Ketamine pour la gestion de la douleur post hystérectomie au CHU Professeur Zafisaona Gabriel Mahajanga Madagascar / Ketamine for the management of post-hysterectomy pain at the Professor Zafisaona Gabriel University Hospital, Mahajanga, Madagascar

Une analgésie multimodale est incontournable pour la prise en charge de la douleur post opératoire. L'objectif de notre étude était de montrer l'intérêt de l'utilisation de la kétamine, avec son effet analgésique, parmi les différentes molécules disponibles. Méthodes : Il s'agit d'une étude prospective monocentrique en simple aveugle de 31 cas d'hystérectomie programmée sur une période de 6 mois (mai­octobre 2016) divisée en deux groupes soumis au même protocole anesthésique : un groupe recevant de la kétamine en bolus suivi d'une perfusion continue peropératoire et sur les premières 24 heures et un groupe contrôle sans kétamine. En période post opératoire les deux groupes bénéficient d'une analgésie multimodale. L'analyse statistique a été faite par le test de Student. Résultats : Les scores de douleur diffèrent peu en moyenne sur les 24 heures de surveillance, tandis qu'une épargne morphinique importante est notée dans le groupe kétamine de l'ordre de 50% avec une valeur de p<0,001 fortement significative. A côté nous n'avons constaté aucun effet indésirable notable. Conclusion : L'adjonction de kétamine même de brève durée dans la prise en charge de la douleur post opératoire a permis de baisser considérablement la consommation morphinique

Scorpion venom component: AGAP exhibits local anaesthetic effects and attenuates nociceptive pain

The incidences of systemic toxicity and other complications associated with existing local anaesthetics can occur at clinical concentration level and vary with the anaesthetic techniques, types of surgery and patient factors. This evidence suggests the need for therapeutic interventions in peripheral and regional anaesthesia. Buthus martensii Karsch (BmK) scorpion venom is a compound that contains mixtures of peptides that have analgesic properties. This study aimed to investigate the local anaesthetic activity of scorpion venom peptide, AGAP (analgesic-antitumor peptide) in mechanical hyperalgesia or acute inflammatory pain. Method: Formalin was injected into the left hind paw after 20 minutes of infiltration of drugs. The time of licking or flinching of the injected hind paw was recorded as indicative of nociceptive or acute inflammatory pain. Paw flinching or quick withdrawal was considered a positive response to pain in the partial sciatic nerve ligation. The paw-withdrawal threshold (PWT) was determined by consecutively increasing and decreasing the magnitude of the stimulus. Results: The results indicated that AGAP exhibited a 67.9% inhibition in licking or flinching time and an 88.1% inhibition in paw withdrawal in mechanical hyperalgesia. The addition of AGAP to lidocaine showed an 89.5% inhibition in paw withdrawal. Conclusion: The data presented in this study suggest that local infiltration of AGAP significantly reduced mechanical hyperalgesia and acute inflammatory pain

Mechanism of anterior cingulate cortex in modulating pain and anxiety-like behavior in chronic non-specific low back pain model rats / 中华行为医学与脑科学杂志

Objective:To explore the potential mechanisms of anterior cingulate cortex (ACC) in modulating pain behavior and anxiety-like behavior of rats with chronic non-specific low back pain induced by nerve growth factor (NGF).Methods:Ninety-six male SPF grade SD rats aged 8 weeks were randomly divided into four groups according the random number table method: control group, model group, control+ D-2-amino-5-phosphonopentanoate (D-AP5) group (control+ D-AP5 group) and model+ D-AP5 group, with 24 rats in each group.Low back pain model of rat was established by injection of NGF into multifidus muscle (left side) of the low backs of rats(two times with a five-day interval). Five days after modeling, rats in model+ D-AP5 group and control+ D-AP5 group were injected with the N-methyl-D-aspartate (NMDA) receptor antagonist D-AP5(2 μg, 0.3 μL) at the right side of the ACC once a day for consecutive 3 days, and rats in control group and model group were injected with the same amount of 0.9% sodium chloride solution. Seven days after modeling, the pain threshold of rats was evaluated by mechanical stimulation test and hot and cold plate test.The anxiety-like behavior was tested by open field test.The density of glial fibrillary acidic protein (GFAP) positive cells and c-Fos(a kind of immediate early gene) positive cells of the spinal cord were observed by immunofluorescence. The expression of GFAP, c-Fos, phosphorylated-c-Jun N-terminal kinases (p-JNK), monocyte chemoattractant protein-1 (MCP-1), and chemokine (C-X-C motif) ligand 1 (CXCL-1) proteins in the L2 segment of the spinal cord were detected by Western blot. SPSS 23.0 software was used for statistical analysis. One-way ANOVA was used to analyze normal distribution measurement data for comparison among multiple groups, and Tukey test was used for further pairwise comparisons. The Kruakal-Wallis H test was used for non-normal distribution measurement data, and Mann-Whitney U test was used for further pairwise comparisons with Bonferroni-corrected P-values. Results:In the experiments measuring pressure pain threshold (PPT) and paw withdrawal threshold (PWT), there were statistically significant differences in the PPT and PWT of rats among the four groups ( F=53.498, 41.939, both P<0.001). Seven days after modeling, PPT ((418.5±46.9) g) and PWT ( (55.6±7.1) g) in the ipsilateral side of the rats in model+ D-AP5 group were higher than those in model group ((290.0±32.0) g, (30.5±7.5) g) (both P<0.001). In the open field test, there were statistically significant differences in percentage of the inner zone distance ( H=11.922, P<0.01) and the percentage of inner zone time ( H=21.614, P<0.001) of rats among the four groups. The percentage of inner zone time in model+ D-AP5 group was higher than that in model group (5.6(4.3, 7.9) %, 3.1(2.1, 3.8) %) ( P<0.01). The results of immunofluorescence showed that there were statistically significant differences in the density of GFAP positive cells and c-Fos positive cells at the ipsilateral side of the superficial laminae of rats among the four groups ( H=49.085, F=18.120, both P<0.001). The density of GFAP positive cells (34.3(21.1, 47.5) cells/mm 2) and c-Fos positive cells ((52.7±39.4) cells/mm 2) at the ipsilateral side of the superficial laminae in model+ D-AP5 group were less than those in model group (76.5(68.6, 94.9) cells/mm 2, (112.4±63.7) cells/mm 2) (both P<0.001). The Western blot results showed that there were statistically significant differences in the protein expression of GFAP, c-Fos, p-JNK, MCP-1 and CXCL-1 in the L2 segment of rats among the four groups ( F=49.413, 38.437, 41.867, 36.735, 130.951, all P<0.001). The protein expression of GFAP (1.7±0.5), c-Fos (1.1±0.1), p-JNK (1.7±0.3), MCP-1 (1.0±0.4) and CXCL-1 (0.8±0.1) in the L2 segment in model+ D-AP5 group were lower than those in model group ((4.3±0.7), (2.6±0.5), (2.8±0.4), (2.9±0.4), (3.5±0.4)) (all P<0.01). Conclusion:ACC modulates mechanical hyperalgesia and anxiety-like behavior in chronic non-specific low back pain rats, which might be associated with the involvement of spinal astrocytes, p-JNK signal pathway and chemokines such as MCP-1 and CXCL-1.

