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Galanin (GAL) is a nociceptive transmitter or modulator in the trigeminal sensory system. In this study, GAL expression was investigated in the rat dura mater to demonstrate its possible function in headache using immunohistochemical techniques. The cerebral falx and cerebellar dura mater received abundant blood and nerve supply, and were significantly thicker compared to other portions in the cerebral dura mater. GAL-immunoreactivity was expressed by cell and nerve fiber profiles. Presumed macrophages and dendritic cells contained GAL-immunoreactivity, and co-expressed with CD11b-immunoreactivity. Many isolated and perivascular nerve fibers also showed GAL-immunoreactivity. In addition, GAL-immunoreactive nerve fibers were present in the vicinity of macrophages and dendritic cells with either GAL- or ED1-immunoreactivity. GAL-immunoreactive cells and nerve fibers were common in the cerebral falx and cerebellar dura mater and infrequent in other portions. And, GAL-immunoreactive nerve fibers usually co-expressed calcitonin gene-related peptide (CGRP)-immunoreactivity. In the trigeminal ganglion, a substantial proportion of sensory neurons innervating the dura mater contained GAL-immunoreactivity (mean ± SD, 3.4 ± 2.2%), and co-expressed CGRP-immunoreactivity (2.7 ± 2.1%). The present study may suggest that GAL is associated with nociceptive transduction or modulation in the dura mater. GAL also possibly plays a role in the immune mechanism of the dura mater.
Learn More >The relieving role of dezocine in pain after surgery was previously reported, while the potential mechanism was not completely clear. Therefore, the current research probed into the regulatory mechanism of dezocine in pain after surgery. A postoperative pain model was established by performing plantar incision surgery on the juvenile Sprague-Dawley rats. After the rats were treated with dezocine or SC79 (Akt1 activator), the paw withdrawal threshold and paw withdrawal latency of rats were detected to evaluate the mechanical allodynia and thermal hyperalgesia. After the plantar tissue, dorsal root ganglions, and spinal cord of rats were collected, the expressions of Akt1, p-Akt1, GSK-3β, and p-GSK-3β in the tissues were determined by western blot to evaluate the activation state of the Akt1/GSK-3β pathway. After surgery, the paw withdrawal threshold and paw withdrawal latency of rats were lessened, whereas the ratios of p-Akt1/Akt1 and p-GSK-3β/GSK-3β were augmented in rat plantar tissue, dorsal root ganglions, and spinal cord. After treatment with dezocine alone, the paw withdrawal threshold and paw withdrawal latency of postoperative rats were elevated, but ratios of p-Akt1/Akt1 and p-GSK-3β/GSK-3β were reduced. After co-treatment with dezocine and SC79, SC79 reversed the effects of dezocine on elevating the paw withdrawal threshold and paw withdrawal latency, and reducing the ratios of p-Akt1/Akt1 and p-GSK-3β/GSK-3β in postoperative rats. Dezocine ameliorated the postoperative hyperalgesia in rats via repressing the hyper-action of Akt1/GSK-3β pathway.
Learn More >Trafficking and activation of N-methyl-D-aspartate (NMDA) receptors play an important role in initiating and maintaining postoperative remifentanil-induced hyperalgesia (RIH). Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome has been linked to the development of inflammatory and neuropathic pain. We hypothesized that activation of NLRP3 inflammasome mediates IL-1β release and contributes to RIH in rats by increasing NMDA receptor NR1 (NR1) subunit phosphorylation and decreasing glutamate transporter-1 (GLT-1) expression.
Learn More >Resistance training-based exercise is commonly prescribed in the clinic for the treatment of chronic pain. Mechanisms of aerobic exercise for analgesia are frequently studied, while little is known regarding resistance training mechanisms. We developed a resistance training model in mice and hypothesized resistance training would protect against development of muscle pain, mediated through the activation of androgen receptors. Activity induced muscle hyperalgesia was produced by two injections of pH 5.0 stimuli with fatiguing muscle contractions. Resistance training was performed by having mice climb a ladder with attached weights, 3x per week. Resistance training acutely increased blood lactate and prolonged training increased strength measured via forepaw grip strength and 1 repetition maximum, validating the exercise program as a resistance training model. Eight weeks of resistance training prior to induction of the pain model blocked the development of muscle hyperalgesia in both sexes. Resistance training initiated after induction of the pain model reversed muscle hyperalgesia in males only. A single resistance training bout acutely increased testosterone in male but not female mice. Administration of the androgen receptor antagonist flutamide (200mg pellets) throughout the eight-week training program blocked the exercise induced protection against muscle pain in both sexes. However, single administration of flutamide (1, 3, 10mg/kg) in resistance trained animals had no effect on existing exercise induced protection against muscle pain. Therefore, resistance training acutely increases lactate and testosterone and strength overtime. Eight weeks of resistance training prevents development of hyperalgesia through activation of androgen receptors in an animal model of muscle pain.
