Cold Pain Research Articles

Neuropathic Pain and Clinical Sensory Testing in Young Patients with Sickle Cell Disease

Abstract Background The pathophysiology of pain in sickle cell disease (SCD) is complex and not fully understood. Neuropathic pain (NP) is an emerging theory of chronic pain in SCD. Nevertheless, assessment of NP is not a part of standard care of patients with SCD. Aim and Objectives To study the frequency of neuropathic pain among young patients with SCD by ID-P questionnaire and Clinical Sensory Testing (CST). Patients and Methods In this cross-sectional study Patients with SCD were recruited and data were collected on sociodemographic and clinical criteria of the disease. ID Pain (ID-P) questionnaire was used as a screening tool for NP. We performed a bedside clinical sensory testing (CST) including cold, warm, and pressure detection, cold, heat, mechanical and pressure pain threshold. Results Fifty-six participants were screened for eligibility and twelve of them were excluded; ten had stroke and two patients were diabetic. A total of 44 participants (25 males and 19 females) were included, their mean age was 12.4 years (SD 4.8; range 5.9-25 years). Screening of NP using the ID-P questionnaire revealed that 22.7% of the study cohort likely had NP. On the other hand, 34% of the participants had abnormal CST; 10 patients (22.7%) had abnormal mechanical pain threshold, 6 (13.6%) showed abnormal cold pain threshold, 2 (4.5%) had abnormal heat pain threshold and 2 (4.5%) with abnormal pressure threshold, while only one patient had delayed cold detection. Conclusion Neuropathic pain, as assessed by ID-P questionnaire and CST, is not uncommon in young patients with SCD.

Abstract A092: Tobacco use and prevalence of oral premalignant lesions, among Malayali tribes, Yelagiri Hills, Tamil nadu, India

Abstract BACKGROUND: India has the second largest tribal population of the world next to the African countries. About half of the world’s autochthonous people live in India, thus making India home to many tribes which have an interesting and varied history of origins, customs and social practices. The present study was conducted to assess the tobacco use and prevalence of precancerous lesions and oral cancer among Malayali tribes, Yelagiri Hills, Tamil nadu, India. METHODOLOGY The inhabitants of the 14 villages of the Yelagiri hills, who have completed 18years and residing for more than 15years present on the day of examination and who were willing to participate in the study were included. Data was collected from a cross-sectional survey, using a Survey Proforma, clinical examination and a pre-tested questionnaire. An intra-oral examination was carried out by a single examiner using WHO Oral Health Surveys – Basic Methods Proforma (1997). ResultsThe overall prevalence of smokeless and smoking tobacco was 78.8% and 65.2% respectively among 1550 study population. Of those who had the habit of smoking, 26% smoked beedi, 10.9% smoked cigarette, 65% chewed raw tobacco, 18% chewed Hans and 28% had a combination of smoking and smokeless tobacco usage. Around 49.8% of samples were stained positive for precancerous and cancerous lesions of the oral cavity. The highest number of positive samples were from buccal mucosa with 46.2% subjects and 12% for labial mucosa. The reason for practicing these habits were as a measure to combat the cold, relieving stress and body pain after work, and the lack of awareness of the hazards of the materials used. Prevalence of oral mucosal lesions in the study population was due to tobacco usage and alcohol consumption and lack of awareness regarding the deleterious effects of the products used. CONCLUSION Oral cancer is highly prevalent in this Malayali tribes owing to high tobacco consumption rates and habits warranting the cessation center a priority. Also, early detection and screening are vital to attaining better outcomes. Citation Format: Delfin Lovelina Francis. Tobacco use and prevalence of oral premalignant lesions, among Malayali tribes, Yelagiri Hills, Tamil nadu, India [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A092.

Slow depolarizing electrical stimuli reveal differential time courses of nociceptor recovery after prolonged topical capsaicin in human skin.