Role of S1PR1 in dorsal root ganglion in remifentanil-induced hyperalgesia in rats with incisional pain / 中华麻醉学杂志

Objective:To evaluate the role of sphingosine-1-phospho-1 receptor(S1PR1)in the dorsal root ganglion in remifentanil-induced hyperalgesia in rats with incisional pain.Methods:Forty-eight male Sprague-Dawley rats with successful intrathecal and caudal vein catheterization, weighing 260-280 g, aged 2-3 months, were divided into 6 groups ( n= 8 each) using a random number table method: control group (group C), S1PR1 antagonist (FTY720) group (group F), remifentanil group (group R), remifentanil + S1PR1 antagonist (FTY720) group (group R+ F), remifentanil + incisional pain group (group R+ I), and remifentanil + incisional pain + S1PR1 antagonist (FTY720) group (group R+ I+ F). In C group, normal saline 0.1 μg·kg -1·min -1 was intravenously infused for 60 min. In R group, remifentanil 1.0 μg· kg -1·min -1 was infused for 60 min through the caudal vein. In F group, FTY720 3 nmol was intrathecally injected, and 10 min later normal saline 1.0 μg· kg -1·min -1 was infused for 60 min via the caudal vein. In R+ F group, FTY720 3 nmol was intrathecally injected, and 10 min later remifentanil 1.0 μg· kg -1·min -1 was infused for 60 min through the caudal vein. In R+ I group, remifentanil 1.0 μg·kg -1·min -1 was infused for 60 min through the caudal vein while the model of incisional pain was developed. In R+ I+ F group, FTY720 3 nmol was intrathecally injected, 10 min later the incisional pain model was prepared, and remifentanil 1.0 μg·kg -1·min -1 was injected for 60 min through the caudal vein at the same time. The mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured at 24 h before remifentanil or normal saline infusion (T 0) and 2, 6, 24 and 48 h after stopping remifentanil or normal saline infusion (T 1-4). Rats were sacrificed after the last measurement of pain threshold, and the L 4-6 segments of dorsal root ganglion were taken for determination of the expression of S1PR1, NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), interleukin-1β (IL-1β) and glutamate transporter-1 (GLT-1) protein and mRNA (by Western blot and quantitative polymerase chain reaction). Results:Compared with C group, the MWT was significantly decreased and TWL was shortened at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in dorsal root ganglion was up-regulated, and the expression of GLT-1 protein and mRNA in dorsal root ganglion was down-regulated in R group ( P<0.05), and no significant change was found in the parameters mentioned above in group F ( P>0.05). Compared with R group, MWT was significantly decreased and TWL was shortened at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in dorsal root ganglion was up-regulated, and GLT-1 protein and mRNA expression in dorsal root ganglion was down-regulated in R+ I group, and MWT was significantly increased and TWL was prolonged at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in the dorsal root ganglion was down-regulated, and GLT-1 protein and mRNA expression in the dorsal root ganglion was up-regulated in R+ F group ( P<0.05). Compared with R+ I group, MWT was significantly increased and TWL was prolonged at T 1-4, the expression of S1PR1, NLRP3 and IL-1β protein and mRNA in the dorsal root ganglion was down-regulated, and the expression of GLT-1 protein and mRNA in the dorsal root ganglion was up-regulated in R+ I+ F group( P<0.05). Conclusions:The mechanism by which remifentanil induces hyperalgesia is associated with up-regulation of S1PR1 expression, activation of inflammatory factors, and down-regulation of GLT-1 expression in the rats with incisional pain.

