Taken together, NL1 in excitatory neurons regulates neuropathic pain by promoting the SNI-dependent increase in p-cofilin and GluR1 in the spinal dorsal horn. Our study provides a better understanding of the role of NL1 in excitatory neurons, which might represent a possible therapeutic target for alleviating neuropathic pain.

Dorsal root ganglion (DRG) neurons process pain signaling through specialized nociceptors located in their peripheral endings. It has long been established low voltage-activated (LVA) CaV3.2 calcium channels control neuronal excitability during sensory perception in these neurons. Silencing CaV3.2 activity with antisense RNA or genetic ablation results in anti-nociceptive, anti-hyperalgesic and anti-allodynic effects. CaV3.2 channels are regulated by many proteins (Weiss and Zamponi, 2017), including KLHL1, a neuronal actin-binding protein that stabilizes channel activity by recycling it back to the plasma membrane through the recycling endosome. We explored whether manipulation of KLHL1 levels and thereby function as a CaV3.2 modifier can modulate DRG excitability and mechanical pain transmission or sensitivity to pain. We first assessed the mechanical sensitivity threshold and DRG properties in the KLHL1 KO mouse model. KO DRG neurons exhibited smaller T-type current density compared to WT without significant changes in voltage dependence, as expected in the absence of its modulator. Western blot analysis confirmed CaV3.2 but not CaV3.1, CaV3.3, CaV2.1, or CaV2.2 protein levels were significantly decreased; and reduced neuron excitability and decreased pain sensitivity were also found in the KLHL1 KO model. Analogously, transient down-regulation of KLHL1 levels in WT mice with viral delivery of anti-KLHL1 shRNA also resulted in decreased pain sensitivity. These two experimental approaches confirm KLHL1 as a physiological modulator of excitability and pain sensitivity, providing a novel target to control peripheral pain.

The Ca2+-binding protein Kv channel interacting protein 3 (KChIP3) or downstream regulatory element antagonist modulator (DREAM), a member of the neuronal calcium sensor (NCS) family, shows remarkable multifunctional properties. It acts as a transcriptional repressor in the nucleus and a modulator of ion channels or receptors, such as Kv4, NMDA receptors and TRPV1 channels on the cytomembrane. Previous studies of Kcnip3 -/- mice have indicated that KChIP3 facilitates pain hypersensitivity by repressing Pdyn expression in the spinal cord. Conversely, studies from transgenic daDREAM (dominant active DREAM) mice indicated that KChIP3 contributes to analgesia by repressing Bdnf expression and attenuating the development of central sensitization. To further determine the role of KChIP3 in pain transmission and its possible involvement in emotional processing, we assessed the pain sensitivity and negative emotional behaviors of Kcnip3 -/- rats. The knockout rats showed higher pain sensitivity compared to the wild-type rats both in the acute nociceptive pain model and in the late phase (i.e., 2, 4 and 6 days post complete Freund's adjuvant injection) of the chronic inflammatory pain model. Importantly, Kcnip3 -/- rats displayed stronger aversion to the pain-associated compartment, higher anxiety level and aggravated depression-like behavior. Furthermore, RNA-Seq transcriptional profiling of the forebrain cortex were compared between wild-type and Kcnip3 -/- rats. Among the 68 upregulated genes, 19 genes (including Nr4a2, Ret, Cplx3, Rgs9, and Itgad) are associated with neural development or synaptic transmission, particularly dopamine neurotransmission. Among the 79 downregulated genes, 16 genes (including Col3a1, Itm2a, Pcdhb3, Pcdhb22, Pcdhb20, Ddc, and Sncaip) are associated with neural development or dopaminergic transmission. Transcriptional upregulation of Nr4a2, Ret, Cplx3 and Rgs9, and downregulation of Col3a1, Itm2a, Pcdhb3 and Ddc, were validated by qPCR analysis. In summary, our studies showed that Kcnip3 -/- rats displayed higher pain sensitivity and stronger negative emotions, suggesting an involvement of KChIP3 in negative emotions and possible role in central nociceptive processing.

