In order to investigate whether the effect of Yuxuebi Tablets on the peripheral and central inflammation resolution of mice with inflammatory pain is related to their regulation of G protein-coupled receptor 37(GPR37), an inflammatory pain model was established by injecting complete Freund's adjuvant(CFA) into the paws of mice, with a sham-operated group receiving a similar volume of normal saline. The mice were assigned randomly to the sham-operated group, model group, ibuprofen group(91 mg·kg~(-1)), and low-, medium-, and high-dose groups of Yuxuebi Tablets(60, 120, and 240 mg·kg~(-1)). The drug was administered orally from days 1 to 19 after modeling. Von Frey method and the hot plate test were used to detect mechanical pain thresholds and heat hyperalgesia. The levels of interleukin-10(IL-10) and transforming growth factor-beta(TGF-β) in the spinal cord were quantified using enzyme-linked immunosorbent assay(ELISA), and the mRNA and protein expression of GPR37 in the spinal cord was measured by real-time quantitative reverse transcription PCR(qRT-PCR) and Western blot. Additionally, immunofluorescence was used to detect the expression of macrosialin antigen(CD68), mannose receptor(MRC1 or CD206), and GPR37 in dorsal root ganglia, as well as the expression of calcium-binding adapter molecule 1(IBA1), CD206, and GPR37 in the dorsal horn of the spinal cord. The results showed that compared with those of the sham-operated group, the mechanical pain thresholds and hot withdrawal latency of the model group significantly declined, and the expression of CD68 in the dorsal root ganglia and the expression of IBA1 in the dorsal horn of the spinal cord significantly increased. The expression of CD206 and GPR37 significantly decreased in the dorsal root ganglion and dorsal horn of the spinal cord, and IL-10 and TGF-β levels in the spinal cord were significantly decreased. Compared with those of the model group, the mechanical pain thresholds and hot withdrawal latency of the high-dose group of Yuxuebi Tablets significantly increased, and the expression of CD68 in the dorsal root ganglion and IBA1 in the dorsal horn of the spinal cord significantly decreased. The expression of CD206 and GPR37 in the dorsal root ganglion and dorsal horn of the spinal cord significantly increased, as well as IL-10 and TGF-β levels in the spinal cord. These findings indicated that Yuxuebi Tablets may reduce macrophage(microglial) infiltration and foster M2 macrophage polarization by enhancing GPR37 expression in the dorsal root ganglia and dorsal horn of the spinal cord of CFA-induced mice, so as to improve IL-10 and TGF-β levels, promote resolution of both peripheral and central inflammation, and play analgesic effects.
Inflammation/genetics* ; Pain/genetics* ; Drugs, Chinese Herbal/administration & dosage* ; Animals ; Mice ; Freund's Adjuvant/pharmacology* ; Ibuprofen ; Pain Threshold/drug effects* ; Hyperalgesia/genetics* ; Ganglia, Spinal ; Interleukin-10/genetics* ; Transforming Growth Factor beta/genetics* ; Reverse Transcriptase Polymerase Chain Reaction ; Tablets ; Receptors, G-Protein-Coupled

OBJECTIVE: Acupuncture has demonstrated efficacy as a treatment for fibromyalgia; however, predictors of short- and long-term analgesic response in this population are not well understood. METHODS: This manuscript describes a secondary analysis of a single-center, blinded, sham-controlled, randomized longitudinal acupuncture clinical trial in fibromyalgia. Baseline characterization included pressure pain threshold and pain interference, while residualized change in pain intensity from baseline to follow-up served as the primary outcome measure. Participants were randomized into groups that received verum (n = 36) or sham (n = 29) acupuncture treatment over a 12-week period (18 treatments) and were followed for 37 weeks from the initiation of treatment. RESULTS: Lower pressure pain thresholds at baseline were associated with greater analgesia only in the sham treatment group immediately following treatment, while those with higher pressure pain thresholds had greater analgesia with verum treatment (B = -13.43, P = 0.001). Additionally, greater perceived impact of pain at baseline was predictive of greater short-term analgesia irrespective of treatment. Pressure pain threshold was not found to be predictive of long-term differential treatment response (B = -1.71, P = 0.66). There was a significant difference in the relationship between perceived impact of pain at baseline and subsequent long-term analgesia between groups where those with greater perceived impact of pain displayed improved long-term analgesia for verum acupuncture compared to the sham group (B = -11.37, P = 0.004). CONCLUSION Our results support the use of a self-reported pain outcome in predicting long-term analgesia following acupuncture in fibromyalgia. Please cite this article as: Murphy AE, Arewasikporn A, Taylor-Swanson L, Williams DA, Harris RE. Pressure pain threshold and perceived impact of pain differentially predict short-term and long-term pain reduction following acupuncture in fibromyalgia. J Integr Med. 2025; 23(2): 152-158.
