Opioid analgesics for nociceptive cancer pain: A comprehensive review.

Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.

Neuropathic and Nociplastic Pain Profiles are Common in Adult Chronic Nonbacterial Osteitis (CNO).

Chronic nonbacterial osteitis (CNO) is a rare musculoskeletal disease causing chronic bone pain. It is known that chronic musculoskeletal pain may involve other mechanisms than nociceptive pain only. We investigate the prevalence of neuropathic and nociplastic pain in adult CNO and their association with clinical characteristics and treatment outcomes. Survey study among the Dutch adult CNO cohort (n = 84/195 participated), including PAIN-detect for neuropathic pain, and the Central Sensitization Inventory (CSI), Fibromyalgia Rapid Screening Tool (FiRST), and ACTTION-APS Pain Taxonomy (AAPT) for nociplastic pain. Clinical characteristics and CNO-related bone pain scores were compared between patients with exclusive nociceptive pain and those with nociceptive pain plus neuropathic and/or nociplastic pain (mixed pain). 31% (95% CI 21-41) of patients classified as likely having neuropathic pain according to PAIN-detect. 53% (41-64) of patients displayed central sensitization on CSI, 61% (50-72) screened positive for fibromyalgia on FiRST and 14% (7-23) of patients fulfilled the AAPT criteria, all indicative of nociplastic pain. Mixed pain was associated with longer diagnostic delay (mean difference 2.8 years, 95% CI 0.4-5.2, p = 0.023), lower educational level (72% versus 20%, p < 0.001), and opioid use (37% versus 13%, p = 0.036). Despite comparable disease severity and extent, patients with mixed pain reported significantly higher CNO-related bone pain scores. This study demonstrates the high prevalence of mixed pain in adult CNO, in which neuropathic and nociplastic pain exist alongside nociceptive inflammatory bone pain. Disease burden in CNO may extend beyond inflammatory activity, highlighting the need for a multifaceted management approach.

A TRP channel trio mediates acute noxious heat sensing.

Acute pain represents a crucial alarm signal to protect us from injury. Whereas the nociceptive neurons that convey pain signals were described more than a century ago, the molecular sensors that detect noxious thermal or mechanical insults have yet to be fully identified. Here we show that acute noxious heat sensing in mice depends on a triad of transient receptor potential (TRP) ion channels: TRPM3, TRPV1, and TRPA1. We found that robust somatosensory heat responsiveness at the cellular and behavioural levels is observed only if at least one of these TRP channels is functional. However, combined genetic or pharmacological elimination of all three channels largely and selectively prevents heat responses in both isolated sensory neurons and rapidly firing C and Aδ sensory nerve fibres that innervate the skin. Strikingly, Trpv1-/-Trpm3-/-Trpa1-/- triple knockout (TKO) mice lack the acute withdrawal response to noxious heat that is necessary to avoid burn injury, while showing normal nociceptive responses to cold or mechanical stimuli and a preserved preference for moderate temperatures. These findings indicate that the initiation of the acute heat-evoked pain response in sensory nerve endings relies on three functionally redundant TRP channels, representing a fault-tolerant mechanism to avoid burn injury.

Recent Advances in Management of Neuropathic, Nociceptive, and Chronic Pain: A Narrative Review with Focus on Nanomedicine, Gene Therapy, Stem Cell Therapy, and Newer Therapeutic Options.

PURPOSE OF REVIEW: This manuscript summarizes novel clinical and interventional approaches in the management of chronic, nociceptive, and neuropathic pain. RECENT FINDINGS: Pain can be defined as a feeling of physical or emotional distress caused by an external stimulus. Pain can be grouped into distinct types according to characteristics including neuropathic pain, which is a pain caused by disease or lesion in the sensory nervous system; nociceptive pain, which is pain that can be sharp, aching, or throbbing and is caused by injury to bodily tissues; and chronic pain, which is long lasting or persisting beyond 6 months. With improved understanding of different signaling systems for pain in recent years, there has been an upscale of methods of analgesia to counteract these pathological processes. Novel treatment methods such as use of cannabinoids, stem cells, gene therapy, nanoparticles, monoclonal antibodies, and platelet-rich plasma have played a significant role in improved strategies for therapeutic interventions. Although many management options appear to be promising, extensive additional clinical research is warranted to determine best practice strategies in the future for clinicians.

