Inflammatory Pain Conditions Research Articles

A cellular mechanism contributing to pain-induced analgesia.

The anterior cingulate cortex (ACC) plays a crucial role in the perception of pain. It is consistently activated by noxious stimuli and its hyperactivity in chronic pain indicates plasticity in the local neuronal network. However, the way persistent pain effects and modifies different neuronal cell types in the ACC and how this contributes to sensory sensitization is not completely understood. This study confirms the existence of 2 primary subtypes of pyramidal neurons in layer 5 of the rostral, agranular ACC, which we could classify as intratelencephalic (IT) and cortico-subcortical (SC) projecting neurons, similar to other cortical brain areas. Through retrograde labeling, whole-cell patch-clamp recording, and morphological analysis, we thoroughly characterized their different electrophysiological and morphological properties. When examining the effects of peripheral inflammatory pain on these neuronal subtypes, we observed time-dependent plastic changes in excitability. During the acute phase, both subtypes exhibited reduced excitability, which normalized to pre-inflammatory levels after day 7. Daily conditioning with nociceptive stimuli during this period induced an increase in excitability specifically in SC neurons, which was correlated with a decrease in mechanical sensitization. Subsequent inhibition of the activity of SC neurons projecting to the periaqueductal gray with in vivo chemogenetics, resulted in reinstatement of the hypersensitivity. Accordingly, it was sufficient to enhance the excitability of these neurons chemogenetically in the inflammatory pain condition to induce hypoalgesia. These findings suggest a cell type-specific effect on the descending control of nociception and a cellular mechanism for pain-induced analgesia. Furthermore, increased excitability in this neuronal population is hypoalgesic rather than hyperalgesic.

The Use of High-Dose Intravenous L-Ascorbate in Pain Therapy: Current Evidence from the Literature.

Pain is the most common reason for seeking medical treatment. Despite extensive research efforts and effective analgesics modulating pain, there is still a major therapeutic gap in addressing the root causes of pain. Pain is associated with tissue damage induced by oxidative stress and induction of inflammatory mediators following high consumption of antioxidants. The role of antioxidants in general, and the administration of L-ascorbate in particular, is still controversially discussed and underestimated in the daily clinical practice. The current literature on the therapeutic effect of L-ascorbate, ascorbic acid, and vitamin C on various pain conditions was evaluated against the background of evidence-based medicine. Those articles, obtained from systematic search in PubMed, were critically assessed and rated in terms of evidence level and methodological quality by two independent experts. The primary purpose of this work was to establish specific pain therapy guidance for intravenous L-ascorbate. A PubMed search revealed 14 suitable articles comprising controlled clinical trials and meta-analyses. An additional ten publications could be identified via secondary literature. There is supporting evidence for the efficacy of ascorbate treatment in inflammatory pain conditions, in the complex regional pain syndrome, in post zoster neuralgia, in neuropathic pain, in post-operative pain conditions, and in tumor-related pain. However, the considered studies differ in the type of administration, in dosage, in duration of treatment, as well as in quality of research. Despite all study heterogeneity, it became evident that research of high scientific quality is in support of the efficacy of L-ascorbate in pain treatment. Oxidative stress is present in almost all pain conditions. Because oral administration of most magistral formulas of vitamin C does not provide biological availability, parenteral administration should be preferred and can be supported by an oral dose with high bioavailability on days without intravenous treatment. L-ascorbate should be preferred for parenteral high dosage, rather than ascorbic acid, as it does not release acid valences under physiological conditions. L-ascorbate is an effective, safe, and economically favorable integrative treatment option for various pain conditions, addressing the root cause of tissue damage and inflammatory mediator burst.

