1. Effect Of TRPV1 On Memory Deficits And Synaptic Function In An A?1-42 Induced Mouse Model Of Alzheimer's Disease 2. GABA_A Receptors In The Central Nucleus Of The Amygdala Are Involved In Pain-and Itch-related Responses

Objective It is reported that TRPV1 activation is required for synaptic plasticity in the hippocampus,which plays a key role in certain types of learning and memory.Alzheimer's disease(AD)is a progressive neurologic disease of the brain,which is characterized by progressive memory loss and other cognitive dysfunctions.Thus,the purpose of this research is to investigate whether the regulation of TRPV1 in a pharmacological way could affect the synaptic function and then rescue the memory impairment in the A?1-42-induced mouse model of AD.Methods We use i.c.v.injection of A?1-42 to induce a AD mouse model.Mice were randomly divided into four groups: Normal control(Ctl)?A??A?+Cap group and A?+Cpz.Mice in Ctl group received PBS injection(2.5 ?l/mouse,i.c.v.).The other three groups were injected with A?1-42(100 ?M,2.5 ?l/mouse,i.c.v.).1.Drugs administration: For the Ctl and A? groups,animals received isopyknic vehicle,which is a 1:1:8 mixture of Tween 80: ethanol: saline.While mice in A?+Cap and A?+Cpz groups were subjected to capsaicin(Cap,1mg/kg,i.p.)and capsazepine(Cpz,1mg/kg,i.p.)treatment,respectively.2.Behavioral tests:After continious administration of drugs for two weeks,the Morris water maze and novel object recognition tasks were performed to test the learning and memory in different groups.3.Western blotting:Mice were sacrificed after behavioral tests,the hippocampus were collected for Western blotting to detect the expression of synaptophysin?PSD95 and TRPV1.4.Transmission electron microscopy(TEM): After transcardially perfused with 2.5% glutaraldehyde,the CA1 region of hippocampus were collected for TEM to measure the alterations of synaptic structure.5.Electrophysiology: LTP were used to detect the synaptic function in different mice group.Results A?1-42 injection significantly impaired spatial learning and memory in the Morris water maze and novel object recognition tests compared with Ctl,whereas Cap treatment dramatically improved cognitive function.In both Western blotting and TEM,A?-injection induced synapse loss in the hippocampus,whereas the administration of Cap rescued the synapse loss.In electrophysiological recordings,Cap also rescued the impairment of hippocampal CA1 LTP in mice-treated with A?1-42.However,Cpz treatment had no effect on both cognitive and synaptic functions in mice-treated with A?1-42.Conclusion Our present results strongly indicate that TRPV1 activation rescues cognitive impairment in the A?1-42-induced mouse model of AD both structurely and functionally,suggesting that TRPV1 channel may be a potential target for AD treatment.Objective Itch and pain are unpleasant sensations that distress many patients with disease.However,most studies have focused on the neural mechanisms of pain,and much less effort has been devoted to itch.It has been reported that itch and pain might share a common pathway,and gaminobutyric acid type A(GABA_A)receptors in the central nucleus of the amygdala(Ce A)are involved in pain modulation.However,the contribution of GABA_A receptors in the Ce A to the modulation of itch remains poorly understood.Methods We use bilateral intra-Ce A microinjection of a selective GABA_A receptor agonist muscimol hydrochloride(Mus;50 ng per side),or a selective GABA_A receptor antagonist bicuculline(Bic;20 ng per side)or vehicle,or a mixture of Bic and Mus to modulate GABA_A receptor in the Ce A.Tail-flick test and allyl isothiocyanate(mustard oil)evoked ipsilateral forelimb wipes were performed to confirme the key role of GABA_A receptor in Ce A on pain modulation.For itch related behavior test,5-HT cheek microinjection as acute itch model and mixture of acetone and diethylether(1:1)to make chronic dry skin itch model.Results Mus group showed significant analgesic effects,reflected by an increase in tail-flick latency and a decrease in allyl isothiocyanate(mustard oil)–evoked ipsilateral forelimb wipes.But BIC rat performed no difference to vehicle.More importantly,rats subjected to intra-Ce A infusion of Bic showed a significantly greater number of scratching bouts and time in acute and chronic pruritus animal models than control rats.Conversely,intra-Ce A infusion of Mus in animal models dramatically decreased the number of scratching bouts and time compared with control rats.In addition,intra-Ce A infusion of Bic or Mus at the current dose had no obvious effects on other behaviors including locomotor activity and spontaneous facial grooming in rats subjected to cheek microinjection of 5-hydroxytryptamine.Conclusion Taken together,these results indicate that the GABA_A receptor–mediated inhibitory system in the Ce A is involved in itch modulation as well as is known in pain control.Itch,especially chronic itch,remains a challenge in clinic.Results of this study showed that the GABA_A receptors in the Ce A play an important role in itch modulation,which might help us to better understand the mechanisms of itch and subsequently develop novel mechanisms-based strategies to treat chronic itch in clinic.