The effect of somatic pain and comorbid mental distress on oral health-related quality of life in orthodontic patients.

OBJECTIVES: The purpose of the present study was to evaluate the prevalence of somatic pain in orthodontic patients and determine whether somatic pain contributes to worsening oral health-related quality of life (OHRQoL) through the mediating effect of psychological discomfort. MATERIALS AND METHODS: Scale measurements and analyses were conducted on a cohort of 769 orthodontic outpatients, encompassing Patient Health Questionnaire-15-pain (PHQ-15-P), Hua-Xi Emotional-Distress Index (HEI), Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ), and Oral Health Impact Profile-14 (OHIP-14). RESULTS: Among the respondents, 56.3% (N = 433) reported somatic pain and 20.0% (N = 154) had mental discomfort based on PHQ-15-P and HEI scores. Patients with somatic pain symptoms had significantly higher scores of HEI and OHIP-14 (P < 0.001), and higher PHQ-15-P and HEI scores emerged as statistically significant predictors of lower OHIP-14 scores (P < 0.001). HEI scores which assessed anxiety and depression partially mediated the correlation between PHQ-15-P and OHIP-14 scores, of which anxiety accounted for 52.9% of the overall mediation effect, dominating the indirect effect. CONCLUSION: Orthodontic patients reporting somatic pains were at a significantly higher risk of worsening OHRQoL during treatment, and this adverse effect is partially mediated by anxiety and depression. CLINICAL RELEVANCE: Our findings highlight the necessity for the assessment of general health and mental well-being during orthodontic interventions. To prevent delays in treating general disorders and the potential failure of orthodontic treatments, we encourage increased attentiveness towards patients with somatic symptoms and consideration of the adverse effects of comorbid mental distress.

Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and positively influences pain sensitivity and work capacity.

The aim of the study was to investigate the effects of rat housing conditions-standard conditions, social isolation, environmental enrichment-and the subsequent reversal of these conditions on the vulnerability of the gastric mucosa to ulcerogenic stimuli, somatic pain sensitivity, and treadmill work capacity. Rats, aged 30 days, were placed in standard conditions (SC), social isolation (Is), and environmental enrichment (EE) for 4 weeks. Then half of each group underwent a reversal of housing conditions: SC rats were moved to Is, Is rats were placed in EE, EE rats were moved to Is, for 2 weeks. The other half served as a control with no change in their initial housing. Two weeks after the reversal, vulnerability of the gastric mucosa to ulcerogenic action of indomethacin (IM, 35 mg/kg, sc), somatic pain sensitivity (hot plate test), and work capacity (measured by the running distance on a treadmill) were assessed in control and reversed groups. Social isolation induced a proulcerogenic effect, increasing IM-induced gastric erosions, which was effectively reversed when rats were transferred to an environmental enrichment. Conversely, transferring rats from an environmental enrichment to social isolation exacerbated ulcerogenic action of IM. Somatic pain sensitivity and treadmill work capacity were also influenced by housing conditions, with environmental enrichment showing positive effects. The present findings show that social isolation of rats induces a proulcerogenic effect. Environmental enrichment reverses proulcerogenic action of social isolation on the gastric mucosa and increases resilience to pain stimuli and treadmill work capacity.

The Phytochemical, Quercetin, Attenuates Nociceptive and Pathological Pain: Neurophysiological Mechanisms and Therapeutic Potential.