We examined de-functionalization and temporal functional recovery of C-nociceptor evoked pain after topical 8% capsaicin applied for 4 consecutive days. Capsaicin and placebo patches were applied to human forearm skin (n = 14). Cold, warmth and heat pain thresholds, pain NRS to electrical and thermal (48°C, 5 s) stimuli and axon reflex flare were recorded weekly for 49 days. Mechanical and heat sensitive ('polymodal') nociceptors were activated by single electrical half-period sinusoidal pulses (0.5 s, 1 Hz). Mechanical and heat insensitive ('silent') nociceptors were activated by 4 Hz sinusoidal stimuli. Capsaicin abolished heat pain. Sensation to electrical sinusoidal stimulation was reduced but never abolished during the treatment. Pain to electrical 1 Hz 'polymodal' nociceptor stimulation took longer to recover than pain ratings to 4 Hz 2.5 s sinusoidal stimulation activating 'polymodal' and 'silent' nociceptors (35 vs. 21 days). Heat pain was indifferent to placebo from day 21-49. Axon reflex flare was abolished during capsaicin and only recovered to ~50% even after 49 days. Capsaicin abolishes heat transduction at terminal nociceptive endings, whereas small-diameter axons sensitive to sinusoidal electrical stimulation can still be activated. 1 Hz depolarizing stimuli evoke burst discharges, as demonstrated before, and recover slower after capsaicin than single pulses induced by 4 Hz. The difference in recovery suggests differential time course of functional regeneration for C-nociceptor sub-types after capsaicin. All sensations recovered completely within 7 weeks in healthy subjects. Our findings contrast analgesia lasting for months in spontaneous neuropathic pain patients treated with 8% capsaicin. Sinusoidal electrical stimulation can still activate small diameter axons desensitized to heat after 4 consecutive days of topical 8% capsaicin application and reveals differential temporal functional regeneration of C-nociceptor sub-types. Electrical sinusoidal stimulation may detect such axons that no longer respond to heat stimuli in neuropathic skin.

Sensory dysfunction in SMA type 2 and 3 - adaptive mechanism or concomitant target of damage?

BackgroundThe motor neuron survival protein performs numerous cellular functions; hence, spinal muscular atrophy (SMA) is considered to be a multi-organ disease with possible sensory system damage. The controversy surrounding the presence of sensory disturbances, prompted us to conduct standard electrophysiological studies and assess the sensory thresholds for different modalities in adults with SMA types 2 and 3. The study group consisted of 44 adult SMA patients (types 2 and 3). All patients underwent neurological examination using the Hammersmith Functional Motor Scale – Expanded (HFMSE). Standard sensory electrophysiological studies in the ulnar nerve and the estimation of vibratory, temperature, and warm- and cold-induced pain thresholds with temperature dispersion assessment were performed using quantitative sensory testing (QST).ResultsThe most repeatable result was the high amplitude of the sensory nerve action potentials (SNAP) in SMA patients compared to controls. This was higher in type 2 patients compared to type 3a and 3b patients and patients with low HFSME scores. Patients with SMA, especially type 3b presented a longer sensory latency and slower conduction velocity than did controls. Cold pain threshold was higher and warm dispersion larger in SMA. The vibratory limit was higher in patients with high HFSME scores.ConclusionsA high SNAP amplitude suggests sensory fibre hyperactivity, which may be based on overactivation of metabolic pathways as an adaptive mechanism in response to SMN protein deficiency with additionally coexisting small C- and A-delta fibre damage. SMA patients seem to have a concomitant, mild demyelinating process present at the early SMA stage.

The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons.

The mechanistic target of rapamycin (mTOR) signalling pathway is a key regulator of cell growth and metabolism. Its deregulation is implicated in several diseases. The macrolide rapamycin, a specific inhibitor of mTOR, has immunosuppressive, anti-inflammatory and antiproliferative properties. Recently, we identified tacrolimus, another macrolide immunosuppressant, as a novel activator of TRPM8 ion channels, involved in cold temperature sensing, thermoregulation, tearing and cold pain. We hypothesized that rapamycin may also have agonist activity on TRPM8 channels. Using calcium imaging and electrophysiology in transfected HEK293 cells and wildtype or Trpm8 KO mouse DRG neurons, we characterized rapamycin's effects on TRPM8 channels. We also examined the effects of rapamycin on tearing in mice. Micromolar concentrations of rapamycin activated rat and mouse TRPM8 channels directly and potentiated cold-evoked responses, effects also observed in human TRPM8 channels. In cultured mouse DRG neurons, rapamycin increased intracellular calcium levels almost exclusively in cold-sensitive neurons. Responses were markedly decreased in Trpm8 KO mice or by TRPM8 channel antagonists. Cutaneous cold thermoreceptor endings were also activated by rapamycin. Topical application of rapamycin to the eye surface evokes tearing in mice by a TRPM8-dependent mechanism. These results identify TRPM8 cationic channels in sensory neurons as novel molecular targets of the immunosuppressant rapamycin. These findings may help explain some of its therapeutic effects after topical application to the skin and the eye surface. Moreover, rapamycin could be used as an experimental tool in the clinic to explore cold thermoreceptors.