Effect of low-dose esketamine on remifentanil-induced postoperative hyperalgesia / 中华麻醉学杂志

Objective:To evaluate the effects of low-dose esketamine on remifentanil-induced postoperative hyperalgesia in the patients.Methods:Ninety-six American Society of Anesthesiologist Physical Status classificationⅠ or Ⅱ patients, aged 18-60 yr, with body mass index of 18-30 kg/m 2, scheduled for elective thyroidectomy under general anesthesia, were divided into 3 groups ( n=32 each) using a random number table method: control group (group C), esketamine administered before anesthesia induction group (group K1), and esketamine administered immediately after the end of surgery group (group K2). Esketamine 0.4 mg/kg was intravenously injected in group K1, and the equal volume of normal saline was given instead in C and K2 groups at 5 min before anesthesia induction. Anesthesia was induced by intravenous injection of propofol, remifentanil and rocuronium. Remifentanil was intravenously infused at a rate of 0.3 μg · kg -1·min -1 and 1.5%-2.5% sevoflurane was inhaled for anesthesia maintenance. Esketamine 0.4 mg/kg was intravenously injected in group K2 and the equal volume of normal saline was given instead in C and K1 groups immediately after the end of surgery. The mechanical pain thresholds of surgical incision and forearm of non-dominant hand were measured at 1 day before surgery and 30 min, 6 h, 24 h and 48 h after surgery, and flurbiprofen axetil was intravenously injected for rescue analgesia when the NRS score≥4 or the patient needed sedation. The intensity of pain was estimated using numeric rating scale at 30 min, 6 h, 24 h and 48 h after surgery. The intraoperative consumption of remifentanil, use of vasoactive drugs, recovery time, tracheal extubation time, duration of PACU stay, postoperative rescue analgesia and adverse reactions were recorded. Results:Compared with C group, the mechanical pain threshold around surgical incision and of the forearm of non-dominant hand was significantly increased at 30 min and 6 h after surgery in K1 and K2 groups ( P<0.05). Compared with C and K1 groups, the emergence time, tracheal extubation time, and duration of PACU stay were significantly prolonged, and the incidence of hallucinations and increased glandular secretion was increased in group K2 ( P<0.05). There were no significant differences in the consumption of remifentanil, intraoperative utilization rate of atropine and ephedrine, numeric rating scale scores at each time point after surgery, incidence of postoperative nausea and vomiting, and rate of rescue analgesia among the three groups ( P>0.05). Conclusions:Intravenous injection of small dose of esketamine (0.4 mg/kg) before anesthesia induction and immediately after the end of surgery can reduce postoperative hyperalgesia induced by remifentanil, and administration before anesthesia induction provides better efficacy in the patients.

Tiaoqi Jieyu acupuncture for treatment-resistant depression: a randomized controlled trial / 中国针灸

OBJECTIVE@#To observe the effect of Tiaoqi Jieyu (regulating qi and relieving depression) acupuncture on the clinical symptoms of treatment-resistant depression (TRD), and to explore the relationship between the acupuncture pain sensitivity and symptom's improvement.@*METHODS@#A total of 78 patients with TRD were randomly divided into an observation group (39 cases, 3 cases dropped off) and a control group (39 cases, 4 cases dropped off). The patients in the control group were treated with medications according to the treatment plan of psychiatrists (at least one medication was 5-hydroxytryptamine reuptake inhibitor). On the basis of the control group, the patients in the observation group were treated with Tiaoqi Jieyu acupuncture, and Baihui (GV 20), Yintang (GV 24+), Yanglingquan (GB 34), Taichong (LR 3), Hegu (LI 4), Neiguan (PC 6), Yinlingquan (SP 9) and Zusanli (ST 36), etc. were selected. The acupuncture was given three times a week. Both groups were treated for 8 weeks. After 8-week treatment, the response rate of Hamilton depression scale-24 (HAMD-24) score after was evaluated in the two groups. The scores of HAMD-24 and Hamilton anxiety scale (HAMA) were compared between the two groups before treatment, after 4, 8-week treatment and 12 weeks after treatment (follow-up). After the first treatment and 8-week treatment, the visual analogue scale (VAS) score in the observation group was evaluated, and the correlation between VAS score after the first treatment and HAMD-24 score before treatment, between VAS score after the first treatment and the course of disease in the observation group was analyzed, and the correlation between difference of VAS after 8-week treatment and after the first treatment and difference of HAMD-24 score before treatment and after 8-week treatment was analyzed.@*RESULTS@#After 8-week treatment, the response rate of HAMD-24 score in the observation group was 52.8% (19/36), higher than 17.1% (6/35) in the control group (P<0.001). Compared before treatment, the scores of HAMD-24 and HAMA in the two groups were decreased after 4-week treatment, 8-week treatment and in follow-up (P<0.05), and those in the observation group were superior to the control group (P<0.05). After 8-week treatment, the acupuncture pain VAS score in the observation group was (5.28±2.13) points, which was higher than (3.33±1.62) points after the first treatment (P<0.001). There was a negative correlation between VAS score after the first treatment and HAMD-24 score before treatment in the observation group (r =-0.486, P=0.003); there was no correlation between acupuncture pain VAS score after the first treatment and the course of disease in the observation group (P>0.05). After 8-week treatment, there was a positive correlation between the difference of VAS score and the difference of HAMD-24 score in the observation group (r =0.514, P=0.001).@*CONCLUSION@#Tiaoqi Jieyu acupuncture could improve the depression and anxiety in patients with TRD, and the symptom's improvement is related to the recovery of acupuncture pain sensitivity.

Remifentanil Down-regulates GIRK2 Expression in Rat Dorsal Root Ganglion and Spinal Dorsal Horn / 中山大学学报(医学科学版)