Although phytochemicals are plant-derived toxins that are primarily produced as a form of defense against insects or microbes, several lines of study have demonstrated that the phytochemical, quercetin, has several beneficial biological actions for human health, including antioxidant and inflammatory effects without side effects. Quercetin is a flavonoid that is widely found in fruits and vegetables. Since recent studies have demonstrated that quercetin can modulate neuronal excitability in the nervous system, including nociceptive sensory transmission via mechanoreceptors and voltage-gated ion channels, and inhibit the cyclooxygenase-2-cascade, it is possible that quercetin could be a complementary alternative medicine candidate; specifically, a therapeutic agent against nociceptive and pathological pain. The focus of this review is to elucidate the neurophysiological mechanisms underlying the modulatory effects of quercetin on nociceptive neuronal activity under nociceptive and pathological conditions, without inducing side effects. Based on the results of our previous research on trigeminal pain, we have confirmed in vivo that the phytochemical, quercetin, demonstrates (i) a local anesthetic effect on nociceptive pain, (ii) a local anesthetic effect on pain related to acute inflammation, and (iii) an anti-inflammatory effect on chronic pain. In addition, we discuss the contribution of quercetin to the relief of nociceptive and inflammatory pain and its potential clinical application.

Translation and cross-cultural adaptation of Polish version of Neuropathic Pain Questionnaire (NPQ-PL) and its comparisons with different questionnaires.

AIM OF THE STUDY: The aim of this study was to assess the validity and reliability of the Polish version of the Neuropathic Pain Questionnaire (NPQ-PL), and to compare it to other diagnostic tools. CLINICAL RATIONALE FOR THE STUDY: Neuropathic pain is a burdensome condition, of which the exact prevalence is difficult to estimate. During initial screening, pain questionnaires are helpful in alerting clinicians about the need for further evaluation. MATERIAL AND METHODS: The NPQ-PL has been developed following the guidelines for translation and cultural adaptation. A total of 140 patients with chronic pain (ChP), 90 with neuropathic pain (NP), and 50 with nociceptive pain (NoP), were enrolled into this study. RESULTS: The study group consisted of 60.71% women and 39.29% men; the mean age of patients (standard deviation, SD) was 53.22 years (15.81), and the average NPQ-PL score (SD) was 0.49 (1.27). Statistically significant relationships were found between higher age distribution and greater pain intensity in the NP group compared to the NoP group. There were also significant differences in pain levels between people of different ages, with the predominance in the elderly. Cronbach's alpha coefficient of the whole questionnaire was 0.85 and the intraclass correlation coefficient (ICC) for test-retest reliability was 0.635. Using receiver-operating characteristic (ROC) curve analysis, the area under the curve (AUC) was 0.97 and the best cut-off value was 0.002, which resulted in the highest sensitivity (93.3%) and specificity (96.0%). CONCLUSIONS AND CLINICAL IMPLICATIONS: The NPQ-PL is a valid tool for discriminating between neuropathic and nociceptive pain. It can be used by physicians of various disciplines when assessing patients with ChP of various origins.

Protein Kinase A Inhibitor Attenuates the Antinociceptive Effect of NMDA-Receptor Channel Antagonists in the Capsaicin Test in Mice.

Acute nociceptive pain in mice caused by subcutaneous (intraplantar) injection of TRPV1 ion channel agonist capsaicin (1.6 µg/mouse) and the effects of protein kinase A inhibitor H-89 (0.05 mg/mouse, intraplantar injection) and NMDA receptor channel antagonists MK-801 (7.5 and 15 µg/mouse, topical application) and hemantane (0.5 mg/mouse, topical application) on the pain were assessed. MK-801 and hemantane were found to reduce the duration of the pain response. H-89 did not significantly affect the pain in animals, but preliminary administration of this drug abolished the antinociceptive effect of MK-801 (7.5 µg/mouse) and weakens the effect of hemantane (0.5 mg/mouse).

Chronic pain conditions and risk of suicidal behavior: a 10-year longitudinal co-twin control study.