Combined use of CLP290 and bumetanide alleviates neuropathic pain and its mechanism after spinal cord injury inrats.

We aimed to explore whether the combination of CLP290 and bumetanide maximally improves neuropathic pain following spinal cord injury (SCI) and its possible molecular mechanism. Rats were randomly divided into five groups: Sham, SCI + vehicle, SCI + CLP290, SCI + bumetanide, and SCI + combination (CLP290 + bumetanide). Drug administration commenced on the 7th day post-injury (7 dpi) and continued for 14 days. All rats underwent behavioral assessments for 56 days to comprehensively evaluate the effects of interventions on mechanical pain, thermal pain, cold pain, motor function, and other relevant parameters. Electrophysiological assessments, immunoblotting, and immunofluorescence detection were performed at different timepoints post-injury, with a specific focus on the expression and changes of KCC2 and NKCC1 proteins in the lumbar enlargement of the spinal cord. CLP290 and bumetanide alleviated SCI-associated hypersensitivity and locomotor function, with the combination providing enhanced recovery. The combined treatment group exhibited the most significant improvement in restoring Rate-Dependent Depression (RDD) levels. In the combined treatment group and the two individual drug administration groups, the upregulation of potassium chloride cotransporter 2 (K+-Cl-cotransporter 2, KCC2) expression and downregulation of sodium potassium chloride cotransporter 1 (Na+-K+-Cl-cotransporter 1, NKCC1) expression in the lumbar enlargement area resulted in a significant increase in the KCC2/NKCC1 ratio compared to the SCI + vehicle group, with the most pronounced improvement seen in the combined treatment group. Compared to the SCI + vehicle group, the SCI + bumetanide group showed no significant paw withdrawal thermal latency (PWTL) improvement at 21 and 35 dpi, but a notable enhancement at 56 dpi. In contrast, the SCI + CLP290 group significantly improved PWTL at 21 days, with non-significant changes at 35 and 56 days. At 21 dpi, KCC2 expression was marginally higher in monotherapy groups versus SCI + vehicle, but not significantly. At 56 dpi, only the SCI + bumetanide group showed a significant difference in KCC2 expression compared to the control group. Combined application of CLP290 and bumetanide effectively increases the ratio of KCC2/NKCC1, restores RDD levels, enhancesGABAA receptor-mediated inhibitory function in the spinal cord, and relieves neuropathic pain in SCI; Bumetanide significantly improves neuropathic pain in the long term, whereas CLP290 demonstrates a notable short-term effect.

Hyperalgesia in Patients With a History of Opioid Use Disorder

Short-term and long-term opioid treatment have been associated with increased pain sensitivity (ie, opioid-induced hyperalgesia). Treatment of opioid use disorder (OUD) mainly involves maintenance with methadone and buprenorphine, and observations of heightened cold pain sensitivity among patients are often considered evidence of opioid-induced hyperalgesia. To critically examine the evidence that hyperalgesia in patients with OUD is related to opioid use. Web of Science, PubMed, and Embase between March 1, 2023, and April 12, 2024, were searched. Studies assessing cold pressor test (CPT) pain responses during treatment seeking, pharmacological treatment, or abstinence in patients with OUD history were included. Multilevel random-effects models with robust variance estimation were used for all analyses. Study quality was rated with the JBI checklist. Funnel plots and Egger regression tests were used to assess reporting bias. Main outcomes were pain threshold, tolerance, and intensity in patients and healthy controls, and unstandardized, standardized (Hedges g), and percentage differences (%Δ) in these measures between patients and controls. The association between pain sensitivity and opioid tolerance, withdrawal, and abstinence indices was tested with meta-regression. Thirty-nine studies (1385 patients, 741 controls) met the inclusion criteria. Most studies reported CPT data on patients undergoing opioid agonist treatment. These patients had a mean 2- to 3-seconds lower pain threshold (95% CI, -4 to -1; t test P = .01; %Δ, -22%; g = -0.5) and 29-seconds lower pain tolerance (95% CI, -39 to -18; t test P < .001; %Δ, -52%; g = -0.9) than controls. Egger tests suggested that these differences may be overestimated. There were some concerns of bias due to inadequate sample matching and participant dropout. Meta-regressions yielded no clear support for hyperalgesia being opioid related. Patients receiving opioid agonist treatment for OUD are hypersensitive to cold pain. It remains unclear whether hyperalgesia develops prior to, independent of, or as a result of long-term opioid treatment. Regardless, future studies should investigate the impact of hyperalgesia on patients' well-being and treatment outcomes.

