Transmembrane member 16 A(TMEM16 A) is involved in many physiological functions, such as epithelial secretion, sensory conduction, nociception, control of neuronal excitability, and regulation of smooth muscle contrac...Transmembrane member 16 A(TMEM16 A) is involved in many physiological functions, such as epithelial secretion, sensory conduction, nociception, control of neuronal excitability, and regulation of smooth muscle contraction, and may be important in peripheral pain transmission. To explore the role of TMEM16 A in the persistent hyperalgesia that results from chronic constriction injury-induced neuropathic pain, a rat model of the condition was established by ligating the left sciatic nerve. A TMEM16 A selective antagonist(10 μg T16 Ainh-A01) was intrathecally injected at L5–6. For measurement of thermal hyperalgesia, the drug was administered once at 14 days and thermal withdrawal latency was recorded with an analgesia meter. For measurement of other indexes, the drug was administered at 12 days,once every 6 hours, totally five times. The measurements were performed at 14 days. Western blot assay was conducted to analyze TMEM16 A expression in the L4–6 dorsal root ganglion. Immunofluorescence staining was used to detect the immunoreactivity of TMEM16 A in the L4–6 dorsal root ganglion on the injured side. Patch clamp was used to detect electrophysiological changes in the neurons in the L4–6 dorsal root ganglion. Our results demonstrated that thermal withdrawal latency was shortened in the model rats compared with control rats.Additionally, TMEM16 A expression and the number of TMEM16 A positive cells in the L4–6 dorsal root ganglion were higher in the model rats, which induced excitation of the neurons in the L4–6 dorsal root ganglion. These findings were inhibited by T16 Ainh-A01 and confirm that TMEM16 A plays a key role in persistent chronic constriction injury-induced hyperalgesia. Thus, inhibiting TMEM16 A might be a novel pharmacological intervention for neuropathic pain. All experimental protocols were approved by the Animal Ethics Committee at the First Affiliated Hospital of Shihezi University School of Medicine, China(approval No. A2017-170-01) on February 27, 2017.展开更多
Aim: Diabetic neuropathic pain is one of the pains which hardly respond to pharmaceutical treat. Today, various chemical and herbal compounds have been used to reduce pain. The aim of this study is to compare the effe...Aim: Diabetic neuropathic pain is one of the pains which hardly respond to pharmaceutical treat. Today, various chemical and herbal compounds have been used to reduce pain. The aim of this study is to compare the effect of date extract and melatonin in preventing pain in diabetic rats.Method: To study hyperalgesia response and to compare the effect of date extract and melatonin in preventing pain, hot plate and tail flick tests were used. After prescribing single dose of streptozotocin to rats and approving their diabetes, treatment rats received date extract (4ml/kg/day) or melatonin [10 mg/kg/day, intraperitoneally (i.p.)] for a period of 6 weeks. At the end of the sixth week, control and treated rats were examined by thermal pain response and explorative activity tests.Results: According to hot plate results, response time to thermal pain in treated group showed a significant decrease in comparison with the control group (P 0.01). Prescription of date extract increased response time to thermal pain in comparison with treated group (P 0.01), so that response time approximated to control group. Although melatonin approximated to the response time to control group, the significant difference was not observed among melatonin receivers and other groups. In the assessment of diabetic neuropathy on the explorative activity of rats in an open field behavioral test, total distance moved and rearing frequency were significantly decreased, while administration of date extract did also improve motor deficits induced by STZ. Conclusions:Findings of this study showed that date extract decreased thermal hyperalgesia and can prevent pain resulted from diabetic neuropathy.展开更多