BACKGROUND: Understanding the relationship between chronic pain conditions and suicidal behavior-suicide attempt, other intentional self-harm, and death by suicide-is imperative for suicide prevention efforts. Although chronic pain conditions are associated with suicidal behaviors, these associations might be attributed to unmeasured confounding or mediated via pain comorbidity. METHODS: We linked a population-based Swedish twin study (N=17,148 twins) with 10 years of longitudinal, nationwide records of suicidal behavior from health and mortality registers through 2016. To investigate whether pain comorbidity versus specific pain conditions were more important for later suicidal behavior, we modeled a general factor of pain and two independent specific pain factors (measuring pain-related somatic symptoms and neck-shoulder pain, respectively) based on 9 self-reported chronic pain conditions. To examine whether the pain-suicidal behavior associations were attributable to familial confounding, we applied a co-twin control model. RESULTS: Individuals scoring one standard deviation above the mean on the general pain factor had a 51% higher risk of experiencing suicidal behavior (odds ratio (OR), 1.51; 95% confidence interval (CI), 1.34-1.72). The specific factor of somatic pain was also associated with increased risk for suicidal behavior (OR, 1.80; 95% CI, 1.45-2.22]). However, after adjustment for familial confounding, the associations were greatly attenuated and not statistically significant within monozygotic twin pairs (general pain factor OR, 0.89; 95% CI, 0.59-1.33; somatic pain factor OR, 1.02; 95% CI, 0.49-2.11) CONCLUSION: Clinicians might benefit from measuring not only specific types of pain, but also pain comorbidity; however, treating pain might not necessarily reduce future suicidal behavior, as the associations appeared attributable to familial confounding.

Lysophosphatidic acid receptor1/3 antagonist inhibits the activation of satellite glial cells and reduces acute nociceptive responses.

Lysophosphatidic acid (LPA) exerts various biological activities through six characterized G protein-coupled receptors (LPA1-6 ). While LPA-LPA1  signaling contributes toward the demyelination and retraction of C-fiber and induces neuropathic pain, the effects of LPA-LPA1  signaling on acute nociceptive pain is uncertain. This study investigated the role of LPA-LPA1  signaling in acute nociceptive pain using the formalin test. The pharmacological inhibition of the LPA-LPA1 axis significantly attenuated formalin-induced nociceptive behavior. The LPA1  mRNA was expressed in satellite glial cells (SGCs) in dorsal root ganglion (DRG) and was particularly abundant in SGCs surrounding large DRG neurons, which express neurofilament 200. Treatment with LPA1/3 receptor (LPA1/3 ) antagonist inhibited the upregulation of glial markers and inflammatory cytokines in DRG following formalin injection. The LPA1/3 antagonist also attenuated phosphorylation of extracellular signal-regulated kinase, especially in SGCs and cyclic AMP response element-binding protein in the dorsal horn following formalin injection. LPA amounts after formalin injection to the footpad were quantified by liquid chromatography/tandem mass spectrometry, and LPA levels were found to be increased in the innervated DRGs. Our results indicate that LPA produced in the innervated DRGs promotes the activation of SGCs through LPA1 , increases the sensitivity of primary neurons, and modulates pain behavior. These results facilitate our understanding of the pathology of acute nociceptive pain and demonstrate the possibility of the LPA1 on SGCs as a novel target for acute pain control.

Electroacupuncture Zusanli (ST36) Relieves Somatic Pain in Colitis Rats by Inhibiting Dorsal Root Ganglion Sympathetic-Sensory Coupling and Neurogenic Inflammation.