Validity of central pain processing biomarkers for predicting the occurrence of oncological chronic pain: a study protocol

BackgroundDespite recent improvements in cancer detection and survival rates, managing cancer-related pain remains a significant challenge. Compared to neuropathic and inflammatory pain conditions, cancer pain mechanisms are poorly understood, despite pain being one of the most feared symptoms by cancer patients and significantly impairing their quality of life, daily activities, and social interactions. The objective of this work was to select a panel of biomarkers of central pain processing and modulation and assess their ability to predict chronic pain in patients with cancer using predictive artificial intelligence (AI) algorithms.MethodsWe will perform a prospective longitudinal cohort, multicentric study involving 450 patients with a recent cancer diagnosis. These patients will undergo an in-person assessment at three different time points: pretreatment, 6 months, and 12 months after the first visit. All patients will be assessed through demographic and clinical questionnaires and self-report measures, quantitative sensory testing (QST), and electroencephalography (EEG) evaluations. We will select the variables that best predict the future occurrence of pain using a comprehensive approach that includes clinical, psychosocial, and neurophysiological variables.DiscussionThis study aimed to provide evidence regarding the links between poor pain modulation mechanisms at precancer treatment in patients who will later develop chronic pain and to clarify the role of treatment modality (modulated by age, sex and type of cancer) on pain. As a final output, we expect to develop a predictive tool based on AI that can contribute to the anticipation of the future occurrence of pain and help in therapeutic decision making.

Effectiveness of Tailored Self-Management Interventions for People with Chronic Musculoskeletal Conditions: a Systematic Review and Meta-Analysis

Purpose: To evaluate the effectiveness of tailored self-management interventions to improve health and behavioural outcomes for individuals living with chronic musculoskeletal (MSK) conditions. Methods: We searched relevant databases and grey literature on January 27, 2022 (CRD42022297624). We included English language randomized controlled trials and quasi-experimental trials that assessed the effect of tailored self-management on health and behavioural outcomes for individuals living with chronic MSK conditions. Eligible studies included: Individually prescribed components based on subjective and/or objective assessments; usual care or non-tailored controls; ≥1 health and behavioural outcome(s). Methodological quality was evaluated using the Cochrane Risk of Bias (RoB 2) tool and certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation. Results: Our search yielded 1558 articles, and 21 studies were included in the review. Compared with usual care/non-tailored controls, positive effects were detected in favour of tailored interventions for pain (standardized mean difference [SMD] = 0.35; 95% CI: 0.20, 0.50; moderate certainty) and quality of life, SF-12/36, (SMD = 0.22; 95% CI: 0.08, 0.37; high certainty) in people with inflammatory arthritis (IA) and chronic pain conditions. Similar effects were detected for pain self-efficacy (SMD = 0.40; 95% CI: 0.20, 0.62; moderate certainty) and quality of life, index score (SMD = 0.19; 95% CI: 0.00, 0.38; moderate certainty) across chronic MSK conditions. Conclusion: Tailored self-management interventions offer modest benefits for select health outcomes; however, clinical significance remains unclear.

Oral Mucositis Management in Children under Cancer Treatment: A Systematic Review.

Children undergoing antineoplastic treatment often present severe side effects due to the dosage and duration of treatments, with oral mucositis emerging as one of the most prevalent and painful inflammatory conditions. There is a growing body of evidence on therapeutic interventions such as cryotherapy, low-level laser therapy, and natural compounds for this condition. The aim of this systematic review was to identify and compare therapies for the management of cancer treatment-induced oral mucositis in pediatric patients. From 2655 articles obtained in initial searches, 39 articles were considered in this systematic review, after applying inclusion/exclusion criteria. Low-level laser therapy, palifermin, honey, and zinc demonstrated reductions in oral mucositis incidence, duration, severity, and pain reported by the patient. Although there are several therapies in place for the prevention and treatment of oral mucositis in children, evidence of their efficacy is still inconclusive to establish accurate clinical protocols.

Distinct local and global functions of mouse Aβ low-threshold mechanoreceptors in mechanical nociception

The roles of Aβ low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions of SplitCre labeled mouse Aβ-LTMRs in this regard. Genetic ablation of SplitCre-Aβ-LTMRs increased mechanical nociception but not thermosensation in both acute and chronic inflammatory pain conditions, indicating a modality-specific role in gating mechanical nociception. Local optogenetic activation of SplitCre-Aβ-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a model, in which Aβ-LTMRs play distinctive local and global roles in transmitting or alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a strategy of global activation plus local inhibition of Aβ-LTMRs for treating mechanical hyperalgesia.

Involvement of interaction of Cav3.2 and nociceptive TRPA1 in pathological pain transmission.