The clinical analgesic effect of electro-acupuncture（EA） stimulation（EAS） on breakthrough pain induced by remifentanil in patients undergoing radical thoracic esophagectomy, and the mechanisms were assessed. Sixty...The clinical analgesic effect of electro-acupuncture（EA） stimulation（EAS） on breakthrough pain induced by remifentanil in patients undergoing radical thoracic esophagectomy, and the mechanisms were assessed. Sixty patients（ASAⅢ） scheduled for elective radical esophagectomy were randomized into three groups： group A（control） receiving a general anesthesia only; group B（sham） given EA needles at PC4（Ximen） and PC6（Neiguan） but no stimulation; and group C（EAS） electrically given EAS of the ipsilateral PC4 and PC6 throughout the surgery. The EAS consisting of a disperse-dense wave with a low frequency of 2 Hz and a high frequency of 20 Hz, was performed 30 min prior to induction of general anesthesia and continued through the surgery. At the emergence, sufentanil infusion was given for postoperative analgesia with loading dose of 7.5 μg, followed by a continuous infusion of 2.25 μg/h. The patient self-administration of sufentanil was 0.75 μg with a lockout of 15 min as needed. Additional breakthrough pain was treated with dezocine（5 mg） intravenously at the patient＇s request. Blood samples were collected before（T1）, 2 h（T2）, 24 h（T3）, and 48 h（T4） after operation to measure the plasma β-EP, PGE2, and 5-HT. The operative time, the total dose of sufentanil and the dose of self-administration, and the rescue doses of dezocine were recorded. Visual Analogue Scale（VAS） scores at 2, 12, 24 and 48 h postoperatively and the incidence of apnea and severe hypotension were recorded. The results showed that the gender, age, weight, operative time and remifentanil consumption were comparable among 3 groups. Patients in EAS group had the lowest VAS scores postoperatively among the three groups（P〈0.05）. The total dose of sufentanil was 115±6.0 μg in EAS group, significantly lower than that in control（134.3±5.9 μg） and sham（133.5±7.0 μg） groups. Similarly, the rescue dose of dezocine was the least in EAS group（P〈0.05） among the three groups. Plasma β-EP levels in EAS group at T3（176.90±45.73） and T4（162.96±35.00 pg/mL） were significantly higher than those in control（132.33±36.75 and 128.79±41.24 pg/mL） and sham（136.56±45.80 and 129.85±36.14 pg/mL） groups, P〈0.05 for all. EAS could decrease the release of PGE2. Plasma PGE2 levels in EAS group at T2 and T3（41±5 and 40±5 pg/mL respectively） were significantly lower than those in control（64±5 and 62±7 pg/mL） and sham（66±6 and 62±6 pg/mL） groups. Plasma 5-HT levels in EAS group at T2（133.66±40.85） and T3（154.66±52.49 ng/mL） were significantly lower than those in control（168.33±56.94 and 225.28±82.03） and sham（164.54±47.53 and 217.74±76.45 ng/mL） groups. For intra-group comparison, plasma 5-HT and PGE2 levels in control and sham groups at T2 and T3, and β-EP in EAS group at T3 and T4 were significantly higher than those at T1（P〈0.05）; PGE2 and 5-HT levels in EAS group showed no significant difference among the different time points（P〉0.05）. No apnea or severe hypotension was observed in any group. It was concluded that intraoperative ipsilateral EAS at PC4 and PC6 provides effective postoperative analgesia for patients undergoing radical esophagectomy with remifentanil anesthesia and significantly decrease requirement for parental narcotics. The underlying mechanism may be related to stimulation of the release of endogenous β-EP and inhibition of inflammatory mediators（5-HT and PGE2）.展开更多
Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular se...Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.展开更多
Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pai...Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pain are still unclear.In this study,a neuropathic pain animal model was created by partial sciatic nerve ligation.Puerarin（30 or 60 mg/kg） was intraperitoneally injected once a day for 7 days.Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment.Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats,especially at 7 days after model establishment.At 7 days after model establishment,quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed m RNA expression of transient receptor potential vanilloid 1（Trpv1） and transient receptor potential ankyrin 1（Trpa1） in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury.These results suggest that puerarin dose-dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up-regulation in dorsal root ganglion of neuropathic pain rats.展开更多