Referred somatic pain triggered by hyperalgesia is common in patients with inflammatory bowel disease (IBD). It was reported that sprouting of sympathetic nerve fibers into the dorsal root ganglion (DGR) and neurogenic inflammation were related to neuropathic pain, the excitability of neurons, and afferents. The purpose of the study was to explore the potential and mechanism of electroacupuncture (EA) at Zusanli (ST36) for the intervention of colon inflammation and hyperalgesia. Sprague-Dawley (SD) was randomly divided into four groups, including control, model, EA, and sham-EA. Our results showed EA treatment significantly attenuated dextran sulfate sodium- (DSS-) induced colorectal lesions and inflammatory cytokine secretion, such as TNF-α, IL-1ß, PGE2, and IL-6. EA also inhibited mechanical and thermal pain hypersensitivities of colitis rats. Importantly, EA effectively abrogated the promotion effect of DSS on ipsilateral lumbar 6 (L6) DRG sympathetic-sensory coupling, manifested as the sprouting of tyrosine hydroxylase- (TH-) positive sympathetic fibers into sensory neurons and colocalization of and calcitonin gene-related peptide (CGRP). Furthermore, EA at Zusanli (ST36) activated neurogenic inflammation, characterized by decreased expression of substance P (SP), hyaluronic acid (HA), bradykinin (BK), and prostacyclin (PGI2) in colitis rat skin tissues corresponding to the L6 DRG. Mechanically, EA treatment reduced the activation of the TRPV1/CGRP, ERK, and TLR4 signaling pathways in L6 DRG of colitis rats. Taken together, we presumed that EA treatment improved colon inflammation and hyperalgesia, potentially by suppressing the sprouting of sympathetic nerve fibers into the L6 DGR and neurogenic inflammation via deactivating the TRPV1/CGRP, ERK, and TLR4 signaling pathways.

Burst Transspinal Magnetic Stimulation Alleviates Nociceptive Pain in Parkinson Disease-A Pilot Phase II Double-Blind, Randomized Study.

BACKGROUND AND AIMS: Nociception is the most prevalent pain mechanism in Parkinson disease (PD). It negatively affects quality of life, and there is currently no evidence-based treatment for its control. Burst spinal cord stimulation has been used to control neuropathic pain and recently has been shown to relieve pain of nociceptive origin. In this study, we hypothesize that burst transspinal magnetic stimulation (bTsMS) reduces nociceptive pain in PD. MATERIALS AND METHODS: Twenty-six patients were included in a double-blind, sham-controlled, randomized parallel trial design, and the analgesic effect of lower-cervical bTsMS was assessed in patients with nociceptive pain in PD. Five daily induction sessions were followed by maintenance sessions delivered twice a week for seven weeks. The primary outcome was the number of responders (≥ 50% reduction of average pain intensity assessed on a numerical rating scale ranging from 0-10) during the eight weeks of treatment. Mood, quality of life, global impression of change, and adverse events were assessed throughout the study. RESULTS: Twenty-six patients (46.2% women) were included in the study. The number of responders during treatment was significantly higher after active than after sham bTsMS (p = 0.044), mainly owing to the effect of the first week of treatment, when eight patients (61.5%) responded to active and two (15.4%) responded to sham bTsMS (p = 0.006); the number needed to treat was 2.2 at week 1. Depression symptom scores were lower after active (4.0 ± 3.1) than after sham bTsMS (8.7 ± 5.3) (p = 0.011). Patients' global impressions of change were improved after active bTsMS (70.0%) compared with sham bTsMS (18.2%; p = 0.030). Minor adverse events were reported in both arms throughout treatment sessions. One major side effect unrelated to treatment occurred in the active arm (death due to pulmonary embolism). Blinding was effective. CONCLUSION: BTsMS provided significant pain relief and improved the global impression of change in PD in this phase-II trial. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT04546529.

Multi-Region Microdialysis Imaging Platform Revealed Dorsal Raphe Nucleus Calcium Signaling and Serotonin Dynamics during Nociceptive Pain.