Learn More >Inclinicalpractice, high-voltage, long-duration pulsed radiofrequency (HL-PRF) is effective for several types of intractable neuropathic pain (NP), but the mechanisms have not been well explored. Cav2.2 channels could increase neuronal excitability and neurotransmission accompanying NP. This study investigated the relationship of the efficacy of HL-PRF on NP with the levels of Cav2.2 in the spinal dorsal horn (SDH) and dorsal root ganglions (DRGs) of chronic constriction injury (CCI) in rats. Sham HL-PRF, GVIA (a specific Cav2.2 channel blocker), HL-PRF, or GVIA + HL-PRF was applied to CCI rats. The results showed: compared with the sham group, the PWT and PWL of CCI rats decreased significantly (P < 0.05), and Cav2.2 expression was elevated significantly in the SDH and DRGs (P < 0.05). Compared with the CCI group, both HL-PRF and ω-conotoxin GVIA treatment reversed the increased PWT and PWL (P < 0.05) and downregulated the overexpression of Cav2.2 in the SDH and DRGs (P < 0.05). Furthermore, PWT, PWL, and the expression of Cav2.2 in the SDH and DRGs were not significantly different among the 3 treatment groups. HL-PRF on L DRG reversed the hyperalgesia behavior of NP and reduced the levels of Cav2.2 in the ipsilateral SDH and DRGs in CCI rats. Moreover, the underlying mechanism may be related to the downregulation of CaV2.2 protein levels in both SDH and DRG.
Learn More >Dysregulation of serum prolactin links the hypothalamus with female nociceptors to promote migraine.
Migraine headache results from activation of meningeal nociceptors, however, the hypothalamus is activated many hours before the emergence of pain. How hypothalamic neural mechanisms may influence trigeminal nociceptor function remains unknown. Stress is a common migraine trigger that engages hypothalamic dynorphin/kappa opioid receptor (KOR) signaling and increases circulating prolactin. Prolactin acts at both long and short prolactin receptor isoforms (PRLR-L and PRLR-S) that are expressed in trigeminal afferents. Following down-regulation of PRLR-L, prolactin signaling at PRLR-S sensitizes nociceptors selectively in females. We hypothesized that stress may activate KOR on tuberoinfundibular dopaminergic neurons to increase circulating prolactin leading to female-selective sensitization of trigeminal nociceptors through dysregulation of PRLR isoforms. A mouse two-hit hyperalgesic priming model of migraine was used. Repeated restraint stress promoted vulnerability (i.e., first-hit priming) to a subsequent subthreshold (i.e., second-hit) stimulus from inhalational umbellulone, a TRPA1 agonist. Periorbital cutaneous allodynia served as a surrogate of migraine-like pain. Female and male KORCre; R26lsl-Sun1-GFP mice showed high percentage of KORCre labeled neurons co-localized in tyrosine hydroxylase positive cells in the hypothalamic arcuate nucleus (ARC). Restraint stress increased circulating prolactin to a greater degree in females. Stress-primed, but not control, mice of both sexes developed periorbital allodynia following inhalational umbellulone. Gi-DREADD activation (i.e., inhibition through Gi-coupled signaling) in KORCre neurons in the ARC also increased circulating prolactin and repeated chemogenetic manipulation of these neurons primed mice of both sexes to umbellulone. CRISPR/Cas9 deletion of ARC KOR prevented restraint stress-induced prolactin release in female mice and priming from repeated stress episodes in both sexes. Inhibition of circulating prolactin with systemic cabergoline, a dopamine D2 receptor agonist, blocked priming selectively in females. Repeated restraint stress down-regulated PRLR-L in the trigeminal ganglia of female mice. Deletion of PRLR in trigeminal ganglia by nasal CRISPR/Cas9 targeting both PRLR isoforms prevented stress-induced priming in female mice. Stress-induced activation of hypothalamic KOR increases circulating prolactin resulting in trigeminal downregulation of PRLR-L and pain responses to a normally innocuous TRPA1 stimulus. These are the first data that provide a mechanistic link between stress-induced hypothalamic activation and the trigeminal nociceptor effectors that produce trigeminal sensitization and migraine-like pain. This sexually dimorphic mechanism may help to explain female prevalence of migraine. KOR antagonists, currently in phase II clinical trials, may be useful as migraine preventives in both sexes, while dopamine agonists and prolactin/PRLR antibodies may improve therapy for migraine, and other stress-related neurological disorders, in women.