Pain associated with cancer that metastasizes to bone is often severe and debilitating.A better understanding of the neural mechanisms that mediate cancer pain is needed for the development of more effective treatment...Pain associated with cancer that metastasizes to bone is often severe and debilitating.A better understanding of the neural mechanisms that mediate cancer pain is needed for the development of more effective treatments.In this study,we used an established model of cancer pain to characterize changes in response properties of dorsal horn neurons.Fibrosarcoma cells were implanted into and around the calcaneus bone in mice and extracellular electrophysiological recordings were made from wide dynamic range(WDR) and high threshold(HT) dorsal horn neurons.Responses of WDR and HT neurons evoked by mechanical,heat,and cold stimuli applied to the plantar surface of the hind paw were compared between tumor bearing mice and control mice.Mice exhibited hyperalgesia to mechanical and heat stimuli applied to their tumor-bearing hind paw.WDR neurons in tumor-bearing mice exhibited an increase in spontaneous activity,and enhanced responses to mechanical,heat,and cold stimuli as compared to controls.Our findings show that sensitization of WDR neurons,but not HT neurons,contributes to tumor-evoked hyperalgesia.展开更多
Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in rats. Behaviora tests showed that the thresholds for thermal and mechanical hyperalgesia were significantly reduced in neuropathic p...Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in rats. Behaviora tests showed that the thresholds for thermal and mechanical hyperalgesia were significantly reduced in neuropathic pain rats 3 28 days following model induction. The results of immunohistochemistry, western blot assays and reverse transcription-PCR showed that Nay1.7 protein and mRNA expression was significantly increased in the injured dorsal root ganglia. These findings indicated that Nay1.7 might play an important role in the model of chronic neuropathic pain展开更多
In a newborn affected by a non involuting congenital hemangioma we measured allodynia through the application of a standard tactile stimulus and hyperalgesia through the regular administration of the Comfort scale whi...In a newborn affected by a non involuting congenital hemangioma we measured allodynia through the application of a standard tactile stimulus and hyperalgesia through the regular administration of the Comfort scale which rates pain intensity. The baby presented signs of these pathological events over long periods of the disease. They may be attributed to the high amount of the nociceptive ligands in the hemangioma microenviroment and to the elevated concentration of TNF-alpha and IL-6 in the blood. For a long time, the pain was relieved by a combination of opioids, adjuvants and paracetamol, but also by thalidomide and unexpectedly by interferon alpha. A mechanism-based pain treatment needs to take into account the processes underlying pain and also the ongoing pathology.展开更多
基金supported by the National Natural Science Foundation of China,No.30160026(to JQS)the High Level Talent Research Project of Shihezi University of China,No.RCSX201705(to YW)
文摘Transmembrane member 16 A(TMEM16 A) is involved in many physiological functions, such as epithelial secretion, sensory conduction, nociception, control of neuronal excitability, and regulation of smooth muscle contraction, and may be important in peripheral pain transmission. To explore the role of TMEM16 A in the persistent hyperalgesia that results from chronic constriction injury-induced neuropathic pain, a rat model of the condition was established by ligating the left sciatic nerve. A TMEM16 A selective antagonist(10 μg T16 Ainh-A01) was intrathecally injected at L5–6. For measurement of thermal hyperalgesia, the drug was administered once at 14 days and thermal withdrawal latency was recorded with an analgesia meter. For measurement of other indexes, the drug was administered at 12 days,once every 6 hours, totally five times. The measurements were performed at 14 days. Western blot assay was conducted to analyze TMEM16 A expression in the L4–6 dorsal root ganglion. Immunofluorescence staining was used to detect the immunoreactivity of TMEM16 A in the L4–6 dorsal root ganglion on the injured side. Patch clamp was used to detect electrophysiological changes in the neurons in the L4–6 dorsal root ganglion. Our results demonstrated that thermal withdrawal latency was shortened in the model rats compared with control rats.Additionally, TMEM16 A expression and the number of TMEM16 A positive cells in the L4–6 dorsal root ganglion were higher in the model rats, which induced excitation of the neurons in the L4–6 dorsal root ganglion. These findings were inhibited by T16 Ainh-A01 and confirm that TMEM16 A plays a key role in persistent chronic constriction injury-induced hyperalgesia. Thus, inhibiting TMEM16 A might be a novel pharmacological intervention for neuropathic pain. All experimental protocols were approved by the Animal Ethics Committee at the First Affiliated Hospital of Shihezi University School of Medicine, China(approval No. A2017-170-01) on February 27, 2017.