The inhibitory glycine receptor (GlyR) plays an important role in rapid synaptic inhibition in mammalian spinal cord, brainstem, higher brain centers, and is involved in transmission of nociceptive signals. Glucose and related mono- and disaccharides potentiate currents mediated by recombinant α1, α1-β, and α3 GlyRs. Here, we confirmed the specific potentiation of α3 GlyR signaling by glucose through: (i) patch-clamp electrophysiology on recombinant receptors; and (ii) by verifying in vitro data in a mouse model in vivo. Mice were intraperitoneally (IP) injected with glucose (2 g/kg) or vehicle, and then challenged with sublethal doses of strychnine (0.2 mg/kg and 0.5 mg/kg). Pain-related behavior was assessed using two established models: (i) touch sensitivity tests using von Frey filaments; and (ii) hotplate assay. We observed a reduction of pain sensitivity in glucose-treated mice relative to vehicle-treated control mice. Injection of strychnine resulted in an increased sensitivity to tactile and heat stimuli, which was reversed in the presence of glucose. Analgesic effects of glucose were more pronounced in von Frey experiments, consistent with the established use of this model for neuropathic pain. Overall, glucose showed mild analgesic effects and was able to compensate for strychnine-induced allodynia in mice. Since the action of strychnine is specific for GlyR, these experiments show for the first time an in vivo potentiation of GlyR activity by glucose and suggest a molecular mechanism for glucose-mediated analgesia.

The C-C motif chemokine ligand 2 (CCL2) has been implicated in chronic pain, but its exact mechanism of peripheral sensitization is unknown. In this study, we aimed to clarify the mechanism of CCL2 regulation of ion channels. Our behavioral experiments revealed that ZD7288, a blocker of Ih current, can inhibit CFA and CCL2-mediated mechanical and thermal nociceptive sensitization. Furthermore, patch clamp studies demonstrated that CFA-induced peripheral sensitization primarily affects the excitability of small-diameter DRG neurons. Further studies revealed that inflammatory pain caused by CFA or incubation of DRG with CCL2 mainly affected Ih currents in small-diameter DRG neurons, which were blocked by co-incubation CCR2 antagonist INCB3344 or adenylate cyclase inhibitor SQ22536. Immunohistochemical staining showed that both intraplantar injection of CFA as well as DRG injection of CCL2 resulted in significant upregulation of CCR2+/HCN2+ expression. In conclusion, we suggest in the inflammatory pain state, CCL2 can act on small-diameter DRG neurons, leading to upregulation of HCN2 expression and consequently Ih, which in turn leads to neuronal hyperexcitability.

The amygdala has emerged as a key player in the emotional response to pain and pain modulation. The lateral and capsular regions of the central nucleus of the amygdala (CeA) represent the "nociceptive amygdala" due to their high content of neurons that process pain-related information. These CeA divisions are the targets of the spino-parabrachio-amygdaloid pain pathway, which is the predominant source of calcitonin gene-related peptide (CGRP) within the amygdala. Changes in lateral and capsular CeA neurons have previously been observed in pain models, and synaptic plasticity in these areas has been linked to pain-related behavior. CGRP has been demonstrated to play an important role in peripheral and spinal mechanisms, and in pain-related amygdala plasticity in male rats in an acute arthritis pain model. However, the role of CGRP in chronic neuropathic pain-related amygdala function and behaviors remains to be determined for both male and female rats. Here we tested the hypothesis that the CGRP1 receptor is involved in neuropathic pain-related amygdala activity, and that blockade of this receptor can inhibit neuropathic pain behaviors in both sexes. CGRP mRNA expression levels in the CeA of male rats were upregulated at the acute stage of the spinal nerve ligation (SNL) model of neuropathic pain, whereas female rats had significantly higher CGRP and CGRP receptor component expression at the chronic stage. A CGRP1 receptor antagonist (CGRP 8-37) administered into the CeA in chronic neuropathic rats reduced mechanical hypersensitivity (von Frey and paw compression tests) in both sexes but showed female-predominant effects on emotional-affective responses (ultrasonic vocalizations) and anxiety-like behaviors (open field test). CGRP 8-37 inhibited the activity of CeA output neurons assessed with calcium imaging in brain slices from chronic neuropathic pain rats. Together, these findings may suggest that CGRP1 receptors in the CeA are involved in neuropathic pain-related amygdala activity and contribute to sensory aspects in both sexes but to emotional-affective pain responses predominantly in females. The sexually dimorphic function of CGRP in the amygdala would make CGRP1 receptors a potential therapeutic target for neuropathic pain relief, particularly in females in chronic pain conditions.