Assessment of small nerve fiber function as an early marker of peripheral neuropathy in children and adolescents with type 1 diabetes mellitus (T1DM).

This study aimed to assess subclinical peripheral diabetic neuropathy (PDN) in adolescents with type 1 diabetes mellitus (T1DM). Subjects included 53 T1DM patients (age (mean ± SE): 15.8 ± 0.54 years, disease duration: 6.0 ± 0.51 years and HbA1c: 7.9 ± 0.19%), and 37 healthy gender matched controls (age: 15.6 ± 0.52 years). PDN was assessed by vibration perception threshold (VPT) and by quantitative sensory testing (QST). In controls, 95% confidence intervals were calculated. Among patients, VPT prevalence of abnormality ranged from 60-73.4% on different sites. Higher VPT was found in patients on all examined sites (p < 0.01). In controls, VPT correlated with height (r = 0.48, p = 0.05). Regarding QST prevalence of abnormality, cold detection threshold (CDT) ranged 7.3-39.0%, cold pain threshold (CPT) ranged 22.22-29.63%, hot detection threshold (HDT) ranged 34.14-63.41%, and hot pain threshold (HPT) ranged 15.79-36.84%. In patients, CPT correlated with BMI (r = 0.42, p = 0.05) and diabetes duration, (r = 0.40, p = 0.05), HPT correlated with age (r = 0.36, p = 0.05) and height (r = 0.35, p = 0.05), while in controls with BMI (r = 0.51, p = 0.05). No correlation of VPT or QST with HbA1c was observed. Adolescents with T1DM in this study, although asymptomatic, showed a high prevalence of impaired indices of PDN, highlighting potential clinical implications of early identification of PDN.

Acute analgesic effect of nicotine vaping using three experimental pain induction tasks: a randomized, placebo-controlled laboratory study.

Pain and nicotine use are co-occurring conditions with a significant impact on health. Experimental evidence supports an acute analgesic effect of nicotine which may reinforce nicotine use among those with chronic pain. Evidence for nicotine analgesia have primarily been gathered in combustible cigarette users and have not been extended to electronic nicotine delivery systems (ENDS or vaping). Furthermore, the mechanisms of nicotine analgesia in humans are not well understood. Assess the effect of acute vaped nicotine on subjective and behavioral indices of pain sensitivity using three tasks designed to probe distinct mechanisms of analgesia. This study recruited ENDS users (N = 86) to undergo a paced vaping protocol followed by pain tasks in counterbalanced order. Across four sessions, participants vaped e-liquid containing nicotine or placebo, and flavor or no-flavor in a 2 × 2 within-subject design. Assessments included cold pressor, submaximal effort tourniquet to induce ischemic pain, and temporal summation of heat pain, an index of central sensitization. Compared to placebo, nicotine increased cold pressor pain tolerance (ηp2 = 0.031), ischemic pain threshold (ηp2 = 0.073) and tolerance (ηp2 = 0.056) but had no effect on temporal summation of pain. Flavor did not affect pain sensitivity. Females reported greater ischemic pain sensitivity (ηp2 = 0.027) and greater reductions in craving (ηp2 = 0.086). Consistent with research from tobacco smoking, analgesia may be reinforcing and contribute to nicotine dependence among ENDS users. More research on sex differences is warranted.

Transient receptor potential melastatin 8 contributes to the interleukin-33-mediated cold allodynia in a mouse model of neuropathic pain.