文摘Aim: Diabetic neuropathic pain is one of the pains which hardly respond to pharmaceutical treat. Today, various chemical and herbal compounds have been used to reduce pain. The aim of this study is to compare the effect of date extract and melatonin in preventing pain in diabetic rats.Method: To study hyperalgesia response and to compare the effect of date extract and melatonin in preventing pain, hot plate and tail flick tests were used. After prescribing single dose of streptozotocin to rats and approving their diabetes, treatment rats received date extract (4ml/kg/day) or melatonin [10 mg/kg/day, intraperitoneally (i.p.)] for a period of 6 weeks. At the end of the sixth week, control and treated rats were examined by thermal pain response and explorative activity tests.Results: According to hot plate results, response time to thermal pain in treated group showed a significant decrease in comparison with the control group (P 0.01). Prescription of date extract increased response time to thermal pain in comparison with treated group (P 0.01), so that response time approximated to control group. Although melatonin approximated to the response time to control group, the significant difference was not observed among melatonin receivers and other groups. In the assessment of diabetic neuropathy on the explorative activity of rats in an open field behavioral test, total distance moved and rearing frequency were significantly decreased, while administration of date extract did also improve motor deficits induced by STZ. Conclusions:Findings of this study showed that date extract decreased thermal hyperalgesia and can prevent pain resulted from diabetic neuropathy.
文摘The clinical analgesic effect of electro-acupuncture（EA） stimulation（EAS） on breakthrough pain induced by remifentanil in patients undergoing radical thoracic esophagectomy, and the mechanisms were assessed. Sixty patients（ASAⅢ） scheduled for elective radical esophagectomy were randomized into three groups： group A（control） receiving a general anesthesia only; group B（sham） given EA needles at PC4（Ximen） and PC6（Neiguan） but no stimulation; and group C（EAS） electrically given EAS of the ipsilateral PC4 and PC6 throughout the surgery. The EAS consisting of a disperse-dense wave with a low frequency of 2 Hz and a high frequency of 20 Hz, was performed 30 min prior to induction of general anesthesia and continued through the surgery. At the emergence, sufentanil infusion was given for postoperative analgesia with loading dose of 7.5 μg, followed by a continuous infusion of 2.25 μg/h. The patient self-administration of sufentanil was 0.75 μg with a lockout of 15 min as needed. Additional breakthrough pain was treated with dezocine（5 mg） intravenously at the patient＇s request. Blood samples were collected before（T1）, 2 h（T2）, 24 h（T3）, and 48 h（T4） after operation to measure the plasma β-EP, PGE2, and 5-HT. The operative time, the total dose of sufentanil and the dose of self-administration, and the rescue doses of dezocine were recorded. Visual Analogue Scale（VAS） scores at 2, 12, 24 and 48 h postoperatively and the incidence of apnea and severe hypotension were recorded. The results showed that the gender, age, weight, operative time and remifentanil consumption were comparable among 3 groups. Patients in EAS group had the lowest VAS scores postoperatively among the three groups（P〈0.05）. The total dose of sufentanil was 115±6.0 μg in EAS group, significantly lower than that in control（134.3±5.9 μg） and sham（133.5±7.0 μg） groups. Similarly, the rescue dose of dezocine was the least in EAS group（P〈0.05） among the three groups. Plasma β-EP levels in EAS group at T3（176.90±45.73） and T4（162.96±35.00 pg/mL） were significantly higher than those in control（132.33±36.75 and 128.79±41.24 pg/mL） and sham（136.56±45.80 and 129.85±36.14 pg/mL） groups, P〈0.05 for all. EAS could decrease the release of PGE2. Plasma PGE2 levels in EAS group at T2 and T3（41±5 and 40±5 pg/mL respectively） were significantly lower than those in control（64±5 and 62±7 pg/mL） and sham（66±6 and 62±6 pg/mL） groups. Plasma 5-HT levels in EAS group at T2（133.66±40.85） and T3（154.66±52.49 ng/mL） were significantly lower than those in control（168.33±56.94 and 225.28±82.03） and sham（164.54±47.53 and 217.74±76.45 ng/mL） groups. For intra-group comparison, plasma 5-HT and PGE2 levels in control and sham groups at T2 and T3, and β-EP in EAS group at T3 and T4 were significantly higher than those at T1（P〈0.05）; PGE2 and 5-HT levels in EAS group showed no significant difference among the different time points（P〉0.05）. No apnea or severe hypotension was observed in any group. It was concluded that intraoperative ipsilateral EAS at PC4 and PC6 provides effective postoperative analgesia for patients undergoing radical esophagectomy with remifentanil anesthesia and significantly decrease requirement for parental narcotics. The underlying mechanism may be related to stimulation of the release of endogenous β-EP and inhibition of inflammatory mediators（5-HT and PGE2）.