Adult ; Female ; Humans ; Male ; Middle Aged ; Acupuncture Therapy ; Fibromyalgia/therapy* ; Pain Management/methods* ; Pain Measurement/statistics & numerical data* ; Pain Threshold/physiology* ; Pressure ; Treatment Outcome ; Longitudinal Studies

Sleep deprivation has been shown to exacerbate pain sensitivity and may contribute to the onset of chronic pain, yet the precise neural mechanisms underlying this association remain elusive. In our study, we explored the contribution of cholinergic neurons within the medial habenula (MHb) to hyperalgesia induced by sleep deprivation in rats. Our findings indicate that the activity of MHb cholinergic neurons diminishes during sleep deprivation and that chemogenetic stimulation of these neurons can mitigate the results. Interestingly, we did not find a direct response of MHb cholinergic neurons to pain stimulation. Further investigation identified the interpeduncular nucleus (IPN) and the paraventricular nucleus of the thalamus (PVT) as key players in the pro-nociceptive effect of sleep deprivation. Stimulating the pathways connecting the MHb to the IPN and PVT alleviated the hyperalgesia. These results underscore the important role of MHb cholinergic neurons in modulating pain sensitivity linked to sleep deprivation, highlighting potential neural targets for mitigating sleep deprivation-induced hyperalgesia.
Animals ; Habenula/physiology* ; Sleep Deprivation/physiopathology* ; Cholinergic Neurons/physiology* ; Male ; Hyperalgesia/physiopathology* ; Rats, Sprague-Dawley ; Rats ; Interpeduncular Nucleus/physiology* ; Pain Threshold/physiology* ; Midline Thalamic Nuclei/physiology* ; Neural Pathways/physiopathology*

OBJECTIVES: This study aimed to investigate whether the microglia in the spinal trigeminal nucleus caudal part (Sp5C) were activated in a rat model of trigeminal neuralgia and to explore whether the activation level of microglia is consistent with maxillofacial pain level. METHODS: Chronic constriction injury of trigeminal nerve (CCI) was induced by partial ligation of infraorbital nerve (IoN) in rats. The behavioral change of rats observed at D1, D5, D10, D15, and D30 days post-surgery and the change of pain threshold were detected with electronic Von Frey filaments served as an evaluation index of maxillofacial pain. Weight change was measured by weighing. Ionized calcium binding adaptor molecule-1 (Iba-1) expression level of Sp5C at each time point was detected, and three microglia morphological categories were analyzed by immunohistochemical staining. RESULTS: The changes of behavioral and pain threshold suggested the maxillofacial pain level first increased and then decreased post-surgery in the IoN-CCI group. Both the expressions of Iba-1 and proportion of ameboid morphology in ipsilateral Sp5C increased from D1 and reached their peaks in D10 and D5, respectively. Then, they recovered nearly to the same level with contralateral Sp5C on D30. This trend was consistent with the maxillofacial change. CONCLUSIONS The model of trigeminal neuralgia in rats constructed by partial ligation of infraorbital nerve can induce the activation of microglia in Sp5C, and the activation level is consistent with maxillofacial pain, which reached its peak at around D10 post-surgery.