T-type Ca2+ channels and TRPA1 expressed in sensory neurons are involved in pain. We previously demonstrated a functional interaction of these channels under physiological conditions. Here we investigated the possible involvement of these channels in inflammatory pain condition. We also evaluated the relationship of these channels endogenously expressed in RIN-14B, a rat pancreatic islet tumor cell line. In dorsal root ganglion (DRG) neurons innervated inflammatory side, [Ca2+]i increases induced by 15 mM KCl (15K) were enhanced in neurons responded to AITC. This enhancement was not observed in genetically TRPA1-deficient neurons. The T-type and AITC-induced currents were larger in neurons of the inflammatory side than in those of the control one. In DRGs of the inflammatory side, the protein expression of Cav3.2, but not TRPA1, was increased. In RIN-14B, 15K-induced [Ca2+]i increases were decreased by blockers of T-type Ca2+ channel and TRPA1, and by TRPA1-silencing. Immunoprecipitation suggested the coexistent of these channels in sensory neurons and RIN-14B. In mice with inflammation, mechanical hypersensitivity was suppressed by blockers of both channels. These data suggest that the interaction of Cav3.2 with TRPA1 in sensory neurons is enhanced via the augmentation of the activities of both channels under inflammatory conditions, indicating that both channels are therapeutic targets for inflammatory pain.

Arabinan-rich pectic polysaccharide fraction from Malpighia emarginata fruits alleviates inflammatory pain in mice

Malpighia emarginata (Malpighiaceae), popularly known as “acerola”, is a tropical and subtropical fruit native to the Americas. Despite its high vitamin C content, which gives it a high antioxidant property, soluble dietary fibers, such as polysaccharides, are also abundant constituents of acerola (10% of the dried fruit). The acerola cold-water soluble (ACWS) fraction presented anti-fatigue and antioxidant effects in vivo and in vitro. To infer further systemic effects of ACWS, this study aimed to investigate the antinociceptive, anti-inflammatory, and antioxidant effects of ACWS in murine models of pain. In formalin-induced nociception, ACWS (0.1, 1, and 10 mg/kg) reduced only the inflammatory phase, and also (10 and 30 mg/kg) attenuated the acetic acid-induced writhing and leukocyte migration in the peritoneal cavity. The mechanical allodynia and paw edema induced by intraplantar injection of carrageenan were greatly reduced by ACWS (10 mg/kg). At the inflammatory pick induced by carrageenan (4 h), ACWS significantly reduced myeloperoxidase activity, TNF-α, IL-1β, and PGE2 levels, and restored IL-10 levels. ACWS also exhibited antioxidant properties by decreasing lipid hydroperoxides content, increasing GSH levels, and restoring superoxide dismutase and catalase activities in the carrageenan model and 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging assay. Collectively, these results support the antinociceptive, anti-inflammatory, and antioxidant effects of ACWS and reveal a promising candidate for the treatment of inflammatory pain conditions.

Eicosanoid profiles in an arthritis model: Effects of a soluble epoxide hydrolase inhibitor

Rheumatoid arthritis is a common systemic inflammatory autoimmune disease characterized by damage to joints, inflammation and pain. It is driven by an increase of inflammatory cytokines and lipids mediators such as prostaglandins. Epoxides of polyunsaturated fatty acids (PUFAs) are lipid chemical mediators in a group of regulatory compounds termed eicosanoids. These epoxy fatty acids (EpFA) have resolutive functions but are rapidly metabolized by the soluble epoxide hydrolase enzyme (sEH) into the corresponding diols. The pharmacological inhibition of sEH stabilizes EpFA from hydrolysis, improving their half-lives and biological effects. These anti-inflammatory EpFA, are analgesic in neuropathic and inflammatory pain conditions. Nonetheless, inhibition of sEH on arthritis and the resulting effects on eicosanoids profiles are little explored despite the physiological importance. In this study, we investigated the effect of sEH inhibition on collagen-induced arthritis (CIA) and its impact on the plasma eicosanoid profile. We measured the eicosanoid metabolites by LC–MS/MS-based lipidomic analysis. The treatment with a sEH inhibitor significantly modulated 11 out of 69 eicosanoids, including increased epoxides 12(13)-EpODE, 12(13)-EpOME, 13-oxo-ODE, 15-HEPE, 20-COOH-LTB4 and decreases several diols 15,6-DiHODE, 12,13-DiHOME, 14,15-DiHETrE, 5,6-DiHETrE and 16,17-DiHDPE. Overall the inhibition of sEH in the rheumatoid arthritis model enhanced epoxides generally considered anti-inflammatory or resolutive mediators and decreased several diols with inflammatory features. These findings support the hypothesis that inhibiting the sEH increases systemic EpFA levels, advancing the understanding of the impact of these lipid mediators as therapeutical targets.