Learn More >Adults with chronic low back pain, disability, moderate to severe pain, and high fear of movement and re-injury were recruited into a trial of a novel, automated, digital therapeutics, virtual reality, psychological intervention for pain (DTxP). We conducted a three-arm, prospective, double-blind, pilot, randomized controlled trial comparing DTxP with a sham placebo comparator, and an open label standard care. Participants were enrolled for 6-8 weeks, after which, the standard care control arm were re-randomized to receive either the DTxP or sham placebo. Forty-two participants completed assessments at baseline, immediately post-treatment (6-8 weeks), 9-week, and 5-month follow-up. We found participants in the DTxP group reported greater reductions in fear of movement and better global impression of change when compared with sham placebo and standard care post-treatment. No other group differences were noted at post-treatment or follow-up. When compared to baseline, participants in the DTxP group reported lower disability at 5-month follow-up, lower pain interference and fear of movement post-treatment and follow-up, and lower pain intensity at post-treatment. The sham placebo group also reported lower disability and fear of movement at 5-month follow-up compared to baseline. Standard care did not report any significant changes. There were a number of adverse events, with one participant reporting a serious adverse event in the sham placebo which was not related to treatment. No substantial changes in medications were noted, and participants in the DTxP group reported positive gaming experiences.
Learn More >The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund's adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.
Learn More >Nociceptin and the nociceptin receptor (NOP) have been described as targets for treatment of pain and inflammation, whereas toll-like receptors (TLRs) play key roles in inflammation and impact opioid receptors and endogenous opioids expression. In this study, interactions between the nociceptin and TLR systems were investigated. Human THP-1 cells were cultured with or without phorbol myristate acetate (PMA 5 ng/mL), agonists specific for TLR2 (lipoteichoic acid, LTA 10 µg/mL), TLR4 (lipopolysaccharide, LPS 100 ng/mL), TLR7 (imiquimod, IMQ 10 µg/mL), TLR9 (oligonucleotide (ODN) 2216 1 µM), PMA+TLR agonists, or nociceptin (0.01-100 nM). Prepronociceptin (), , and mRNAs were quantified by RT-qPCR. Proteins were measured using flow cytometry. PMA upregulated mRNA, intracellular nociceptin, and cell membrane NOP proteins (all < 0.05). LTA and LPS prevented PMA's upregulating effects on mRNA and nociceptin protein (both < 0.05). IMQ and ODN 2216 attenuated PMA's effects on mRNA. PMA, LPS, IMQ, and ODN 2216 increased NOP protein levels (all < 0.05). PMA+TLR agonists had no effects on NOP compared to PMA controls. Nociceptin dose-dependently suppressed TLR2, TLR4, TLR7, and TLR9 proteins (all < 0.01). Antagonistic effects observed between the nociceptin and TLR systems suggest that the nociceptin system plays an anti-inflammatory role in monocytes under inflammatory conditions.
Learn More >SignificanceFunctional plasticity of the nociceptive circuit is a remarkable feature and is of clinical relevance. As an example, nociceptors lower their threshold upon tissue injury, a process known as allodynia that would facilitate healing by guarding the injured areas. However, long-lasting hypersensitivity could lead to chronic pain, a debilitating disease not effectively treated. Therefore, it is crucial to dissect the mechanisms underlying basal nociception and nociceptive hypersensitivity. In both vertebrate and invertebrate species, conserved transient receptor potential (Trp) channels are the primary transducers of noxious stimuli. Here, we provide a precedent that in larvae, heat sensing in the nociception and hypersensitivity states is mediated by distinct heat-sensitive neurons and TrpA1 alternative isoforms.
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