Rats ; Animals ; Trigeminal Neuralgia ; Rats, Sprague-Dawley ; Microglia ; Pain Threshold/physiology* ; Pain

OBJECTIVE: To observe the pressure pain threshold (PPT), skin conductance (SC) and blood perfusion (BP) of the sensitized acupoints in patients with knee osteoarthritis (KOA), and explore the mechanism of acupuncture at the sensitized acupoints for treating diseases. METHODS: Eleven healthy subjects and 11 unilateral KOA patients were recruited from July 2020 to March 2021 in this study. The PPT, SC and BP of control acupoints in healthy controls, and non-sensitized and sensitized acupoints in KOA patients were measured and compared between baseline and after manual acupuncture (MA) treatment. RESULTS: Before MA treatment, lower PPT was observed at the sensitized acupoints compared with non-sensitized and control acupoints (P<0.05). After MA treatment, PPT at the sensitized acupoints increased significantly in KOA patients (P<0.05). Before MA treatment, there was no statistical difference in SC and BP among control, non-sensitized and sensitized acupoints (P>0.05). Compared with the control and non-sensitized acupoints, there were significant increases of SC and BP in sensitized acupoints of KOA patients after MA treatment (P<0.05 or P<0.01). CONCLUSION MA at sensitized acupoints could elevate PPT of KOA patients, which may be associated with the increment of SC and BP.
Humans ; Acupuncture Points ; Pain Threshold ; Osteoarthritis, Knee/therapy* ; Acupuncture ; Acupuncture Therapy ; Pain

Nicotine is the main addictive component in cigarettes that motivates dependence on tobacco use for smokers and makes it difficult to quit through regulating a variety of neurotransmitter release and receptor activations in the brain. Even though nicotine has an analgesic effect, clinical studies demonstrated that nicotine abstinence reduces pain threshold and increases pain sensitivity in smoking individuals. The demand for opioid analgesics in nicotine abstinent patients undergoing surgery has greatly increased, which results in many side effects, such as nausea, vomiting, and respiratory depression, etc. In addition, these side effects would hinder patients' physical and psychological recovery. Therefore, identifying the neural mechanism of the increase of pain sensitivity induced by nicotine abstinence and deriving a way to cope with the increased demand for postoperative analgesics would have enormous basic and clinical implications. In this review, we first discussed different experimental pain stimuli (e.g., cold, heat, and mechanical pain)-induced pain sensitivity changes after a period of nicotine dependence/abstinence from both animal and human studies. Then, we summarized the effects of the brain neurotransmitter release (e.g., serotonin, norepinephrine, endogenous opioids, dopamine, and γ-aminobutyric acid) and their corresponding receptor activation changes after nicotine abstinence on pain sensitivity. Finally, we discussed the limits in recent studies. We proposed that more attention should be paid to human studies, especially studies among chronic pain patients, and functional magnetic resonance imaging might be a useful tool to reveal the mechanisms of abstinence-induced pain sensitivity changes. Besides, considering the influence of duration of nicotine dependence/abstinence and gender on pain sensitivity, we proposed that the effects of nicotine abstinence and individual differences (e.g., duration of abstinence from smoking, chronic/acute abstinence, and gender) on abstinence-induced pain sensitivity should be fully considered in formulating pain treatment protocols. In summary, this paper could deepen our understanding of nicotine abstinence-induced pain sensitivity changes and its underlying neural mechanism, and could also provide effective scientific theories to guide clinical pain diagnosis and treatment, which has important clinical significance.
Animals ; Humans ; Nicotine/adverse effects* ; Pain ; Pain Threshold ; Smoking Cessation ; Tobacco Use Disorder

OBJECTIVE: To compare the orofacial pain sensitivity with operant test and mechanical hyperalgesia with von Frey filaments of two orofacial pain models (EOI: experimental occlusal interference; pIONX: partial infraorbital nerve transection). To investigate the operant and evoked characteristics of EOI-rats. METHODS: The orofacial operant behaviors were tested by Ugo Basile Orofacial Stimulation Test System. The mechanical thresholds of vibrissal pads were tested by von Frey filaments. Male Sprague-Dawley rats were randomly divided into eight groups: von Frey group: sham-EOI, EOI, sham-pIONX, pIONX (sham: sham-operated group); operant test group: sham-EOI, EOI, sham-pIONX, pIONX (sham: sham-operated group). The mechanical thresholds and orofacial operant behaviors were tested on pre-operation and post-operation days l, 3, 7, 10, 14 and 21. RESULTS: In pIONX of von Frey group, the mechanical withdrawal threshold decreased from days 1 to 21 (P<0.05), peaking from days 7 to 10, and lasted until the end of the experiment. There was no significant difference between the bilateral sides. In pIONX of operant test group, the total contact time decreased from days 10 to 21 (P<0.05), peaking from days 10 to 14, and lasted until the end of the experiment. In EOI of von Frey group, the mechanical withdrawal threshold decreased from days 3 to 21 (P<0.05), peaking on day 7, and lasted until the end of the experiment. There was no significant difference between the bilateral sides. In EOI of operant test group, the total contact time decreased from days 1 to 21 (P<0.05), peaking from days 7 to 10, and lasting until the end of experiment. CONCLUSION Orofacial operant test is a stable method to evaluate orofacial pain behaviors, which could discriminate the feature of neuropathic and EOI orofacial pain. In these two animal models, both of the operant behaviors and the mechanical hyperalgesia exhibited different time courses. Orofacial operant test provides a novel method for evaluating the orofacial pain sensitivity and studying the orofacial pain mechanism thoroughly.