Pyroptosis and necroptosis inhibitor necrosulfonamide ameliorates lipopolysaccharide-induced inflammatory hyperalgesia in mice

Objectives: This study aimed to investigate the effect of the gasdermin D (GSDMD) and mixed lineage kinase domain-like pseudokinase (MLKL) inhibitor, necrosulfonamide (NSA), on lipopolysaccharide (LPS)-induced hyperalgesia in mice. Methods: Reaction time to a thermal stimulus within 30 seconds was measured in male mice injected with saline, LPS, and/or NSA after 6 hours using the hot plate test. Immunoblotting studies were performed to determine changes in caspase-11/GSDMD-mediated pyroptosis, receptor-interacting serine/threonine-protein kinase (RIPK) 1/RIPK3/MLKL necrosome-mediated necroptosis, demyelination, and remyelination in the brains and spinal cords of animals. Results: NSA demonstrated significant antinociceptive activity compared with LPS-treated mice. In the tissues of LPS-treated mice, NSA decreased expression of caspase-11 p20, p30-GSDMD, interleukin-1β, high-mobility-group-box 1, and semaphorin 3A, and activity of RIPK1, RIPK3, and MLKL. NSA also increased the expression of myelin proteolipid protein. Conclusion: Therefore, NSA may have therapeutic potential in the treatment of inflammatory painful conditions due to bacterial infections.

PGE2 Potentiates Orai1-Mediated Calcium Entry Contributing to Peripheral Sensitization.

Peripheral sensitization is one of the primary mechanisms underlying the pathogenesis of chronic pain. However, candidate molecules involved in peripheral sensitization remain incompletely understood. We have shown that store-operated calcium channels (SOCs) are expressed in the dorsal root ganglion (DRG) neurons. Whether SOCs contribute to peripheral sensitization associated with chronic inflammatory pain is elusive. Here we report that global or conditional deletion of Orai1 attenuates Complete Freund's adjuvant (CFA)-induced pain hypersensitivity in both male and female mice. To further establish the role of Orai1 in inflammatory pain, we performed calcium imaging and patch-clamp recordings in wild-type (WT) and Orai1 knockout (KO) DRG neurons. We found that SOC function was significantly enhanced in WT but not in Orai1 KO DRG neurons from CFA- and carrageenan-injected mice. Interestingly, the Orai1 protein level in L3/4 DRGs was not altered under inflammatory conditions. To understand how Orai1 is modulated under inflammatory pain conditions, prostaglandin E2 (PGE2) was used to sensitize DRG neurons. PGE2-induced increase in neuronal excitability and pain hypersensitivity was significantly reduced in Orai1 KO mice. PGE2-induced potentiation of SOC entry (SOCE) was observed in WT, but not in Orai1 KO DRG neurons. This effect was attenuated by a PGE2 receptor 1 (EP1) antagonist and mimicked by an EP1 agonist. Inhibition of Gq/11, PKC, or ERK abolished PGE2-induced SOCE increase, indicating PGE2-induced SOCE enhancement is mediated by EP1-mediated downstream cascade. These findings demonstrate that Orai1 plays an important role in peripheral sensitization. Our study also provides new insight into molecular mechanisms underlying PGE2-induced modulation of inflammatory pain.Significance Statement Store-operated calcium channel (SOC) Orai1 is expressed and functional in dorsal root ganglion (DRG) neurons. Whether Orai1 contributes to peripheral sensitization is unclear. The present study demonstrates that Orai1-mediated SOC function is enhanced in DRG neurons under inflammatory conditions. Global and conditional deletion of Orai1 attenuates complete Freund's adjuvant (CFA)-induced pain hypersensitivity. We also demonstrate that prostaglandin E2 (PGE2) potentiates SOC function in DRG neurons through EP1-mediated signaling pathway. Importantly, we have found that Orai1 deficiency diminishes PGE2-induced SOC function increase and reduces PGE2-induced increase in neuronal excitability and pain hypersensitivity. These findings suggest that Orai1 plays an important role in peripheral sensitization associated with inflammatory pain. Our study reveals a novel mechanism underlying PGE2/EP1-induced peripheral sensitization. Orai1 may serve as a potential target for pathological pain.