Inflammatory pain encompasses many clinical symptoms, and there is no satisfactory therapeutic target. Neuronal hyperexcitability and/or sensitization of the primary nociceptive neurons in the dorsal root ganglion (DRG) and spinal dorsal horn are critical to the development and maintenance of inflammatory pain. The sodium leak channel (NALCN), a non-selective cation channel, mediates the background Na+ leak conductance and controls neuronal excitability. It is unknown whether abnormal activity of NALCN mediates the pathological process of inflammatory pain. Complete Freund's adjuvant (CFA) was injected into the left footpad of rats to induce inflammatory pain. The thresholds of mechanical and thermal sensation and spontaneous pain behaviors were assessed. The expression of NALCN in DRG and spinal dorsal cord was measured. NALCN currents and the contribution of NALCN to neuronal excitability in the DRG and spinal dorsal cord were recorded using whole-cell patch-clamping recording. NALCN was abundantly expressed in neurons of the DRG and spinal dorsal cord. In acutely isolated DRG neurons and spinal cord slices from rats with CFA-induced inflammatory pain, NALCN currents and neuronal excitability were increased. Subsequently, intrathecal and sciatic nerve injection of NALCN-small interfering RNA (siRNA) decreased NALCN mRNA and reverted NALCN currents to normal levels, and then reduced CFA-induced neuronal excitability and alleviated pain symptoms. Furthermore, pain-related symptoms were significantly prevented by the NALCN-shRNA-mediated NALCN knockdown in DRG and spinal cord. Therefore, increased expression and activity of NALCN contributed to neuronal sensitization in CFA-induced inflammatory pain. NALCN may be a novel molecular target for the control of inflammatory pain.

Central post-stroke pain (CPSP) is an intractable neuropathic pain, which can be caused by primary lesion of central somatosensory system. It is also a common sequelae of the thalamic hemorrhagic stroke (THS). So far, the underlying mechanisms of CPSP remain largely unknown. Our previous studies have demonstrated that SDF1-CXCR4 signaling in the hemorrhagic region contributes to the maintenance of the THS pain hypersensitivity via mediation of the thalamic neuroinflammation. But whether the spinal dorsal horn, an initial point of spinothalamic tract (STT), suffers from retrograde axonal degeneration from the THS region is still unknown. In this study, neuronal degeneration and loss in the spinal dorsal horn were detected 7 days after the THS caused by intra-thalamic collagenase (ITC) injection by immunohistochemistry, TUNEL staining, electron microscopy, and extracellular multi-electrode array (MEA) recordings, suggesting the occurrence of secondary apoptosis and death of the STT projecting neuronal cell bodies following primary THS via retrograde axonal degeneration. This retrograde degeneration was accompanied by secondary neuroinflammation characterized by an activation of microglial and astrocytic cells and upregulation of SDF1-CXCR4 signaling in the spinal dorsal horn. As a consequence, central sensitization was detected by extracellular MEA recordings of the spinal dorsal horn neurons, characterized by hyperexcitability of both wide dynamic range and nociceptive specific neurons to suprathreshold mechanical stimuli. Finally, it was shown that suppression of spinal neuroinflammation by intrathecal administration of inhibitors of microglia (minocycline) and astrocytes (fluorocitrate) and antagonist of CXCR4 (AMD3100) could block the increase in expression levels of Iba-1, GFAP, SDF1, and CXCR4 proteins in the dorsal spinal cord and ameliorate the THS-induced bilateral mechanical pain hypersensitivity, implicating that, besides the primary damage at the thalamus, spinal secondary damage and neuroinflammation also play the important roles in maintaining the central post-THS pain hypersensitivity. In conclusion, secondary neuronal death and neuroinflammation in the spinal dorsal horn can be induced by primary thalamic neural damage via retrograde axonal degeneration process. SDF1-CXCR4 signaling is involved in the mediation of secondary spinal neuroinflammation and THS pain hypersensitivity. This finding would provide a new therapeutic target for treatment of CPSP at the spinal level.