Cold allodynia is a common complaint of patients suffering from neuropathic pain initiated by peripheral nerve injury. However, the mechanisms that drive neuropathic cold pain remain elusive. In this study, we show that the interleukin (IL)-33/ST2 signaling in the dorsal root ganglion (DRG) is a critical contributor to neuropathic cold pain by interacting with the cold sensor transient receptor potential melastatin 8 (TRPM8). By using the St2-/- mice, we demonstrate that ST2 is required for the generation of nociceptor hyperexcitability and cold allodynia in a mouse model of spared nerve injury (SNI). Moreover, the selective elimination of ST2 function from the Nav1.8-expressing nociceptor markedly suppresses SNI-induced cold allodynia. Consistent with the loss-of-function studies, intraplantar injection of recombinant IL-33 (rIL-33) is sufficient to induce cold allodynia. Mechanistically, ST2 is co-expressed with TRPM8 in both mouse and human DRG neurons and rIL-33-induced Ca2+ influx in mouse DRG neurons through TRPM8. Co-immunoprecipitation assays further reveal that ST2 interacts with TRPM8 in DRG neurons. Importantly, rIL-33-induced cold allodynia is abolished by pharmacological inhibition of TRPM8 and genetic ablation of the TRPM8-expressing neurons. Thus, our findings suggest that the IL-33/ST2 signaling mediates neuropathic cold pain through downstream cold-sensitive TRPM8 channels, thereby identifying a potential analgesic target for the treatment of neuropathic cold pain.

Recovery of the Infraorbital Nerve Following Open Reduction and Fixation Surgery of Zygomaticomaxillary Complex Fractures-A Prospective Cohort Study Based on Quantitative Sensory Testing.

This study aimed to assess the sensory function of the infraorbital nerve in patients with fractures of the zygomatic complex who underwent open reduction and internal fixation at different time points using quantitative sensory testing, which was established by the German Neuropathic Pain Research Network, comprising a 7-item mechanical and thermal sensory test. A total of 21 patients (age range 17-46y, 14 males) with unilateral zygomatic complex fractures were included. Quantitative sensory testing was conducted before the operation and at 1 week, 3 months, and 6 months operatively, with cold detection threshold, warmth detection threshold, cold pain threshold, heat pain threshold, mechanical detection threshold, mechanical pain threshold, pressure pain threshold, and vibration detection threshold being measured in bilateral infraorbital regions. Notable changes in sensitivity were observed in all values except for the mechanical pain threshold. In the majority of patients with zygomaticomaxillary complex fractures, infraorbital hypoesthesia was significantly improved within 3 months postoperatively, and almost complete recovery could be achieved by 6 months postoperatively.

Pain From a Distance: Can Third-Person Self-Talk Mitigate Pain Sensitivity and Pain Related Distress During Experimentally Induced Pain?

Pain is self-immersive, leading to a narrow, egocentric focus on the self in the here and now. Preliminary evidence suggests that distancing oneself from the pain can reduce experimentally induced pain. The primary aim of this experimental study was to examine whether a hitherto unexplored, simple self-distancing strategy - "third-person self-talk" - has an analgesic effect on physiological and psychological pain variables. Participants (N = 292) were randomly assigned to one of four conditions (third-person self-talk, first-person self-talk, and two control conditions). Pain was induced with a cold pressor apparatus and pain tolerance, pain intensity, negative affect and blood pressure were measured for each group. While in pain, participants engaged in strategic self-talk aided by cue-cards. Data were analyzed with univariate planned comparisons. Few significant differences emerged for the third-person self-talk versus the other conditions. It is concluded that third-person self-talk does not seem to have a meaningful effect on physiological and psychological pain variables, although a small effect size could not be ruled out. Practical implications are discussed.The study was registered at ClinicalTrials.gov with the ClinicalTrials.gov ID NCT05511857.

Neuroinflammatory activation in sensory and motor regions of the cortex is related to sensorimotor function in individuals with low back pain maintained by nociplastic mechanisms: A preliminary proof-of-concept study.