Upregulation of Calhm2 in the anterior cingulate cortex contributes to the maintenance of bilateral mechanical allodynia and comorbid anxiety symptoms in inflammatory pain conditions

Peripheral inflammation-induced chronic pain tends to evoke concomitant anxiety disorders. It's common knowledge that the anterior cingulate cortex (ACC) plays a vital role in maintaining pain modulation and negative emotions. However, the potential mechanisms of chronic inflammation pain and pain-related anxiety remain elusive. Here, it was reported that injecting complete Freund’s adjuvant (CFA) unilaterally resulted in bilateral mechanical allodynia and anxiety-like symptoms in mice via behavioral tests. In addition, CFA induced the bilateral upregulation and activation of calcium homeostasis modulator 2 (Calhm2) in ACC pyramidal neurons by quantitative analysis and double immunofluorescence staining. The knockdown of Calhm2 in the bilateral ACC by a lentiviral vector harboring ribonucleic acid (RNA) interference sequence reversed CFA-induced pain behaviors and neuronal sensitization. Furthermore, the modulating of ACC pyramidal neuronal activities via a designer receptor exclusively activated by designer drugs (DREADD)-hM4D(Gi) greatly changed Calhm2 expression, mechanical paw withdrawal thresholds (PWTs) and comorbid anxiety symptoms. Moreover, it was found that Calhm2 regulates inflammation pain promoting the upregulation of N-methyl-D-aspartic acid (NMDA) receptor 2B (NR2B) subunits. Calhm2 knockdown in ACC exhibited a significant decrease in NR2B expression. These results demonstrated that Calhm2 in ACC pyramidal neurons modulates chronic inflammation pain and pain-related anxiety symptoms, which provides a novel underlying mechanism for the development of inflammation pain.

Caffeine Impaired Acupuncture Analgesia in Inflammatory Pain by Blocking Adenosine A1 Receptor

Caffeine consumption inhibits acupuncture analgesic effects by blocking adenosine signaling. However, existing evidence remains controversial. Hence, this study aimed to examine the adenosine A1 receptor (A1R) role in moderate-dose caffeine-induced abolishing effect on acupuncture analgesia using A1R knockout mice (A1R−/−). We assessed the role of A1R in physiological sensory perception and its interaction with caffeine by measuring mechanical and thermal pain thresholds and administering A1R and adenosine 2A receptor antagonists in wild-type (WT) and A1R−/− mice. Formalin- and complete Freund's adjuvant (CFA)-induced inflammatory pain models were recruited to explore moderate-dose caffeine effect on pain perception and acupuncture analgesia in WT and A1R−/− mice. Moreover, a C-fiber reflex electromyogram in the biceps femoris was conducted to validate the role of A1R in the caffeine-induced blockade of acupuncture analgesia. We found that A1R was dispensable for physiological sensory perception and formalin- and CFA-induced hypersensitivity. However, genetic deletion of A1R impaired the antinociceptive effect of acupuncture in A1R−/− mice under physiological or inflammatory pain conditions. Acute moderate-dose caffeine administration induced mechanical and thermal hyperalgesia under physiological conditions but not in formalin- and CFA-induced inflammatory pain. Moreover, caffeine significantly inhibited electroacupuncture (EA) analgesia in physiological and inflammatory pain in WT mice, comparable to that of A1R antagonists. Conversely, A1R deletion impaired the EA analgesic effect and decreased the caffeine-induced inhibitory effect on EA analgesia in physiological conditions and inflammatory pain. Moderate-dose caffeine administration diminished the EA-induced antinociceptive effect by blocking A1R. Overall, our study suggested that caffeine consumption should be avoided during acupuncture treatment. PerspectiveModerate-dose caffeine injection attenuated EA-induced antinociceptive effect in formalin- and CFA-induced inflammatory pain mice models by blocking A1R. This highlights the importance of monitoring caffeine intake during acupuncture treatment.

Readiness of nociceptor cell bodies to generate spontaneous activity results from background activity of diverse ion channels and high input resistance.

