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Effects of a non-selective TRPC channel blocker, SKF-96365, on melittin-induced spontaneous persistent nociception and inflammatory pain hypersensitivity

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Neuroscience Bulletin 2012年第2期28卷 173-181页

作者： Jing Ding Jia-RuiZhang Yan Wang Chun-Li Li Dan Lu Su-Min Guan Jun Chen Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders Tangdu Hospital Fourth MilitaryMedical University Xi ＇an 710038 China Institute for Biomedical Sciences of Pain Capital Medical University Beij＇ing 100069 China Sehool of Stomatology Fourth Military Medical University Xi＇an 710032 China Department of Anesthesiology Beo＇ing Anzhen Hospital Capital Medical University Beijing 100029 China

Objective Melittin is the main peptide in bee venom and causes both persistent spontaneous nociception and pain hypersensitivity. Our recent studies indicated that both transient receptor potential （TRP） vanilloid receptor 1 （TRPV 1） and canonical TRPs （TRPCs） are involved in mediating the melittin-induced activation of different subpopulations of pri- mary nociceptive cells. Here, we further determined whether TRPC channels are involved in melittin-induced inflamma- tory nociceptive responses in behavioral assays. Methods The anti-nociceptive and anti-hyperalgesic effects of localized peripheral administration of three doses of the non-selective TRPC antagonist, SKF-96365 （1-{[3-[3-（4-methoxyphenyl） propoxy]-4-methoxyphenyl}-lH-imidazole hydrochloride）, were evaluated in melittin tests. Pain-related behaviors were rated by counting the number of paw flinches, and measuring paw withdrawal thermal latency （s） and paw withdrawl me- chanical threshold （g）, over a l-h time-course. Results Localized peripheral SKF-96365 given before melittin prevented, and given after melittin significantly suppressed, the melittin-evoked persistent spontaneous nociception. Pre-blockade and post-suppression of activation of primary nociceptive activity resulted in decreased hypersensitivity to both thermal and mechanical stimuli applied to the primary injury site of the ipsilateral hindpaw, despite dose-effect differences between thermal and mechanical hyperalgesia. However, local administration of SKF-96365 into the contralateral hindpaw had no significant effect on any pain-associated behaviors. In addition, SKF-96365 had no effect on baseline threshold for either thermal or mechanical sensitivity under normal conditions. Conclusion Besides TRPV1, SKF-96365-sensitive TRPC channels might also be involved in the pathophysiological processing of melittin-induced inflammatory pain and hyper- sensitivity. Therapeutically, SKF-96365 is equally effective in preventing primary thermal and mech

关键词： TRPC channels melittin persistent spontaneous nociception primary thermal hyperalgesia primary mechanicalhyperalgesia

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Roles of TRPC3/6/7 channels in a rat model of inflammatory pain

Roles of TRPC3/6/7 channels in a rat model of inflammatory p...

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中国生理学会第23届全国会员代表大会暨生理学学术大会

作者： Jing DING~1,Xiu-Yu CUI~1,Jun CHEN~(1,2,*) 1 Institute for Biomedical Sciences of Pain,Capital Medical University,Beijing 100069,China 2 Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders,Tangdu Hospital,Fourth Military Medical University,Xi’an 710038,China

Background:The transient receptor potential canonical(TRPC) channels,which are abundantly expressed in central nervous system(CNS),are Ca permeable nonselective cation channels with different biological *** studies indicated that TRPC1 and TRPC6 channels were likely to be involved in the pathological process of mechanical hyperalgesia and nociceptor *** whether TRPC channels are involved in melittin- or formalin-induced inflammatory nociceptive responses remains ***:In this study,we used behavioral tests combined with pharmacological manipulations to explore the potential roles of TRPC channels in inflammatory pain and ***:In this study,we used the well-established bee-venom(melittin) and formalin *** flinch test was to examine whether TRPC channels are involved in inflammatory paininduced primary *** pain sensitivity of rats was determined by testing paw withdrawal thermal latency(PWTL,s) in response to heat stimuli applied to the injected *** pain hypersensitivity was tested as the paw withdrawal mechanical threshold(PWMT,g).Results:Post- and pre-treatment of the primary injury site with *** of SKF96365,a TRPC3/6/7 antagonist,significantly suppressed the development of inflammatory pain-evoked persistent spontaneous nociception(PSN) and hypersensitivity(thermal and mechanical). Whereas local administration of SKF96365 into the contralateral hindpaw produced no significant effect on any of the pain-associated *** together,these data indicate that TRPC3/6/7 channels might be involved in pathophysiological processing associated with inflammatory ***:In conclusion,we demonstrated for the first time that,although SKF96365 do not affect baseline thermal latency and mechanical nociceptive threshold,it reversed the inflammatory pain-induced spontaneous nociception,heat and mechanical hyperalgesia, indicating that TRPC3/6/7 channels might pla