Antinociceptive pathways are activated in the periphery in inflammatory pain, for instance resolvins and opioid peptides. Resolvins are biosynthesized from omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Resolvin D1 (RvD1) and resolvin E1 (RvE1) initiate the resolution of inflammation and control of hypersensitivity via induction of anti-inflammatory signaling cascades. RvD1 binds to lipoxin A4/annexin-A1 receptor/formyl-peptide receptor 2 (ALX/FPR2), RvE1 to chemerin receptor 23 (ChemR23). Antinociception of RvD1 is mediated by interaction with transient receptor potential channels ankyrin 1 (TRPA1). Endogenous opioid peptides are synthesized and released from leukocytes in the tissue and bind to opioid receptors on nociceptor terminals. Here, we further explored peripheral mechanisms of RvD1 and chemerin (Chem), the ligand of ChemR23, in complete Freund's adjuvant (CFA)-induced hindpaw inflammation in male Wistar rats. RvD1 and Chem ameliorated CFA-induced hypersensitivity in early and late inflammatory phases. This was prevented by peripheral blockade of the μ-opioid peptide receptor (MOR) using low dose local naloxone or by local injection of anti-β-endorphin and anti-met-enkephalin (anti-ENK) antibodies. Naloxone also hindered antinociception by the TRPA1 inhibitor HC-030031. RvD1 did not stimulate the release of β-endorphin from macrophages and neutrophils, nor did RvD1 itself activate G-proteins coupled MOR or initiate β-arrestin recruitment to the membrane. TRPA1 blockade by HC-030031 in inflammation in vivo as well as inhibition of the TRPA1-mediated calcium influx in dorsal root ganglia neurons in vitro was hampered by naloxone. Peripheral application of naloxone alone in vivo already lowered mechanical nociceptive thresholds. Therefore, either a perturbation of the balance of endogenous pro- and antinociceptive mechanisms in early and late inflammation, or an interaction of TRPA1 and opioid receptors weaken the antinociceptive potency of RvD1 and TRPA1 blockers.

Experimental studies on the pathogenetic process of paclitaxel-induced neuropathic pain (PINP) have been initially carried out, but PINP still has no effective therapy. Recently reported studies have highlighted the involvement of glutamate receptors and neuroinflammation in peripheral and central nociceptive transmission in PINP. Artesunate is a first-line antimalarial drug with established efficacy in alleviating pain in a variety of pathologies. The current work assessed whether artesunate inhibits PINP by modulating metabotropic glutamate receptor 5 (mGluR5) and neuroinflammation in mice. The anti-hyperalgesic effect of artesunate was verified by assessing mechanical frequency and thermal latency in the paw withdrawal test as well as spontaneous pain. The expression levels of mGluR5, pain-related receptors and neuroinflammatory markers in dorsal root ganglion (DRG) were examined. In addition, treatment with CHPG and 2-methyl-6-(phenyl ethynyl) pyridine (MPEP) (mGluR5 agonist and antagonist, respectively) was performed to determine mGluR5's role in the anti-hyperalgesic properties of artesunate. We demonstrated artesunate prevented PINP in a dose-dependent manner, while exerting a clear anti-hyperalgesic effect on already existing PINP. Artesunate normalized paclitaxel-related expression changes in DRG mGluR5, NR1, and GluA2, as well as six paclitaxel related neuroinflammation markers. Intrathecal application of MPEP treated PINP by reversing NR1 and GluA2 expression changes but had no effects on chemokines and inflammatory factors. Furthermore, artesunate treatment reversed acute pain following CHPG application. In conclusion, this study revealed that artesunate alleviates paclitaxel-induced hyperalgesia and spontaneous pain by decreasing DRG mGluR5 expression and neuroinflammation in the mouse model of PINP.