Chronic pain involves communication between neural and immune systems. Recent data suggest localization of glial (brain immune cells) activation to the sensorimotor regions of the brain cortex (S1/M1) in chronic low back pain (LBP). As glia perform diverse functions that impact neural function, activation might contribute to sensorimotor changes, particularly in LBP maintained by increased nervous system sensitivity (i.e., nociplastic pain). This preliminary proof-of-concept study aimed to: (i) compare evidence of neuroinflammatory activation in S1/M1 between individuals with and without LBP (and between nociceptive and nociplastic LBP phenotypes), and (ii) evaluate relationships between neuroinflammatory activation and sensorimotor function. Simultaneous PET-fMRI measured neuroinflammatory activation in functionally defined S1/M1 in pain-free individuals (n = 8) and individuals with chronic LBP (n = 9; nociceptive: n = 4, nociplastic: n = 5). Regions of S1/M1 related to the back were identified using fMRI during motor tasks and thermal stimuli. Sensorimotor measures included single and paired-pulse transcranial magnetic stimulation (TMS) and quantitative sensory testing (QST). Sleep, depression, disability and pain questionnaires were administered. Neuroinflammatory activation was greater in the lower back cortical representation of S1/M1 of the nociplastic LBP group than both nociceptive LBP and pain-free groups. Neuroinflammatory activation in S1/M1 was positively correlated with sensitivity to hot (r = 0.52) and cold (r = 0.55) pain stimuli, poor sleep, depression, disability and BMI, and negatively correlated with intracortical facilitation (r = -0.41). This preliminary proof-of-concept study suggests that neuroinflammation in back regions of S1/M1 in individuals with nociplastic LBP could plausibly explain some characteristic features of this LBP phenotype. Neuroinflammatory activation localized to sensorimotor areas of the brain in individuals with nociplastic pain might contribute to changes in sensory and motor function and aspects of central sensitization. If cause-effect relationships are established in longitudinal studies, this may direct development of therapies that target neuroinflammatory activation.

Effects of Zhoutian moxibustion on pain symptoms and inflammatory factors in patients with ankylosing spondylitis of cold-damp obstruction

To observe the effects of Zhoutian moxibustion on pain symptoms and serum inflammatory factors in patients with ankylosing spondylitis of cold-damp obstruction. Eighty-four patients with ankylosing spondylitis of cold-damp obstruction were randomly divided into a Zhoutian moxibustion group (42 cases, 2 cases dropped out) and a governor vessel moxibustion group (42 cases, 2 cases dropped out, 1 case discontinued). Both groups were given oral administration of sulfasalazine enteric-coated tablets as basic treatment. The governor vessel moxibustion group was treated with moxibustion box from Dazhui (GV 14) to Yaoyangguan (GV 3), one hour per treatment; the Zhoutian moxibustion group was treated with moxibustion box from Tiantu (CV 22) to Zhongji (CV 3) in addition to the governor vessel moxibustion group, two hours per treatment. Both groups were treated once every 3 days, twice a week, for a total of 9 weeks. The pain symptom scores of the two groups were observed before treatment and at the 3rd, 6th, and 9th weeks into treatment. ELISA was used to detect the levels of serum interleukin (IL)-1β, IL-18, and tumor necrosis factor-α (TNF-α) before and after treatment, and the clinical efficacy of the two groups was evaluated after treatment. Except for the joint pain scores at the 3rd week into treatment, the total scores and the each sub-item score of pain symptom in the two groups were lower than those before treatment at the 3rd, 6th, and 9th weeks into treatment (P<0.05); at the 3rd, 6th, and 9th weeks into treatment, the total scores of pain symptom and the scores of lumbar sacral pain, back pain, joint cold pain, and limited mobility in the Zhoutian moxibustion group were lower than those in the governor vessel moxibustion group (P<0.05). After treatment, the levels of serum IL-1β, IL-18 and TNF-α in both groups were lower than those before treatment (P<0.05), and the levels of serum IL-1β, IL-18, and TNF-α in the Zhoutian moxibustion group were lower than those in the governor vessel moxibustion group (P<0.05). The total effective rate was 90.0% (36/40) in the Zhoutian moxibustion group, which was higher than 76.9% (30/39) in the governor vessel moxibustion group (P<0.05). Zhoutian moxibustion could effectively improve various pain symptoms in patients with ankylosing spondylitis of cold-damp obstruction, and reduce the expression of inflammatory factors.

Rat Model of Neuropathic Pain Induced by Spinal Nerve Ligation: A New Approach via an Oblique Lateral Incision.