ObjectiveTo observe the changes in the expression and distribution of G protein-gated inwardly rectifying potassium channel subunit 2 （GIRK2） in the dorsal root ganglion （DRG） and spinal cord dorsal horn of rats with remifentanil-induced hyperalgesia. MethodsHyperalgesia was induced by intravenous infusion of remifentanil 4 μg/kg/min for 2 h in adult male SD rats. At 6th hour and on days 1， 3 and 5 following remifentanil treatment， we used immunofluorescence to examine the changes in the GIRK2 distribution and expression. Immunoblotting was used to detect GIRK2 expression of the total protein and membrane protein in DRG and spinal dorsal horn of rats. Behavioral testing was applied to evaluate the effect of intrathecal injection of GIRK2-specific agonist ML297 on thermal nociceptive threshold on day 1 after remifentanil infusion. Resultsmmunofluorescence results showed that GIRK2 was mainly co-localized with IB4-positive small neurons in DRG and nerve fibers in spinal dorsal horn. GIRK2 expression was significantly downregulated following remifentanil treatment. Immunoblotting results revealed that on day 1 following intravenous infusion of remifentanil， compared with those in the control group， GIRK2 expression levels of the total protein and membrane protein in DRG （0.47 ± 0.10 vs. 1.01 ± 0.17， P < 0.001； 0.47 ± 0.11 vs. 1.06 ± 0.12， P < 0.001） and spinal dorsal horn （0.52 ± 0.09 vs. 1.10 ± 0.08， P < 0.001； 0.54 ± 0.10 vs. 1.01 ± 0.13， P < 0.001） were all significantly decreased. The behavioral results showed that intrathecal ML297 effect on thermal withdrawal latency was significantly reduced following remifentanil treatment （P < 0.001）. ConclusionsRemifentanil might induce hyperalgesia via down-regulating GIRK2 expression in rat DRG and spinal cord dorsal horn.

CYP1B1-derived epoxides modulate the TRPA1 channel in chronic pain

Pain is often debilitating, and current treatments are neither universally efficacious nor without risks. Transient receptor potential (TRP) ion channels offer alternative targets for pain relief, but little is known about the regulation or identities of endogenous TRP ligands that affect inflammation and pain. Here, transcriptomic and targeted lipidomic analysis of damaged tissue from the mouse spinal nerve ligation (SNL)-induced chronic pain model revealed a time-dependent increase in Cyp1b1 mRNA and a concurrent accumulation of 8,9-epoxyeicosatrienoic acid (EET) and 19,20-EpDPA post injury. Production of 8,9-EET and 19,20-EpDPA by human/mouse CYP1B1 was confirmed in vitro, and 8,9-EET and 19,20-EpDPA selectively and dose-dependently sensitized and activated TRPA1 in overexpressing HEK-293 cells and Trpa1-expressing/AITC-responsive cultured mouse peptidergic dorsal root ganglia (DRG) neurons. TRPA1 activation by 8,9-EET and 19,20-EpDPA was attenuated by the antagonist A967079, and mouse TRPA1 was more responsive to 8,9-EET and 19,20-EpDPA than human TRPA1. This latter effect mapped to residues Y933, G939, and S921 of TRPA1. Intra-plantar injection of 19,20-EpDPA induced acute mechanical, but not thermal hypersensitivity in mice, which was also blocked by A967079. Similarly, Cyp1b1-knockout mice displayed a reduced chronic pain phenotype following SNL injury. These data suggest that manipulation of the CYP1B1-oxylipin-TRPA1 axis might have therapeutic benefit.

Mechanical hyperalgesia in athletes' shoulder: integrative review / Hiperalgesia mecânica no ombro de atletas: revisão integrativa

ABSTRACT BACKGROUND AND OBJECTIVES: Chronic shoulder pain in throwing athletes is a common complaint in everyday practice. Despite the growing number of publications, it is unclear whether these athletes have mechanical hyperalgesia associated with pain, which could alter the treatment options undertaken. The aim of the study was to summarize the results of the main evidence found on the pressure pain threshold in the shoulder, to compare these results in athletes of different sports. METHODS: Electronic search via PubMed/Medline, PEDro, SPORTDiscuss, Web of Science and Scielo databases was done verifying studies in English or Portuguese. The keywords: pressure pain threshold; athletes; shoulder; pressure algometry and its derivations were searched in both languages. The articles should have included athletes from sports that use upper limbs and that assess the pressure pain threshold in the shoulder. Five studies were included for analysis. RESULTS: Athletes with shoulder pain had a lower pressure pain threshold. In swimmers, changes in mechanical sensitivity to pain seem to be related to weekly training hours, years of sports practice and age group. Sports competitions apparently have an influence on the reduction of pressure pain threshold in amateur tennis players. CONCLUSION: Swimming athletes have a lower pressure pain threshold and this is related to the volume and time of training in the modality. This variable seems to be sport-dependent, and the absence of a greater number of studies in sports such as tennis and wheelchair basketball limits conclusions on this subject.

RESUMO JUSTIFICATIVA E OBJETIVOS: A dor crônica no ombro de atletas arremessadores é uma queixa comum no cotidiano do esporte. Apesar do número crescente de publicações sobre o tema, não está claro se esses atletas apresentam hiperalgesia mecânica associada a dor, o que poderia alterar as abordagens de tratamento realizadas. O objetivo da presente pesquisa foi sintetizar os resultados das principais evidências encontradas sobre o limiar de dor a pressão no ombro, comparando estes resultados em esportistas de diversas modalidades. MÉTODOS: Para esta revisão integrativa, as buscas eletrônicas ocorreram nas bases de dados Pubmed/Medline, PEDro, SPORTDiscuss, Web of Science e Scielo, verificando estudos em inglês ou português. As palavras-chave pressure pain threshold; athletes; shoulder; pressure algometry e suas derivações foram pesquisadas em ambas as linguagens. Os artigos deveriam incluir atletas de esportes com gestos esportivos no membro superior e que avaliassem o limiar de dor a pressão no ombro. Cinco estudos foram incluídos para análise. RESULTADOS: Atletas com dor no ombro apresentaram menor limiar de dor a pressão. Em nadadores, as alterações na sensibilidade mecânica a dor parecem estar relacionadas com horas de treino semanais, anos de prática esportiva e faixa etária. As competições esportivas aparentemente possuem influência na redução do limiar de dor a pressão em tenistas amadores. CONCLUSÃO: Atletas de natação apresentam menor limiar de dor a pressão, o qual se relaciona com o volume e tempo de treinamento na modalidade. Essa variável parece ser esporte-dependente, e a ausência de um maior número de estudos em esportes como tênis e basquete em cadeiras de rodas limita conclusões acerca do assunto. DESTAQUES Dor no ombro é uma condição comum em atletas overhead e atletas com dor no ombro apresentam alterações no limiar de dor a pressão (LDP). Na natação, o LDP parece sofrer influência do volume de treinamento semanal, de anos de prática da modalidade e da faixa etária. Alterações no LDP em tenistas e jogadores de basquete em cadeira de rodas ainda carecem de dados mais conclusivos.