Animals ; Disease Models, Animal ; Facial Pain ; Hyperalgesia ; Male ; Pain Threshold ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To observe the direct intervention effects of electroacupuncture (EA) and non-steroid anti-inflammatory drugs (NSAIDs) on pain memory, and to explore their effects on cAMP/PKA/cAMP pathway in anterior cingulate gyrus (ACC). METHODS: Fifty clean healthy male SD rats were randomly divided into a control group, a model group, an indomethacin group, an EA group and a sham EA group, 10 rats in each group. Except the control group, the pain memory model was established in the remaining four groups by twice injection of carrageenan at foot; 0.1 mL of 2%λ-carrageenan was subcutaneously injected at the left foot of rats; 14 days later, when the pain threshold of rats of each group returned to the basic level, the second injection was performed with the same procedure. The rats in the EA group were treated with EA at bilateral "Zusanli" (ST 36) for 30 min; the rats in the indomethacin group was treated with indomethacin intragastric administration with the dose of 3 mg/kg; the rats in the sham EA group was treated with EA without electricity at the point 0.3 mm forward "Zusanli" (ST 36) with the depth of 2 mm for 30 min; the rats in the control group was not given any invention. All the above interventions were performed 5 h, 1 d, 2 d and 3 d after the second injection of 2% λ-carrageenan. The left-side paw withdrawal thresholds (PWT) were observed before the first injection, 4 h, 3 d, 5 d after the first injection, before the second injection and 4 h, 1 d, 2 d, 3 d after the second injection. Three days after the second injection, the number of positive cells of cAMP, p-PKA, p-CREB and the number of positive cells of protein co-expression in the right ACC brain area were detected by immunofluorescence, and the relative protein expression of p-PKA and p-CREB were detected by Western blot. RESULTS: Compared with the control group, the PWTs in the model group decreased significantly 4 h, 3 d and 5 d after the first injection and 1 d, 2 d and 3 d after the second injection (<0.05); compared with the control group, the positive expression of cAMP, p-PKA and p-CREB in the right ACC brain area in the model group increased significantly (<0.05), and the number of positive cells of the co-expression of cAMP/p-PKA and p-PKA/p-CREB also increased significantly (<0.05). Compared with the model group, indomethacin group and sham EA group, the PWTs in the EA group were increased significantly 1 d, 2 d and 3 d after the second injection (<0.05); compared with the model group, indomethacin group and sham EA group, the positive expression of p-PKA and p-CREB in the right ACC brain area in the EA group decreased significantly (<0.05), and the number of positive cells of co-expression of cAMP/p-PKA and p-PKA/p-CREB was decreased significantly (<0.05). Compared with the model group and sham EA group, the positive expression of cAMP in the right ACC brain area was decreased in the EA group (<0.05). CONCLUSION EA have a direct intervention effect on pain memory, which have significant advantage over NSAIDs in the treatment of chronic pain. The advantage effect of EA on pain memory may be related to the inhibition of cAMP/PKA/CREB pathway in ACC area.