The spinal nerve ligation (SNL) model is a typical peripheral neuropathic pain model. During its construction, the removal of paraspinal muscles and transverse processes typically occurs, resulting in additional trauma that may potentially affect the pathophysiologic process of neuropathic pain. This study aimed to investigate the feasibility of establishing a more reliable SNL model using an oblique lateral approach. 36 adult male Sprague-Dawley rats were randomly divided into three groups: the traditional SNL (T-SNL) group, the new SNL (N-SNL) group (where the left L5 spinal nerve was ligated with a titanium clip via an oblique lateral approach), and the sham-operated (Sham) group. The operation time, Intraoperative bleeding, the number of rats that died, gait behavior, mechanical and cold pain threshold were recorded and measured. Stereology technology was used to calculate the number of microglia in spinal dorsal horn, and the Enzyme-linked immunosorbent assay (ELISA) technology was used to detect the expression of TNF-α and IL-1β in spinal cord as well as C-reactive protein (CRP) in serum in order to assess the effect of surgery on animal inflammation. Compared with the T-SNL group, operative time and intraoperative bleeding were significantly decreased in the N-SNL group. Within 14 days postoperation, one rat in the N-SNL group was died, two rats in the T-SNL group were died. Compared with the Sham group, the N-SNL group showed obvious spontaneous pain behavior, decreased the pain thresholds, the number of microglia and the expression of TNF-α and IL-1β were significantly increased, and there was no significant difference in these indexes compared with T-SNL group. There was no significant difference in serum CRP levels among the three groups. This study suggests that the oblique lateral approach SNL model is a reliable NP model with the advantages of good reproducibility, accessibility, and low trauma.

Somatosensory alterations after single-unit dental implant immediate loading: A 1-year follow-up study

ObjectiveThis cohort study aimed to assess the incidence of somatosensory alterations after implant surgery using standardized quantitative and qualitative sensory testing. Methods33 participants with single-tooth loss, undergoing immediate implant loading were included. Quantitative Sensory Testing (QST) and Qualitative Sensory Testing (QualST) were conducted at eight time points over a year (baseline to 1 year). Two-Way Repeated Measures ANOVA and post hoc Tukey test were used on QST values and Cochran Q test on QualST. ResultsThe study revealed significant increase in thermal thresholds overtime. At the operated side, overall Cold Pain Threshold (extraoral: p = 0.030; intraoral: p < 0.001), and Cold Detection Threshold (intraoral: p < 0.001) increased overtime. In contralateral region, maxilla Cold Detection Threshold (extraoral: p = 0.024; intraoral: p = 0.031), Warm Detection Threshold (extraoral: p = 0.026; intraoral: p = 0.047) and overall Cold Pain Threshold (extraoral and intraoral: p < 0.001) also increased. QualST showed extraoral pinprick (p = 0.032) and intraoral pinprick (p = 0.000), cold (p = 0.000) and touch (p = 0.002) stimuli abnormalities overtime. ConclusionsSomatosensory alterations after implant surgery were detected in both quantitative and qualitative sensory assessments, but rapidly decreased during the first follow-ups, and then continuously until 1-year. Clinical SignificanceThis study provides clinical and controlled evidence on the real effect of the somatosensory alterations overtime, leading to a better understanding of neurosensory behaviour after single-tooth dental implant rehabilitation.

TMC6 functions as a GPCR-like receptor to sense noxious heat via Gαq signaling

Thermosensation is vital for the survival, propagation, and adaption of all organisms, but its mechanism is not fully understood yet. Here, we find that TMC6, a membrane protein of unknown function, is highly expressed in dorsal root ganglion (DRG) neurons and functions as a Gαq-coupled G protein-coupled receptor (GPCR)-like receptor to sense noxious heat. TMC6-deficient mice display a substantial impairment in noxious heat sensation while maintaining normal perception of cold, warmth, touch, and mechanical pain. Further studies show that TMC6 interacts with Gαq via its intracellular C-terminal region spanning Ser780 to Pro810. Specifically disrupting such interaction using polypeptide in DRG neurons, genetically ablating Gαq, or pharmacologically blocking Gαq-coupled GPCR signaling can replicate the phenotype of TMC6 deficient mice regarding noxious heat sensation. Noxious heat stimulation triggers intracellular calcium release from the endoplasmic reticulum (ER) of TMC6- but not control vector-transfected HEK293T cell, which can be significantly inhibited by blocking PLC or IP3R. Consistently, noxious heat-induced intracellular Ca2+ release from ER and action potentials of DRG neurons largely reduced when ablating TMC6 or blocking Gαq/PLC/IP3R signaling pathway as well. In summary, our findings indicate that TMC6 can directly function as a Gαq-coupled GPCR-like receptor sensing noxious heat.

