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 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

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

BACKGROUND: This study investigated the role of NR2B in a modulated pain process in the painful diabetic neuropathy (PDN) rat using various pain stimuli. METHODS: Thirty-two Sprague-Dawley male rats were randomly allocated into four groups (n=8): control, diabetes mellitus (DM) rats and diabetic rats treated with ifenprodil at a lower dose (0.5 µg/day) (I 0.5) or higher dose (1.0 µg/day) (I 1.0). DM was induced by a single injection of streptozotocin at 60 mg/kg on day 0 of experimentation. Diabetic status was assessed on day 3 of the experimentation. The responses on both tactile and thermal stimuli were assessed on day 0 (baseline), day 14 (pre-intervention), and day 22 (post-intervention). Ifenprodil was given intrathecally for 7 days from day 15 until day 21. On day 23, 5% formalin was injected into the rats' hind paw and the nociceptive responses were recorded for 1 hour. The rats were sacrificed 72 hours post-formalin injection and an analysis of the spinal NR2B expression was performed. RESULTS: DM rats showed a significant reduction in pain threshold in response to the tactile and thermal stimuli and higher nociceptive response during the formalin test accompanied by the higher expression of phosphorylated spinal NR2B in both sides of the spinal cord. Ifenprodil treatment for both doses showed anti-allodynic and anti-nociceptive effects with lower expression of phosphorylated and total spinal NR2B. CONCLUSION: We suggest that the pain process in the streptozotocin-induced diabetic rat that has been modulated is associated with the higher phosphorylation of the spinal NR2B expression in the development of PDN, which is similar to other models of neuropathic rats.
Animals ; Diabetes Mellitus ; Diabetic Neuropathies ; Formaldehyde ; Humans ; Hyperalgesia ; Male ; N-Methylaspartate ; Pain Measurement ; Pain Threshold ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; Spinal Cord ; Streptozocin

PURPOSE: The purpose of this paper is to determine effects of auricular acupressure on knee pain, range of motion, and sleep in the elderly with knee osteoarthritis. METHODS: This is an experimental study designed with randomization and single-blind in a placebo-control approach. The subjects included the elderly with knee osteoarthritis who were using an elderly welfare facility. In each of the groups, 28 subjects were assigned. For the experimental group, auricular acupressure was applied to five pressure points related to the pain caused by osteoarthritis and sleep. In the case of the placebo-control group, auricular acupressure was applied to other five points than the former. The intervention lasted eight weeks. In order to examine intervention effects of auricular acupressure, joint pain, Pressure Pain Thresholds (PPTs), and extension and flexion range of motion (ROM) were measured weekly. As for the pre- and post-examinations, pain, sleep quality, and the time-by-sleep stage of the patients with knee osteoarthritis were measured. RESULTS: The VAS scores in the experimental group with auricular acupressure significantly decreased through time (p<.001) and WOMAC also significantly decreased (p<.01) compared with the placebo-control group. However, there were no significant differences in PPTs. The flexion (p<.01) and extension (p<.001) ROMs measured for eight weeks improved over time. Meanwhile, sleep quality improved significantly after the intervention termination (p<.01), but there was no significant difference found in the time-by-sleep stage. CONCLUSION: Auricular acupressure applied for eight weeks was found to be effective in reducing joint pain, improving knee ROM, and improving sleep quality in patients with degenerative knee arthritis.
Acupressure ; Aged ; Arthralgia ; Arthritis ; Humans ; Joints ; Knee ; Osteoarthritis ; Osteoarthritis, Knee ; Pain Threshold ; Random Allocation ; Range of Motion, Articular ; Sleep Stages

OBJECTIVE: To observe the correlation between referred pain distribution and acupoint sensitization in patients with intestinal diseases. METHODS: In clinical research, 443 patients from 8 hospitals were recruited, including the outpatients and inpatients of Crohn's disease (=143), ulcerative colitis (=108), chronic appendicitis (=87) and other intestinal diseases (=105). The site with tenderness on the body surface and the morphological changes of local skin were observed and recorded in the patients. Using a sensory tenderness instrument, the pain threshold at the sensitization point was measured in 60 patients with ulcerative colitis. In animal experiment, SD rats were used and divided into a enteritis group (=8), in which the enteritis model were established, and a control group (=3), in which no any intervention was given. After the injection of Evans blue (EB) at caudal vein, the blue exudation points on the body surface were observed and the distribution rule was analyzed statistically. RESULTS: The referred pain on the body surface in the patients with intestinal diseases was mainly located in the lower abdomen (93.9%, 416/443), the lumbar region (70.9%, 314/443) and the lower legs (33.0%, 146/443). The diameter of tenderness region was 1.5 to 2.5 cm. Compared with the region without sensitization, the pain threshold of the sensitization point in the patients with ulcerative colitis was reduced significantly (<0.001). The referred pain on the body surface in the patients with appendicitis was located in the right lower abdomen (97.7%, 85/87), the waist and back (54.0%, 47/87) and the right lower limbs on the medial side (71.3%, 62/87). The tenderness region was 1 to 2 cm in diameter and was irregular in form. After modeling of enteritis in the rats, the EB exudation points were visible from T to L. CONCLUSION Intestinal diseases induce referred pain on the body surface where is the same as or adjacent to the location of the spinal segment corresponding to the affected intestinal section. These sensitization regions are related to the locations of acupoints.
Acupuncture Points ; Animals ; Colitis, Ulcerative ; Humans ; Intestinal Diseases ; Pain Threshold ; Pain, Referred ; diagnosis ; therapy ; Rats ; Rats, Sprague-Dawley ; Sensation