In this research, we combined our ultralight micro-imaging device for calcium imaging with microdialysis to simultaneously visualize neural activity in the dorsal raphe nucleus (DRN) and measure serotonin release in the central nucleus of the amygdala (CeA) and the anterior cingulate cortex (ACC). Using this platform, we observed brain activity following nociception induced by formalin injection in the mouse's hind paw. Our device showed that DRN fluorescence intensity increased after formalin injection, and the increase was highly correlated with the elevation in serotonin release in both the CeA and ACC. The increase in calcium fluorescence intensity occurred during the acute and inflammatory phases, which suggests the biphasic response of nociceptive pain. Furthermore, we found that the increase in fluorescence intensity was positively correlated with mouse licking behavior. Lastly, we compared the laterality of pain stimulation and found that DRN fluorescence activity was higher for contralateral stimulation. Microdialysis showed that CeA serotonin concentration increased only after contralateral stimulation, while ACC serotonin release responded bilaterally. In conclusion, our study not only revealed the inter-regional serotonergic connection among the DRN, the CeA, and the ACC, but also demonstrated that our device is feasible for multi-site implantation in conjunction with a microdialysis system, allowing the simultaneous multi-modal observation of different regions in the brain.

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.

Memory surfacing among veterans with PTSD receiving hyperbaric oxygen therapy.

Introduction: Growing evidence demonstrates that hyperbaric oxygen therapy (HBO2) induces neuroplasticity and can benefit individuals with post-traumatic stress disorder (PTSD). The aim of the current study was to evaluate the rate and pattern of memory surfacing during the course of HBO2 among veterans with combat-related PTSD. Methods: In a post-hoc analysis of a prospective study of the effect of HBO2 on PTSD symptoms in veterans, we evaluated the rate and character of memory surfacing during the course of HBO2 treatment. The treatment consisted of 60 daily 90-minute sessions, at 2 atmospheres absolute (ATA) pressure and 100% oxygen. Results: For 10 (35.7%) of the 28 participants, surfacing of new memories was reported during the HBO2 treatment course. Memories surfaced mainly during the second month of the treatment, at the mean session of 30.5±13.2. For 9 of these 10 participants, prodromal symptoms such as distress, anxiety, or worsening depression were documented; and in four, somatic pain was reported prior to memory surfacing. The pain and distress of memory surfacing resolved over the course of one to 10 days. Discussion: Among individuals with PTSD, the surfacing of new memories, accompanied by emotional distress and somatic pain, is common during HBO2. The surfacing of memories sheds light on the biological effect of HBO2 on the brain sequela of PTSD. It is highly important that in treating patients for any indication, HBO2 medical teams be aware and capable of addressing memory surfacing, particularly in those with a history of trauma.

The complement cascade in the regulation of neuroinflammation, nociceptive sensitization, and pain.

The complement cascade is a key component of the innate immune system that is rapidly recruited through a cascade of enzymatic reactions to enable the recognition and clearance of pathogens and promote tissue repair. Despite its well-understood role in immunology, recent studies have highlighted new and unexpected roles of the complement cascade in neuroimmune interaction and in the regulation of neuronal processes during development, aging, and in disease states. Complement signaling is particularly important in directing neuronal responses to tissue injury, neurotrauma, and nerve lesions. Under physiological conditions, complement-dependent changes in neuronal excitability, synaptic strength, and neurite remodeling promote nerve regeneration, tissue repair, and healing. However, in a variety of pathologies, dysregulation of the complement cascade leads to chronic inflammation, persistent pain, and neural dysfunction. This review describes recent advances in our understanding of the multifaceted cross-communication that takes place between the complement system and neurons. In particular, we focus on the molecular and cellular mechanisms through which complement signaling regulates neuronal excitability and synaptic plasticity in the nociceptive pathways involved in pain processing in both health and disease. Finally, we discuss the future of this rapidly growing field and what we believe to be the significant knowledge gaps that need to be addressed.

Engineering of highly potent and selective HNTX-III mutant against hNav1.7 sodium channel for treatment of pain.