关键词： TRPC channels melittin formalin test persistent spontaneous nociception primary thermal hyperalgesia primary mechanical hyperalgesia

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Melittin excites primary nociceptive sensory neurons via activation of TRPV1 receptors by phospholipase A2-cyclooxygenases/lipoxygenases metabolites

Melittin excites primary nociceptive sensory neurons via act...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Han FU~1,Yi-Ru DU~2,Yong XIAO~1,Zhuo-Min LU~1,Jing DING~2,Fang XIE~1,Yan WANG~1,Jun CHEN~(1,2,*) 1 Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders,Tangdu Hospital,The Fourth Military Medical University,Xi’an 710038,China 2 Institute for Biomedical Sciences of Pain,Capital Medical University,Beijing 100069,China

Objective Melittin is the main peptide in bee *** studies demonstrated that this peptide could cause persistent spontaneous pain,primary heat and mechanical hyperalgesia,and enhance the excitability of spinal nociceptive ***,the underlying mechanism of melittin-induced cutaneous hypersensitivity is still not *** In the present study,melittin was applied topically to acutely dissociated rat dorsal root ganglion(DRG)neurons to examine its effects on the excitability of sensory neurons and the underlying cellular mechanisms using whole-cell patch clamp and calcium imaging *** It was found that melittin induced intracellular calcium([Ca])increases in 60%of small(<25μm)and medium(<40μm)diameter sensory *** clamp recording showed that topical application of melittin evoked long-lasting firing in 55%(56/102) of small and medium neurons *** sodium channel blocker tetrodotoxin(TTX)failed to eliminate firing evoked by *** clamp experiments showed that melittin evoked inward currents in sensory neurons in a concentration-dependent *** application of melittin caused increased amplitude of the inward currents. Most of the melittin-sensitive neurons were capsaicin-sensitive,and 65%were isolectin B4(IB4)*** results showed that capsazepine,the TRPV1 receptor inhibitor,completely abolished the melittin-induced inward currents and intracellular calcium *** signaling pathways involved in the melittin-induced inward current were also ***,but not PLC,was involved in producing the melittin-induced inward *** of cyclooxygenase(COX)and lipoxygenase(LOX),two key components of the arachidonic acid metabolism pathway, each partially suppressed the inward current evoked by *** of protein kinase A(PKA),but not of PKC, also abolished the melittin-induced inward *** These results indicate that melittin can directly excite smal

关键词： bee venom test dose-effect persistent spontaneous nociception thermal hyperalgesia mechanical hyperalgesia local inflammation

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Quantitative evaluation of dose-effect of subcutaneous injection of bee venom on persistent nociception,pain hypersensitivity and inflammatory responses in rats

Quantitative evaluation of dose-effect of subcutaneous injec...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Jia-Rui ZHANG~1,Yun-Fei LV~1,Yan WANG~1,Jun CHEN~(1,2,*) 1 Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders,Tangdu Hospital,The Fourth Military Medical University,Xi''an 710038,China 2 Institute for Biomedical Sciences of Pain,Capital Medical University,Beijing 100069,China

＜正＞Objective The bee venom test has long been used to evaluate the antinociceptive,antihyperalgesic and anti-inflammatory effects of endogenous and exogenous substances,however,the dose-effect of subcutaneous（s.c.） injection of bee venom on each pain-related behavior has not been ***,in the current report we used six doses（0.001,0.005,0.01,0.05,0.1,and 0.2 mg in 50 uL）of bee venom solution to see whether there are differences in *** Quantitative methods were used for evaluation of each pain-related *** the number of paw flinches of each 5-min time block from 0-60 min was used to evaluate the intensity of persistent spontaneous nociception,while paw withdrawal thermal latency（PWTL,s）and paw withdrawal mechanical threshold （PWMT,g）were used to evaluate thermal and mechanical hyperalgesia,*** of paw volume, cross-dimensional paw thickness,skin temperature and volume of plasma extravasation were used to evaluate local inflammatory *** Generally,there were significant differences in peak responses between persistent spontaneous nociception,PWTL,PWMT,and local inflammation following *** of bee ***, there was a dose-dependent effect of bee venom on the number and time period of paw flinches,and the dose-effect curve showed a typical ’S’ that reached plateau at 0.1 ***,the peak%maximal possible effect（MPE）of bee venom on the reduction in PWTL and PWMT at 2 h after injection was caused by different doses of bee venom, namely 0.05 mg for PWTL and 0.01 mg for *** results suggest that the dose required for%MPE is different from each other in terms of persistent spontaneous nociception,thermal hyperalgesia and mechanical hyperalgesia. Furthermore,the dose for%MPE of four quantitative measurements was also different between paw volume（or thickness）,plasma extravasation and skin *** dose of 0.1 mg was required for%MPE of both paw volume and paw thickness,wh

关键词： bee venom test dose-effect persistent spontaneous nociception thermal hyperalgesia mechanical hyperalgesia local inflammation

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