Animals ; Anti-Inflammatory Agents, Non-Steroidal ; therapeutic use ; Cyclic AMP ; metabolism ; Cyclic AMP Response Element-Binding Protein ; metabolism ; Cyclic AMP-Dependent Protein Kinases ; metabolism ; Electroacupuncture ; Gyrus Cinguli ; metabolism ; Male ; Pain Threshold ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Signal Transduction

OBJECTIVE: To quantify pain pressure threshold(PPT) in the patients with lumbar intervertebral disc herniation before and after treatment, and to study the clinical effects of the PPT test in lumbar intervertebral disc herniation. METHODS: From January to December 2017, 59 patients with lumbar intervertebral disc hernation were treated, and another 59 normal persons were recruited as the normal control group. Visual analogue scale (VAS) was used to measure the patient's subjective pain intensity at admission, and the pain threshold of lumbar posterior joints was measured by the tenderness gauge. The pain threshold was measured three times with an interval of 1 min at the most painful posterior joints and the contralateral posterior joints, and the average value was recorded as the T-value.All patients were treated with one course of conservative treatment ( spine fixed-point rotation reduction plus routine dehydration and anti-inflammation). VAS score and pain threshold of posterior lumbar joints were measured after the treatment. One lumbar posterior joint was randomly selected in the normal control group to measure the pain threshold. RESULTS: (1)The patient group and the normal control group were comparable. There was no significant difference in age, body height, body weight and BMI between the two groups(>0.05). (2) The pressure pain threshold test was consistent:variance analysis on the T-value before treatment [(4.72±2.14) kg / cm, (4.96±2.10) kg / cm, (5.11±2.09) kg / cm] of the affected posterior joint, the T-value after treatment [(7.38±2.36) kg / cm, (7.62±2.51) kg / cm, (7.58±2.47) kg / cm], the T-value of before treatment [(7.18±2.80) kg / cm, (7.19±2.68) kg / cm, (7.20±2.69) kg / cm] of the contralateral posterior joint, T value after treatment [(9.54±2.89) kg / cm, (9.76±3.01) kg / cm, (9.77±3.09) kg / cm]; and normal joint T-value [(12.23±1.56) kg / cm, (12.51±1.48) kg / cm, (12.6±1.63) kg / cm] showed that there were no significant differences in the three successive measurements of pain threshold (>0.05). (3) After conservative treatment, the pain threshold of the affected side[(7.58±2.38) kg / cm] and the contralateral lumbar posterior joints [(9.70±2.92) kg / cm] increased significantly, but T-value of the affected side was still lower than that of the contralateral side, and T value of the both sides were lower than that of the normal group [(12.48±1.44) kg / cm]. The T-value of the affected side and the contralateral side had significant difference between before and after treatment (<0.05). After treatment, there was significant difference in T-value between the affected side and the contralateral side (<0.05);there were significant differences in T-value among the affected side, contralateral side and the normal group(<0.05). (4)Greater the subjective pain intensity of the patient was lower the posterior joint pain threshold of the affected side would be. As the subjective pain intensity decreased, the posterior joint pain threshold of the lumbar spine also increased. There was a significant difference in the VAS score before and after treatment (<0.05). Multiple regression analysis showed that the correlation coefficient r between the VAS score before and after treatment and the corresponding T-value of the affected side were significantly different(<0.05), and the corresponding T-value of the contralateral side were not significantly different(>0.05). CONCLUSION The pressure pain threshold test can accurately evaluate the pain intensity and its changing patterns in the lumbar posterior joint. The pain pressure threshold test is clinically significantin the lumbar disc herniation.
Humans ; Intervertebral Disc ; Intervertebral Disc Degeneration ; Intervertebral Disc Displacement ; Lumbar Vertebrae ; Pain ; Pain Threshold

OBJECTIVE: To observe the distribution characteristics and rules of pain sensitivity points on body surface in patients with knee osteoarthritis (KOA). METHODS: A total of 916 patients with KOA were selected in this study, the pain sensitivity points of local site of knee joint were probed by thumb palpation. Tape was used to measure the distance between the pain sensitivity points and the most nearby acupoints. The Wagner tenderness measuring instrument was used to measure the tenderness threshold of pain sensitivity points. RESULTS: A total of 3618 pain sensitivity points were probed, among them, 3338 pain sensitivity points were sensitized. The minimum sensitization degree was 1.00, the maximum sensitization degree was 3.39, while the average sensitization degree was (2.16±0.60). Pain sensitivity points were distributed 0.37-1.73 CONCLUSION The pain sensitivity points of patients with KOA may be the expansion effect of acupoint areas in the disease states, pain sensitivity points are more likely to appear on the medial side of knee joint.
Acupuncture Points ; Humans ; Knee Joint ; Osteoarthritis, Knee/therapy* ; Pain Threshold