Effect of photobiomodulation therapy (660 nm and 830 nm) on carrageenan-induced edema and pain behavior in mice / Efeito da terapia por fotobiomodulação (660 nm e 830 nm) no comportamento da dor e edema induzidos por carragenina em camundongos

ABSTRACT BACKGROUND AND OBJECTIVES: Photobiomodulation (PBM) is an important therapeutic tool for inflammatory process modulation. In this study, the anti-inflammatory and analgesic effect of two different energies and two different wavelengths (660 nm and 830 nm) were investigate and compared through the model of carrageenan-induced paw edema in mice. METHODS: Male Swiss mice, 36 animals (n=6 animals/group) were divided into six groups: Group 1 (saline-control), Group 2 (carrageenan), Group 3 (carrageenan + laser 660 nm, 5.88 J), Group 4 (carrageenan + laser 660 nm, 2.94 J), Group 5 (carrageenan + laser 830 nm, 5.88 J), and Group 6 (carrageenan + laser 830 nm, 2.94 J). PBM was applied 1h after the carrageenan injection which induced paw edema and hyperalgesia, which were measured by means of a plethysmometer and by flicker test using a water bath at 38ºC (±0.5ºC), respectively. Left paws of mice injected with carrageenan exhibited local edema that persisted for up to 6h after its administration. All animals were evaluated before, 1, 2, 3, 4, and 6 h after the injection of carrageenan. RESULTS: PBM, specially the 830 nm wavelength with 2.94 J of energy, reduced the paw edema induced by carrageenan. In addition, the 660 nm wavelengths (5.88 J / 2.94 J) and 830 nm (2.94 J) inhibited thermal hyperalgesia induced by carrageenan after 4 h of paw injection. CONCLUSION: There was evidence that the PBM 830 nm (2.94 J) produced a more pronounced anti-inflammatory effect, while the 660 nm (5.88 J / 2.94 J) energy laser was more effective to inhibit the hyperalgesia response induced by the carrageenan injection.

RESUMO JUSTIFICATIVA E OBJETIVOS: A fotobiomodulação (FBM) é uma importante ferramenta terapêutica para modulação dos processos inflamatórios. Neste estudo, investigou-se o efeito anti-inflamatório e analgésico de duas energias e dois comprimentos de onda diferentes (660 nm e 830 nm) através do modelo de edema de pata induzido por carragenina em camundongos. MÉTODOS: Trinta e seis camundongos Swiss machos (n=6 animais/grupo) foram divididos em seis grupos: Grupo 1 (controle salino), Grupo 2 (carragenina), Grupo 3 (carragenina + laser 660 nm, 5,88 J), Grupo 4 (carragenina + laser 660 nm, 2,94 J), Grupo 5 (carragenina + laser 830 nm, 5,88 J) e Grupo 6 (carragenina + laser 830 nm, 2,94 J). A FBM foi aplicada 1h após a injeção de carragenina que induziu o edema de pata e a hiperalgesia térmica, os quais foram medidos por meio de um pletismômetro e pelo flicker test em banho-maria a 38ºC (±0,5ºC), respectivamente. As patas esquerdas injetadas com carragenina apresentaram edema local que persistiu por até 6h após sua administração. Todos os animais foram avaliados antes, 1, 2, 3, 4, e 6 horas após a injeção de carragenina. RESULTADOS: A FBM, principalmente o comprimento de onda 830 nm com 2,94 J de energia, reduziu o edema de pata induzido pela carragenina. Além disso, o comprimento de onda 660 nm (5,88 J / 2,94 J) e o 830 nm (2,94 J) inibiram a hiperalgesia térmica induzida pela carragenina após 4h da injeção na pata. CONCLUSÃO: Evidenciou-se que a FBM 830 nm (2,94 J) produziu efeito anti-inflamatório mais pronunciado, enquanto o laser de 660 nm (5,88 J / 2,94 J) de energia foi mais eficaz para reduzir a resposta de hiperalgesia induzida pela injeção de carragenina.

Comparative study of cold hyperalgesia and mechanical allodynia in two animal models of neuropathic pain: different etiologies and distinct pathophysiological mechanisms

Abstract Neuropathic pain (NP) affects more than 8% of the global population. The proposed action of the transient receptor potential ankyrin 1 (TRPA1) as a mechanosensor and the characterization of the transient receptor potential melastatin 8 (TRPM8) as a cold thermosensor raises the question of whether these receptors are implicated in NP. Our study aimed to evaluate the involvement of TRPA1 and TRPM8 in cold and mechanical signal transduction to obtain a comparative view in rat models of streptozotocin-induced diabetes (STZ) and chronic constriction injury of the sciatic nerve (CCI). The electronic von Frey test showed that STZ rats presented mechanical allodynia that was first evidenced on the 14th day after diabetes confirmation, and four days after CCI. This phenomenon was reduced by the intraplantar (ipl) administration of a TRPA1 receptor antagonist (HC-030031; 40 µL/300 µg/paw) in both NP models. Only CCI rats displayed cold hyperalgesia based on the cold plate test. The pharmacological blocking of TRPA1 through the injection of the antagonist attenuated cold hyperalgesia in this NP model. STZ animals showed a reduction in the number of flinches induced by the intraplantar injection of mustard oil (MO; TRPA1 agonist; 0.1%/50 µL/paw), or intraplantar injection of menthol (MT; TRPM8 agonist; 0.5% and 1%/50 µL/paw). The response induced by the ipl administration of MT (1%/50 µL/paw) was significantly different between the CCI and SHAM groups. Together, these data suggest a different pattern in nociceptive behavior associated with different models of NP, suggesting a variant involvement of TRPA1 and TRPM8 in both conditions