Sleep is essential for the body's repair and recovery, including supplementation with antioxidants to maintain the balance of the body's redox state. Changes in sleep patterns have been reported to alter this repair function, leading to changes in disease susceptibility or behavior. Here, we recruited healthy male physicians and measured the extent of the effect of overnight sleep deprivation (SD) and recovery sleep (RS) on nociceptive thresholds and systemic (plasma-derived) redox metabolism, namely, the major antioxidants glutathione (GSH), catalase (CAT), malondialdehyde (MDA), and superoxide dismutase (SOD). Twenty subjects underwent morning measurements before and after overnight total SD and RS. We found that one night of SD can lead to increased nociceptive hypersensitivity and the pain scores of the Numerical Rating Scale (NRS) and that one night of RS can reverse this change. Pre- and post-SD biochemical assays showed an increase in MDA levels and CAT activity and a decrease in GSH levels and SOD activity after overnight SD. Biochemical assays before and after RS showed a partial recovery of MDA levels and a basic recovery of CAT activity to baseline levels. An animal study showed that SD can cause a significant decrease in the paw withdrawal threshold and paw withdrawal latency in rats, and after 4 days of unrestricted sleep, pain thresholds can be restored to normal. We performed proteomics in the rat medial prefrontal cortex (mPFC) and showed that 37 proteins were significantly altered after 6 days of SD. Current findings showed that SD causes nociceptive hyperalgesia and oxidative stress, and RS can restore pain thresholds and repair oxidative stress damage in the body. However, one night of RS is not enough for repairing oxidative stress damage in the human body.

Neuropathic pain (NP) is one of intractable complications of spinal cord injury (SCI) and lacks effective treatment. Resveratrol (Res) has been shown to possess potent anti-inflammatory and anti-nociceptive effects. In this study, we investigated the analgesic effect of Res and its underlying mechanism in a rat model of SCI.

Lysophosphatidyl-choline (LPC), a member of the phospholipid family, is an emerging player in pain. It is known to modulate different pain-related ion channels, including Acid-Sensing Ion Channel 3 (ASIC3), a cationic channel mainly expressed in peripheral sensory neurons. LPC potentiates ASIC3 current evoked by mild acidifications, but can also activate the channel at physiological pH. Very recently, LPC has been associated to chronic pain in patients suffering from fibromyalgia or osteoarthritis. Accordingly, repetitive injections of LPC within mouse muscle or joint generate both persistent pain-like and anxiety-like behaviors in an ASIC3-dependent manner. LPC has also been reported to generate acute pain behaviors when injected intraplantarly in rodents. Here, we explore the mechanism of action of a single cutaneous injection of LPC by studying its effects on spinal dorsal horn neurons. We combine pharmacological, molecular and functional approaches including in vitro patch clamp recordings and in vivo recordings of spinal neuronal activity. We show that a single cutaneous injection of LPC exclusively affects the nociceptive pathway, inducing an ASIC3-dependent sensitization of nociceptive fibers that leads to hyperexcitabilities of both high threshold (HT) and wide dynamic range (WDR) spinal neurons. ASIC3 is involved in LPC-induced increase of WDR neuron's windup as well as in WDR and HT neuron's mechanical hypersensitivity, and it participates, together with TRPV1, to HT neuron's thermal hypersensitivity. The nociceptive input induced by a single LPC cutaneous rather induces short-term sensitization, contrary to previously described injections in muscle and joint. If the effects of peripheral LPC on nociceptive pathways appear to mainly depend on peripheral ASIC3 channels, their consequences on pain may also depend on the tissue injected. Our findings contribute to a better understanding of the nociceptive signaling pathway activated by peripheral LPC via ASIC3 channels, which is an important step regarding the ASIC3-dependent roles of this phospholipid in acute and chronic pain conditions.

PR domain-containing member 12 (PRDM12) is a key developmental transcription factor in sensory neuronal specification and survival. Patients with rare deleterious variants in PRDM12 are born with congenital insensitivity to pain (CIP) due to the complete absence of a subtype of peripheral neurons that detect pain. In this paper, we report two additional CIP cases with a novel homozygous PRDM12 variant. To elucidate the function of PRDM12 during mammalian development and adulthood, we generated temporal and spatial conditional mouse models. We find that PRDM12 is expressed throughout the adult nervous system. We observed that loss of PRDM12 during mid-sensory neurogenesis but not in the adult leads to reduced survival. Comparing cellular biophysical nociceptive properties in developmental and adult-onset PRDM12 deletion mouse models, we find that PRDM12 is necessary for proper nociceptive responses throughout life. However, we find that PRDM12 regulates distinct age-dependent transcriptional programs. Together, our results implicate PRDM12 as a viable therapeutic target for specific pain therapies even in adults.