The Interrelationships Between Cognitive Biases for Pain: An Experimental Study

Contemporary pain models highlight cognitive-processing biases (ie, attention bias [AB], interpretation bias [IB], and memory bias [MB]) as key processes that contribute to poor pain outcomes. However, existing research has yielded inconsistent findings regarding the presence and impact of these biases on pain outcomes. Recognizing the need to explore these biases simultaneously, contemporary pain models suggest that cognitive biases (CBs) are interrelated, and may have a combined impact upon pain problems. The current study aims to investigate the interrelationships between CBs using the PainAIM paradigm, a novel approach enabling simultaneous evaluation of pain-related AB, IB, and MB using cues signaling actual pain rather than symbolic information. We hypothesized the presence and positive associations of biases for pain-related cues and the predictive value of combined AB and IB for poor pain outcomes. Eighty-four healthy participants completed the PainAIM paradigm, followed by a cold pressor task probing pain experience and pain-related task interference. The results indicated an inverse relationship between AB and IB for ambiguous pain cues. In addition, there was a positive association between participants’ AB for ambiguous pain and their MB for the same cues. Contrary to our hypotheses, CB indices did not predict experimental pain outcomes. These findings provide support for the interrelationships between pain-related CBs. However, future research on the temporal order of CBs and their combined impact on pain outcomes is needed. By overcoming the limitations associated with traditional paradigms, the PainAIM paradigm offers a promising research tool for the further study of combined CBs in the context of pain. PerspectiveThe current study provides insight into the associations between pain-related CBs (AB, IB, and MB) using ecologically valid (ambiguous) pain cues. The results indicated an inverse association between pain-related AB and IB, while a positive association was found between AB and MB. CBs did however not predict experimental pain outcomes.

Effect of repeated topical capsaicin gel administration on oral thermal quantitative sensory testing: A two-arm longitudinal study.

Few studies used thermal quantitative sensory testing to assess the effects of repeated capsaicin gel administration in the oral cavity. This study aimed to investigate thermal sensory and pain thresholds before and after repeated capsaicin gel administration. Ten healthy females (22 ± 2 years) applied a capsaicin gel on the gingival mucosa twice daily for 14 days, and heat pain threshold, warm detection threshold, cold pain threshold, and cold detection threshold were assessed on the oral mucosa. Measurements were performed before and after the 14 days and were compared to a control sample (n = 10, all females, 23 ± 3 years). Capsaicin increased heat pain threshold in the anterior maxilla by 2.9°C (95% CI: 1.6-4.2) (p < 0.001) and in the anterior mandible by 2.2°C (95% CI: 1.0-3.4) (p = 0.001), similar to warm detection threshold that increased by Δ1.1°C (95% CI: 0.3-1.9) (p = 0.009). No significant changes were found in the controls. These findings encourage the use of thermal quantitative sensory testing in the oral cavity to assess thermal sensation, which might be useful for assessing the effects of therapies aimed at reducing pain.

Assessing the effectiveness of high frequency repetitive transcranial magnetic stimulation for post-mastectomy pain in breast cancer patients: A randomized controlled trial.

Post-mastectomy pain Syndrome (PMPS), characterized by chronic neuropathic pain stemming from intercostobrachial nerve lesions, presents a formidable clinical challenge. With the incidence of breast cancer surging, effective interventions for PMPS are urgently needed. To address this, we conducted this double-blind, placebo-controlled, randomized clinical trial to study the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) therapy over the motor cortex on pain, quality of life and thermal sensitivity in PMPS patients. We delivered 15 rTMS sessions over three weeks in a cohort of 34 PMPS patients. These patients were allocated randomly to either rTMS therapy or sham therapy groups. Pain assessments, utilizing the Visual Analogue Scale (VAS) and Short Form McGill Pain Questionnaire (SF-MPQ), alongside quality-of-life evaluations through the Functional Assessment of Cancer Therapy-Breast (FACT-B), were recorded before and after the 15 sessions. Additionally, we assessed thermal sensitivity using Quantitative Sensory Testing (QST). Our findings demonstrate the superior efficacy of rTMS therapy (over sham therapy) in reducing VAS and SF-MPQ scores (p < 0.0001), improving physical (p = 0.037), emotional (p = 0.033), and functional well-being (p = 0.020) components of quality of life, as quantified by FACT-B. Our investigation also unveiled marked enhancements in thermal sensitivity within the rTMS therapy group, with statistically significant improvements in cold detection threshold (p = 0.0001), warm detection threshold (p = 0.0033), cold pain threshold (p = 0.0078), and hot pain tolerance threshold (p = 0.0078). The study underscores the profound positive impact of rTMS therapy on pain, quality of life, and thermal sensitivity in patients havingPMPS, opening new avenues for pain management strategies.