Anterior Cingulate Cortex Mediates Hyperalgesia and Anxiety Induced by Chronic Pancreatitis in Rats / 神经科学通报·英文版

Central sensitization is essential in maintaining chronic pain induced by chronic pancreatitis (CP), but cortical modulation of painful CP remains elusive. Here, we examined the role of the anterior cingulate cortex (ACC) in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid (TNBS). TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats. Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii (NTS) and ACC, and some FOS-expressing neurons in the NTS projected to the ACC. In addition, a larger portion of ascending fibers from the NTS innervated pyramidal neurons, the neural subpopulation primarily expressing FOS under the condition of painful CP, rather than GABAergic neurons within the ACC. CP rats showed increased expression of vesicular glutamate transporter 1, and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor (NMDAR) subunit NR2B and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) subunit GluR1 within the ACC. Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats, which was similar to the analgesic effect of endomorphins injected into the ACC. Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety, whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats. Taken together, these findings provide neurocircuit, biochemical, and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats, as well as novel insights into the cortical modulation of painful CP, and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

Hippocampus is involved in 17β-estradiol exacerbating experimental occlusal inter- ference-induced chronic masseter hyperalgesia in ovariectomized rats / 北京大学学报(医学版)

OBJECTIVE@#To investigate the influence of chronic masseter hyperalgesia induced by 17β-estradiol (E2) and experimental occlusal interference (EOI) on underlying mechanism in hippocampus of ovariectomized (OVX) rats.@*METHODS@#In the study, 32 OVX rats were randomly divided into 4 groups (8 rats/group): The control group was OVX group, and 0 μg/d E2 (vehicle) injection was started 7 d after OVX without EOI; in the experimental group (1) OVX + E2 group, 80 μg/d E2 injection was started 7 d after OVX without EOI; in the experimental group (2) OVX + EOI group, vehicle injection was started 7 d after OVX and EOI was applied 17 d after OVX; in the experimental group (3) OVX + E2 + EOI group, 80 μg/d E2 injection was started 7 d after OVX and EOI was applied 17 d after OVX. Bilateral masseter muscle mechanical withdrawal thresholds were measured before OVX, 7 days after OVX (before E2 injection), 17 days after OVX (10 days after E2 injection and before EOI) and 24 days after OVX (7 days after EOI). Immunofluorescence staining was used to reveal phospho-extracellular signal regulated kinase 1/2 (p-ERK1/2)-positive neurons in CA3 of hippocampus. The protein expression of p-ERK1/2 in hippocampus was detected using Western Blot.@*RESULTS@#Compared with the control group [left side: (135.3±8.5) g, right side: (135.4±10.8) g], bilateral masseter muscle mechanical withdrawal thresholds of OVX+E2 group [left side: (113.3±5.6) g, right side: (112.5 ± 5.6) g] and OVX+EOI group [left side: (93.3±5.4) g, right side: 90.8±5.5) g] were decreased (P < 0.01). Bilateral masseter muscle mechanical withdrawal thresholds were significantly lower in OVX+E2+EOI group [left side: (81.2±6.2) g, right side: 79.8±7.7) g] than in the control, OVX+E2 and OVX+EOI groups (P < 0.05). The proportion of p-ERK1/2 positive neurons in the CA3 region of the hippocampus was increased in the control, OVX+E2, OVX+EOI and OVX+E2+EOI groups in turn, and the difference between the groups was statistically significant (P < 0.05). p-ERK1/2 protein expression was increased in the control, OVX+E2 and OVX+EOI groups in turn, but the difference was not statistically significant (P>0.05). p-ERK1/2 expression was significantly higher in OVX+E2+EOI group than in the other three groups (P < 0.05).@*CONCLUSION@#High concentration of E2 could exacerbated EOI-induced chronic masseter hyperalgesia in ovariectomized rats, and its central mechanism may be related to the upregulation of the phosphorylation of ERK1/2 in hippocampus.

Relationship between CCL21 and TREM2/DAP12 signaling pathways in spinal dorsal horn in remifentanil-induced hyperalgesia in mice with incisional pain / 中华麻醉学杂志

Objective:To evaluate the relationship between CCL21 and triggering receptor expressed on myeloid cells 2 (TREM2)/DNAX-activating protein of 12 kDa (DAP12) signaling pathways in the spinal dorsal horn in remifentanil-induced hyperalgesia in mice with incisional pain.Methods:Thirty-two SPF healthy male C57BL/6J mice, weighing 18-22 g, aged 8-10 weeks, were divided into 4 groups ( n=8 each) using a random number table method: control group (group C), CCL21 neutralizing antibody group (group anti-CCL21), remifentanil + incisional pain group (group R+ I), and CCL21 neutralizing antibody + remifentanil + incisional pain group (group anti-CCL21+ R+ I).A CCL21 neutralizing antibody 0.3 μg (diluted to 10 μl in normal saline) was intrathecally injected in anti-CCL21 and anti-CCL21+ R+ I groups twice a day.Normal saline 10 μl was intrathecally injected at the same time point twice a day in C and R+ I groups.Fifteen min after intrathecal injection, normal saline 0.1 ml was injected via the caudal vein for 4 consecutive times at an interval of 15 min in C and anti-CCL21 groups, and remifentanil 10 μg/kg (diluted to 0.1 ml in normal saline) was injected via the caudal vein for 4 consecutive times at an interval of 15 min in R+ I and anti-CCL21+ R+ I groups.The tail-flick latency (TFL) and mechanical paw withdrawal threshold (MWT) were measured at 24 h before remifentanil or normal saline injection (T 0) and 3, 6, 24 and 48 h after stopping injection of remifentanil or normal saline (T 1-4).The mice were sacrificed after the last measurement of pain threshold, and L 4-6 segments of the spinal cord were removed for determination of the expression of TREM2 and DAP12 protein and mRNA (by Western blot or quantitative real-time polymerase chain reaction). Results:Compared with group C, TFL was significantly shortened and MWT was decreased at T 1-4, and the expression of TREM2 and DAP12 protein and mRNA was up-regulated in group R+ I and R+ I+ anti-CCL21 ( P<0.05), and no significant change was found in the parameters mentioned above in group anti-CCL21 ( P>0.05).Compared with group R+ I, TFL was significantly prolonged and MWT was increased at T 1-4, and the expression of TREM2 and DAP12 protein and mRNA was down-regulated in group anti-CCL21+ R+ I ( P<0.05). Conclusions:CCL21 is involved in remifentanil-induced hyperalgesia by activating TREM2/DAP12 signaling pathways in the spinal dorsal horn of mice with incisional pain.