Nociceptor cell bodies generate "spontaneous" discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia have shown that previous pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Using mouse nociceptors, we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na + or Ca 2+ and that Ca 2+ -permeable channels are especially important for larger DSFs. Partial reduction of the amplitude or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca 2+ channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na + or Ca 2+ produces DSFs that are poised to reach AP threshold if resting membrane potential depolarizes, AP threshold decreases, or DSFs become enhanced-all of which can occur under painful neuropathic and inflammatory conditions.

Chemogenetic Modulation of Posterior Insula CaMKIIa Neurons Alters Pain and Thermoregulation

The posterior insular cortex (PIC) is well positioned to perform somatosensory-limbic integration; yet, the function of neuronal subsets within the PIC in processing the sensory and affective dimensions of pain remains unclear. Here, we employ bidirectional chemogenetic modulation to characterize the function of PIC CaMKIIa-expressing excitatory neurons in a comprehensive array of sensory, affective, and thermoregulatory behaviors. Excitatory pyramidal neurons in the PIC were found to be sensitized under inflammatory pain conditions. Chemogenetic activation of excitatory CaMKIIa-expressing PIC neurons in non-injured conditions produced an increase in reflexive and affective pain- and anxiety-like behaviors. Moreover, activation of PIC CaMKIIa-expressing neurons during inflammatory pain conditions exacerbated hyperalgesia and decreased pain tolerance. However, Chemogenetic activation did not alter heat nociception via hot plate latency or body temperature. Conversely, inhibiting CaMKIIa-expressing neurons did not alter either sensory or affective pain-like behaviors in non-injured or under inflammatory pain conditions, but it did decrease body temperature and decreased hot plate latency. Our findings reveal that PIC CaMKIIa-expressing neurons are a critical hub for producing both sensory and affective pain-like behaviors and important for thermoregulatory processing. PerspectiveThe present study reveals that activation of the posterior insula produces hyperalgesia and negative affect, and has a role in thermal tolerance and thermoregulation. These findings highlight the insula as a key player in contributing to the multidimensionality of pain.

Genetic Polymorphisms of ENPP2 Are Possibly Associated with Pain Severity and Opioid Dose Requirements in Patients with Inflammatory Pain Conditions: Clinical Observation Study.

Autotaxin, encoded by the ENPP2 gene, is a known key element of neuropathic pain; however, its involvement in nociceptive pain processing remains unclear. We explored the associations between postoperative pain intensity, 24-h postoperative opioid dose requirements, and 93 ENNP2-gene single-nucleotide polymorphisms (SNPs) in 362 healthy patients who underwent cosmetic surgery using the dominant, recessive, and genotypic models. Next, we validated the associations between relevant SNPs on the one hand and pain intensity and daily opioid dosages on the other in 89 patients with cancer-related pain. In this validation study, a Bonferroni correction for multiplicity was applied on all relevant SNPs of the ENPP2 gene and their respective models. In the exploratory study, three models of two SNPs (rs7832704 and rs2249015) were significantly associated with postoperative opioid doses, although the postoperative pain intensity was comparable. In the validation study, the three models of the two SNPs were also significantly associated with cancer pain intensity (p < 0.017). Patients with a minor allele homozygosity complained of more severe pain compared with patients with other genotypes when using comparable daily opioid doses. Our findings might suggest that autotaxin is associated with nociceptive pain processing and the regulation of opioid requirements.

Prefrontal engrams of long-term fear memory perpetuate pain perception

A painful episode can lead to a life-long increase in an individual’s experience of pain. Fearful anticipation of imminent pain could play a role in this phenomenon, but the neurobiological underpinnings are unclear because fear can both suppress and enhance pain. Here, we show in mice that long-term associative fear memory stored in neuronal engrams in the prefrontal cortex determines whether a painful episode shapes pain experience later in life. Furthermore, under conditions of inflammatory and neuropathic pain, prefrontal fear engrams expand to encompass neurons representing nociception and tactile sensation, leading to pronounced changes in prefrontal connectivity to fear-relevant brain areas. Conversely, silencing prefrontal fear engrams reverses chronically established hyperalgesia and allodynia. These results reveal that a discrete subset of prefrontal cortex neurons can account for the debilitating comorbidity of fear and chronic pain and show that attenuating the fear memory of pain can alleviate chronic pain itself.