Human voltage-gated sodium channel Nav1.7 (hNav1.7) is involved in the generation and conduction of neuropathic and nociceptive pain signals. Compelling genetic and preclinical studies have validated that hNav1.7 is a therapeutic target for the treatment of pain; however, there is a dearth of currently available compounds capable of targeting hNav1.7 with high potency and specificity. Hainantoxin-III (HNTX-III) is a 33-residue polypeptide from the venom of the spider Ornithoctonus hainana. It is a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels. Here, we report the engineering of improved potency and Nav selectivity of hNav1.7 inhibition peptides derived from the HNTX-III scaffold. Alanine scanning mutagenesis showed key residues for HNTX-III interacting with hNav1.7. Site-directed mutagenesis analysis indicated key residues on hNav1.7 interacting with HNTX-III. Molecular docking was conducted to clarify the binding interface between HNTX-III and Nav1.7 and guide the molecular engineering process. Ultimately, we obtained H4 [K0G1-P18K-A21L-V] based on molecular docking of HNTX-III and hNav1.7 with a 30-fold improved potency (IC50 0.007 ± 0.001 µM) and >1000-fold selectivity against Nav1.4 and Nav1.5. H4 also showed robust analgesia in the acute and chronic inflammatory pain model and neuropathic pain model. Thus, our results provide further insight into peptide toxins that may prove useful in guiding the development of inhibitors with improved potency and selectivity for Nav subtypes with robust analgesia.

Greater interruption of visual processing and memory encoding by visceral than somatic pain in healthy volunteers - An fMRI study.

Visceral pain is regarded as more salient than somatic pain. It has greater affective and emotional components, i.e., it elicits higher levels of pain-related fear and is perceived as more unpleasant than somatic pain. In this fMRI study, we examined the neural effects of painful visceral as compared to painful somatic stimulation on visual processing and memory encoding in a visual categorization and surprise recognition task in healthy volunteers. During the categorization task, participants received either rectal distensions or heat stimuli applied to the forearm, with stimuli being individually matched for unpleasantness. Behaviorally, visceral pain reduced memory encoding as compared to somatic pain (Kleine-Borgmann et al., 2021). Imaging analyses now revealed that visceral pain was associated with reduced activity (i.e., greater pain-related interruption) in neural areas typically involved in visual processing and memory encoding. These include the parahippocampal gyrus, fusiform gyrus, striatum, occipital cortex, insula, and the amygdala. Moreover, reduced engagement of the lateral occipital complex during visual categorization under visceral pain was associated with higher visceral pain-related fear. These findings obtained in healthy volunteers shed light on the neural circuitry underlying the interruptive effect of visceral pain and pave the way for future studies in patient samples.

Pinocembrin relieves hip fracture-induced pain by repressing spinal substance P signaling in aged rats.

Whether pinocembrin (PCN) could be used to alleviate hip fracture-induced pain is investigated in this research. Aged rats with hip fractures were treated with vehicle or 80 mg/kg/day PCN from week 3 to week 4. Then, hind paw mechanical allodynia, unweighting, warmth, and thickness were measured. The microglia and astrocytes activation and proliferation markers in the spinal dorsal horn were detected with real-time PCR and immunofluorescence staining. The relative expression of substance P and its receptor, tachykinin receptor 1 (Tacr1), was detected with enzyme-linked immunosorbent assay (ELISA) and Western blots. The antinociceptive effect of Tacr1 inhibitor LY303870 was also testified. PCN alleviated hip fracture-induced hind paw nociceptive (allodynia and unweighting) and vascular changes (warmth and thickness) in aged rats with diminished microglia and astrocytes activation and proliferation in the spinal dorsal horn. Upregulated substance P and Tacr1 were induced after hip fracture, which could be reversed by PCN treatment. Furthermore, LY303870 treatment partially reversed both spinal nociceptive sensitization and vascular changes after hip fracture. Substance P signaling contributes to the nociceptive and vascular changes observed in the hip fracture, which could be alleviated by PCN.NEW & NOTEWORTHY Substance P signaling contributes to the nociceptive and vascular changes observed in hip fracture, which could be alleviated by PCN.