Analgesic efficacy of dexmedetomidine combined with dizosine after lumbar internal fixation and its effects on hyperalgesia / 中国基层医药

Objective:To investigate the analgesic efficacy of dexmedetomidine combined with dizosine after lumbar internal fixation and its effects on hyperalgesia.Methods:Seventy-two patients who underwent lumbar internal fixation in General Hospital of Armed Police and Marine Police between April 2018 and June 2019 were included in this study. They were randomly assigned to undergo either flurbiprofen axetil and dizosine administration (control group) or dexmedetomidine and dizosine (observation group) for postoperative analgesia. Mechanical pain, degree of postoperative pain, and incidence of complications were recorded in each group.Results:At 6, 24 and 48 hours after surgery, peri-wound pain threshold in the observation group was (119.52 ± 20.42) points, (120.19 ± 17.44) points, (120.94 ± 20.73) points, respectively, which were significantly higher than (108.42 ± 15.24) points, (107.63 ± 16.83) points, (108.47 ± 17.82) points in the control group ( t = 0.01, 0.00, 0.01, all P < 0.05). At 24 and 48 hours after surgery, forearm pain threshold in the observation group was (109.93 ± 15.87) points and (110.79 ± 22.85) points, respectively, which were significantly higher than (97.07 ± 16.49) points and (95.63 ± 24.06) points ( t = 3.37, 2.74, both P < 0.05). There was no significant difference in Ramsay Sedation Scale score between the two groups ( P > 0.05). There was no significant difference in the dose of dizosine used within 48 hours after surgery between the two groups ( P > 0.05). The incidence of postoperative complications in the observation group was significantly lower than that in the control group [8.33% (3/36) vs. 27.78% (10/36), χ2 = 4.60, P < 0.05]. Conclusion:Dexmedetomidine combined with dizosine exhibits obvious analgesic efficacy after lumbar internal fixation. The combined therapy can effectively prevent hyperalgesia with a low incidence of comphications.

Anti-arthritic effect of Distemonanthus benthamianus extracts against rheumatoid arthritis in rats

Objective: To evaluate the anti-arthritic effect of aqueous and methanolic extracts of Distemonanthus benthamianus. Methods: Monoarthritis was induced by an injection of 0.3 mL zymosan A (0.9% NaCl, v/v) in the right posterior knee joints of rats. Then, joint diameter and pain threshold were determined. Polyarthritis was induced by an intracaudal injection of complete Freund’s adjuvant and rats were treated from day 14 post 1st complete Freund’s adjuvant injection until 28 day. The clinical, hematological, biochemical and oxidative stress parameters were evaluated. In addition, histological analysis of the knee joint was perfomed in both tests. Results: The aqueous and methanolic extracts of Distemonanthus benthamianus at a dose of 500 mg/kg ameliorated zymosan A-induced monoarthritis, as evidenced by reduced joint diameter, increased pain threshold, as well as improved joint architecture. In addition, both extracts of Distemonanthus benthamianus markedly increased body weight and pain threshold, while reducing paw edema in polyarthritic rats. They also led to a marked decrease in platelets and white blood cells (P<0.05), as well as a significant increase in red blood cells, hemoglobin and hematocrit (P<0.05). The aqueous and methanolic extracts of Distemonanthus benthamianus significantly reduced alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase activities, while increasing serum protein levels (P<0.05) with no significant variation in creatinine level. Moreover, both extracts increased catalase and glutathione activities (P<0.05), and inhibited malondialdehyde and nitric oxide production (P<0.01 and P<0.001) in the liver and kidneys. Histological analysis of the joints showed that both extracts triggered tissue reparation. Conclusions: Distemonanthus benthamianus could be used as a potential candidate in the treatment of rheumatoid arthritis.

Relationship between autophagy and oxidative stress during remifentanil-induced hyperalgesia in rats with incisional pain / 中华麻醉学杂志