基金supported by the National Institutes of Health,USA(DE018549,UL1TR001117,P30AR066527,and AR48182 to WL,AR48182-S1 to WL as co-investigatorF33DE024668 and K12DE022793 to YC)+1 种基金the US Department of Defense(W81XWH-13-1-0299 to WL)the Harrington Discovery Institute,Cleveland OH(to WL)
文摘Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.
基金supported by the National Natural Science Foundation of China,No.81671891
文摘Puerarin is a major active ingredient of the traditional Chinese plant medicine,Radix Puerariae,and commonly used in the treatment of myocardial and cerebral ischemia.However,the effects of puerarin on neuropathic pain are still unclear.In this study,a neuropathic pain animal model was created by partial sciatic nerve ligation.Puerarin（30 or 60 mg/kg） was intraperitoneally injected once a day for 7 days.Mechanical allodynia and thermal hyperalgesia were examined at 1 day after model establishment.Mechanical threshold and paw withdrawal latency markedly increased in a dose-dependent manner in puerarin-treated rats,especially at 7 days after model establishment.At 7 days after model establishment,quantitative real-time reverse transcriptase-polymerase chain reaction results showed that puerarin administration reversed m RNA expression of transient receptor potential vanilloid 1（Trpv1） and transient receptor potential ankyrin 1（Trpa1） in a dose-dependent manner in dorsal root ganglion neurons after peripheral nerve injury.These results suggest that puerarin dose-dependently ameliorates neuropathic pain by suppressing Trpv1 and Trpa1 up-regulation in dorsal root ganglion of neuropathic pain rats.
基金grants from the University of Minnesota Graduate School(DTH)and the National Institutes of HealthDA18231(DTH),DA11471and CA91007(DAS)
文摘Pain associated with cancer that metastasizes to bone is often severe and debilitating.A better understanding of the neural mechanisms that mediate cancer pain is needed for the development of more effective treatments.In this study,we used an established model of cancer pain to characterize changes in response properties of dorsal horn neurons.Fibrosarcoma cells were implanted into and around the calcaneus bone in mice and extracellular electrophysiological recordings were made from wide dynamic range(WDR) and high threshold(HT) dorsal horn neurons.Responses of WDR and HT neurons evoked by mechanical,heat,and cold stimuli applied to the plantar surface of the hind paw were compared between tumor bearing mice and control mice.Mice exhibited hyperalgesia to mechanical and heat stimuli applied to their tumor-bearing hind paw.WDR neurons in tumor-bearing mice exhibited an increase in spontaneous activity,and enhanced responses to mechanical,heat,and cold stimuli as compared to controls.Our findings show that sensitization of WDR neurons,but not HT neurons,contributes to tumor-evoked hyperalgesia.
基金This study was supported by the National Natural Science Foundation of China(The mechanism of Na_v 1.7 (encoded by SCN9A gene) activated by chronic neuropathic pain and the experimental study of analgesia by SCN9A RNAi), No.81171059
文摘Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in rats. Behaviora tests showed that the thresholds for thermal and mechanical hyperalgesia were significantly reduced in neuropathic pain rats 3 28 days following model induction. The results of immunohistochemistry, western blot assays and reverse transcription-PCR showed that Nay1.7 protein and mRNA expression was significantly increased in the injured dorsal root ganglia. These findings indicated that Nay1.7 might play an important role in the model of chronic neuropathic pain
文摘In a newborn affected by a non involuting congenital hemangioma we measured allodynia through the application of a standard tactile stimulus and hyperalgesia through the regular administration of the Comfort scale which rates pain intensity. The baby presented signs of these pathological events over long periods of the disease. They may be attributed to the high amount of the nociceptive ligands in the hemangioma microenviroment and to the elevated concentration of TNF-alpha and IL-6 in the blood. For a long time, the pain was relieved by a combination of opioids, adjuvants and paracetamol, but also by thalidomide and unexpectedly by interferon alpha. A mechanism-based pain treatment needs to take into account the processes underlying pain and also the ongoing pathology.