Multiplex epigenome editing of ion channel expression in nociceptive neurons abolished degenerative IVD-conditioned media-induced mechanical sensitivity.

Low back pain is a major contributor to disability worldwide and generates a tremendous socioeconomic impact. The degenerative intervertebral disc (IVD) has been hypothesized to contribute to discogenic pain by sensitizing nociceptive neurons innervating the disc to stimuli that is nonpainful in healthy patients. Previously, we demonstrated the ability of degenerative IVDs to sensitize neurons to mechanical stimuli; however, elucidation of degenerative IVDs discogenic pain mechanisms is required to develop therapeutic strategies that directly target these mechanisms. In this study, we utilized CRISPR epigenome editing of nociceptive neurons to identify mechanisms of degenerative IVD-induced changes to mechanical nociception and demonstrated the ability of multiplex CRISPR epigenome editing of nociceptive neurons to modulate inflammation-induced mechanical nociception. Utilizing an in vitro model, we demonstrated degenerative IVD-produced IL-6-induced increases in nociceptive neuron activity in response to mechanical stimuli, mediated by TRPA1, ASIC3, and Piezo2 ion channel activity. Once these ion channels were identified as mediators of degenerative IVD-induced mechanical nociception, we developed singleplex and multiplex CRISPR epigenome editing vectors that modulate endogenous expression of TRPA1, ASIC3, and Piezo2 via targeted gene promoter histone methylation. When delivered to nociceptive neurons, the multiplex CRISPR epigenome editing vectors abolished degenerative IVD-induced mechanical nociception while preserving nonpathologic neuron activity. This work demonstrates the potential of multiplex CRISPR epigenome editing as a highly targeted gene-based neuromodulation strategy for the treatment of discogenic pain, specifically; and, for the treatment of inflammatory chronic pain conditions, more broadly.

Peripheral transient receptor potential vanilloid type 4 hypersensitivity contributes to chronic sickle cell disease pain.

Debilitating pain affects the lives of patients with sickle cell disease (SCD). Current pain treatment for patients with SCD fail to completely resolve acute or chronic SCD pain. Previous research indicates that the cation channel transient receptor potential vanilloid type 4 (TRPV4) mediates peripheral hypersensitivity in various inflammatory and neuropathic pain conditions that may share similar pathophysiology with SCD, but this channel's role in chronic SCD pain remains unknown. Thus, the current experiments examined whether TRPV4 regulates hyperalgesia in transgenic mouse models of SCD. Acute blockade of TRPV4 alleviated evoked behavioral hypersensitivity to punctate, but not dynamic, mechanical stimuli in mice with SCD. TRPV4 blockade also reduced the mechanical sensitivity of small, but not large, dorsal root ganglia neurons from mice with SCD. Furthermore, keratinocytes from mice with SCD showed sensitized TRPV4-dependent calcium responses. These results shed new light on the role of TRPV4 in SCD chronic pain and are the first to suggest a role for epidermal keratinocytes in the heightened sensitivity observed in SCD.

Standardization of Ajmodadichurna and Haritakichurna

Introduction-Standardization is an essential process to evaluate the quality,purity, safety andefficacyof a drug. Standardization meansthecomparison of a test substance with a reference substance on the basis of organoleptic,physical and physiochemical parameters.This article reportson thestandardization ofAjmodadichurnaand Haritakichurna.Ajmodadichurna is a polyherbal classical Ayurvedic medicine containing 12 ingredients. It gives relief in inflammatory painful conditions such as Rheumatism, Sciatica, Neuralgic pain etc. Haritaki is an excellent antioxidant and rejuvenativeherb (Rasayana),having digestive and mild laxative action. It is a potent detoxifying and anti-aging herb that efficiently supports liver functions and metabolism as well.&#x0D; Material and Methods-Ajmodadichurna and Haritakichurna (Patanjali Company).&#x0D; Result and Discussion- In this study we have done the standardization of Ajmodadichurna and Haritakichurna. All the set parameters were sufficient to standardize both the drugs and are helpful not only to ensure the quality of drugs but also to find out the purity of the drugs.&#x0D; Conclusion-The present article deals with the importance and methods of standardization of Ajmodadichurna and Haritakichurna in order to ensure their quality, purity, safety, and efficacy.