Objective:To evaluate the relationship between autophagy and oxidative stress during remifentanil-induced hyperalgesia in the rats with incisional pain.Methods:Thirty-two clean-grade healthy male Sprague-Dawley rats, weighing 230-250 g, aged 2-3 months, were divided into 4 groups ( n=8 each) using a random number table method: incisional pain group (I group), remifentanil + incisional pain group (RI group), autophagy inhibitor 3-methyladenine + remifentanil + incisional pain group (MRI group) and autophagy agonist rapamycin group + remifentanil + incisional pain group (RRI group). The model of incision pain was developed and the equal volume of normal saline was intravenously infused simultaneously for 60 min.In RI, MRI and RRI groups, the model of incision pain was developed and remifentanil 1 μg·kg -1·min -1 was simultaneously infused for 60 min.In MRI group, 3-methyladenine 15 mg/kg was intraperitoneally injected at 12 h before developing the model, and rapamycin 10 mg/kg was intraperitoneally injected at 12 h before developing the model in RRI group.Thermal paw withdrawal latency (TWL) and mechanical paw withdrawal threshold (MWT) were measured at 24 h before infusion of remifentanil or normal saline (T 0) and at 2, 6, 24 and 48 h after the end of infusion (T 1-4). The rats were sacrificed after the end of behavioral testing, and the lumbar enlargement segments of the spinal cord were harvested for determination of the expression of autophagy microtubule-associated protein 1 light chain 3Ⅱ (LC3Ⅱ), Beclin-1 and P62 (by Western blot), activity of superoxide dismutase (SOD) (by xanthine oxidase method) and content of malondialdehyde (MDA) (by thiobarbital method). Results:Compared with the baseline at T 0, PWT was significantly decreased and TWL was shortened at T 1-4 in the four groups ( P<0.05). Compared with I group, MWT was significantly decreased and TWL was shortened at T 1-4, the expression of LC3 Ⅱand Beclin-1 was up-regulated, the expression of P62 was down-regulated, SOD activity was decreased, and MDA content was increased in RI group ( P<0.05). Compared with RI group, MWT was significantly decreased and TWL was shortened at T 1-4, the expression of LC3 Ⅱand Beclin-1 was down-regulated, the expression of P62 was up-regulated, SOD activity was decreased, and MDA content was increased in MRI group ( P<0.05), and MWT was significantly increased and TWL was prolonged at T 1-4, the expression of LC3 Ⅱand Beclin-1 was up-regulated, the expression of P62 was down-regulated, SOD activity was increased, and MDA content was decreased in RRI group ( P<0.05). Conclusions:Autophagy is involved in the process of remifentanil-induced incisional hyperalgesia through regulating the level of oxidative stress in rats.

Antinociceptive and anxiolytic-like effects of Lavandula angustifolia essential oil on rat models of orofacial pain

Abstract Nociceptive and inflammatory orofacial pain is highly prevalent in the population, which justifies the search for safer analgesics. There is increasing evidence of the analgesic and anxiolytic potential of Lavandula angustifolia essential oil (LAV EO), which may represent, when administered through inhalation, may represent a safer alternative for pain treatment. Objective to evaluate whether LAV EO has antinociceptive effect in the formalin test, and anti-hyperalgesic and anxiolytic-like effects in rats subjected to a model of orofacial postoperative pain. Methodology Female Wistar rats were exposed to LAV EO (5%) by inhalation for 30 minutes. After exposure, animals were injected with formalin (2.5%, 50 μL) or saline into the hind paw or upper lip and the number of flinches or facial grooming time, respectively, were evaluated. Likewise, on day 3 after intraoral mucosa incision, the animals were exposed to LAV EO and facial mechanical, and heat hyperalgesia were assessed. The influence of LAV EO inhalation on anxiety-like behavior was assessed in operated rats by testing them on the open field (OF) and elevated plus maze (EPM). Results LAV EO reduced the phase II of the paw formalin test and both phases of the orofacial formalin test. On day three post-incision, LAV EO reduced heat and mechanical hyperalgesia, from 30 minutes up to three hours, and reduced the anxiety-like behavior in operated rats without causing locomotor deficit. Conclusion LAV EO inhalation results in antinociceptive and anxiolytic-like effects in orofacial pain models, which encourages further studies on LAV EO indications and effectiveness on orofacial pain conditions.

Alleviation of neuropathic pain by trazodone in rats

Abstract Neuropathic pain is generally characterised by an abnormal sensation (dysesthesia), an increased response to painful stimuli (hyperalgesia), and pain in response to a stimulus that does not normally provoke pain (allodynia). The present study was designed to investigate the effect of trazodone (5mg/kg and 10mg/kg) on peripheral neuropathic pain induced by partial sciatic nerve ligation in rats. Mechanical hyperalgesia, cold allodynia and thermal hyperalgesia were assessed by performing the pinprick, acetone, and hot plate tests, respectively. Biochemically, lipid peroxidation level and total calcium levels were measured. However, trazodone administration (5 and 10 mg/ kg i.p.) for 21days significantly diminished partial sciatic nerve ligation-induced neuropathic pain along with areduction in oxidative stress and calcium levels. The results of the present study suggest that trazodone is effective in attenuating partial sciatic nerve ligation-inducedpainful neuropathic states, which may be attributed to decreased oxidative stress and calcium levels.

Neuroprotective role of Tinospora cordifolia extract in streptozotocin induced neuropathic pain

Abstract Diabetic Neuropathy (DN) is one of the prevailing micro vascular complications of diabetes which can be characterized by neuropathic pain. Streptozotocin (STZ) induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy. STZ injection leads to neurotoxicity of peripheral nerves that leads to development of Peripheral Diabetic Neuropathy in rat model. The present study was aimed at exploring the protective role of Tinospora cordifolia extract in STZ induced neurotoxicity and evaluating mechanisms responsible for attenuating neuropathic pain. Neuropathic pain markers like hyperalgesia, allodynia and motor deficits were assessed before STZ injection and after the treatment with 250 mg/kg and 500 mg/kg dose of Tinospora cordifolia. Oxidative stress markers, NGF expression in sciatic nerve were observed after seven weeks treatment. Our results demonstrated that seven weeks treatment with Tinospora cordifolia leaf extract significantly relieved thermal hyperalgesia and allodynia by increasing the antioxidant enzyme levels, decreasing the lipid peroxidation and by increasing the Nerve growth factor (NGF) expression in diabetic rat sciatic nerves. Our findings highlighted the beneficial effects of oral administration of Tinospora cordifolia extract in attenuating diabetic neuropathic pain, possibly through a strong antioxidant activity and by inducing NGF m RNA in sciatic nerves.