We have previously demonstrated that antagonism of glutamate NMDA receptors or activation of endocannabinoid receptors could reduce experimentally induced neuroinflammation within the hippocampus of young rats. In the...We have previously demonstrated that antagonism of glutamate NMDA receptors or activation of endocannabinoid receptors could reduce experimentally induced neuroinflammation within the hippocampus of young rats. In the current study, we investigated whether pharmacological manipulation of glutamate or endocannabinoid neurotransmission could reduce naturally-occurring neuroinflammation within the hippocampus of aged rats. We investigated whether UCM707, an inhibitor of endocannabinoid re-uptake, WIN- 55,212-2, an endocannabinoid receptor agonist, and URB597, an inhibitor of endocannabinoid catabolism, or memantine, a non-competitive, low-affinity, inhibitor of the open NMDA receptor channel, could reduce the number of MHC II-IR microglia within the hippocampus. All of the drugs, except URB597, reduced the number of reactive microglia, as compared to vehicle treated rats. The current results suggest potential pharmacological approaches that may mitigate the pathological consequences of chronic brain inflammation associated with numerous neurodegenerative diseases.展开更多
This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique...This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3–300 μmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 μmol/L), a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01–1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners. The concentra-tion-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC50 values of two curves were very close (17.5±4.5) mmol/L vs. (15.2±4.5) mmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HT3 by (48.65±4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I5-HT3 by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I5-HT3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor. WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner. The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2, but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.展开更多
Summary: To investigate the effects of WIN 55,212-2 on I K in cultured rat trigeminal ganglion (TG) neurons, whole-cell patch clamp techniques were used to record the I K before and after WIN 55,212-2 perfusion at d...Summary: To investigate the effects of WIN 55,212-2 on I K in cultured rat trigeminal ganglion (TG) neurons, whole-cell patch clamp techniques were used to record the I K before and after WIN 55,212-2 perfusion at different concentrations. 30 μmol/L WIN 55,212-2 markedly (35 7 %± 7 3 %, P<0.01, n=8) inhibited I K currents, and the currents were partially recovered after washing. 30 μmol/L WIN 55,212-2 also induced a significant depolarizing shift in conductance-voltage parameters (control: V 0 5=10 43 ± 4.25 mV, k=16 27±3 86; WIN 55,212-2: V 0.5=24.71±3.91 mV, k =16.69±2.75; n = 8, P<0.01 for V 0.5). 0.01 μmol/L WIN 55,212-2 slightly (27.0 %± 7.9 %, P<0.05, n=7) increased I K currents, but had no significant change in conductance–voltage parameters (control: V 0.5=10.74±5.27 mV, k=17.33±2.96; WIN 55,212-2: V 0.5=11.06±2.05 mV, k=19.69±6.60; n=7, P>0.05 for V 0.5 and k). These results suggested that WIN 55,212-2 has dual action, which might be through different receptors.展开更多
文摘We have previously demonstrated that antagonism of glutamate NMDA receptors or activation of endocannabinoid receptors could reduce experimentally induced neuroinflammation within the hippocampus of young rats. In the current study, we investigated whether pharmacological manipulation of glutamate or endocannabinoid neurotransmission could reduce naturally-occurring neuroinflammation within the hippocampus of aged rats. We investigated whether UCM707, an inhibitor of endocannabinoid re-uptake, WIN- 55,212-2, an endocannabinoid receptor agonist, and URB597, an inhibitor of endocannabinoid catabolism, or memantine, a non-competitive, low-affinity, inhibitor of the open NMDA receptor channel, could reduce the number of MHC II-IR microglia within the hippocampus. All of the drugs, except URB597, reduced the number of reactive microglia, as compared to vehicle treated rats. The current results suggest potential pharmacological approaches that may mitigate the pathological consequences of chronic brain inflammation associated with numerous neurodegenerative diseases.
基金supported by National Natural Science Foundation of China(No.30271500)Science and Tech-nology Research Project Fund from the Department of Edu-cation of Hubei Province of China(No.B20115101)
文摘This study investigated the modulatory effect of synthetic cannabinoids WIN55,212-2 on 5-HT3 receptor-activated currents (I5-HT3) in cultured rat trigeminal ganglion (TG) neurons using whole-cell patch clamp technique. The results showed that: (1) The majority of examined neurons (78.70%) were sensitive to 5-HT (3–300 μmol/L). 5-HT induced inward currents in a concentration-dependent manner and the currents were blocked by ICS 205-930 (1 μmol/L), a selective antagonist of the 5-HT3 receptor; (2) Pre-application of WIN55,212-2 (0.01–1 μmol/L) significantly inhibited I5-HT3 reversibly in concentration-dependent and voltage-independent manners. The concentra-tion-response curve of 5-HT3 receptor was shifted downward by WIN55,212-2 without any change of the threshold value. The EC50 values of two curves were very close (17.5±4.5) mmol/L vs. (15.2±4.5) mmol/L and WIN55,212-2 decreased the maximal amplitude of I5-HT3 by (48.65±4.15)%; (3) Neither AM281, a selective CB1 receptor antagonist, nor AM630, a selective CB2 receptor antagonist reversed the inhibition of I5-HT3 by WIN55,212-2; (4) When WIN55,212-2 was given from 15 to 120 s before 5-HT application, inhibitory effect was gradually increased and the maximal inhibition took place at 90 s, and the inhibition remained at the same level after 90 s. We are led to concluded that-WIN55,212-2 inhibited I5-HT3 significantly and neither CB1 receptor antagonist nor CB2 receptor antagonist could reverse the inhibition of I5-HT3 by WIN55,212-2. Moreover, WIN55,212-2 is not an open channel blocker (OCB) of 5-HT3 receptor. WIN55,212-2 significantly inhibited 5-HT-activated currents in a non-competitive manner. The inhibition of I5-HT3 by WIN55,212-2 is probably new one of peripheral analgesic mechanisms of WIN55,212-2, but the mechanism by which WIN55,212-2 inhibits I5-HT3 warrants further investigation.
基金his project was supported by a grant from National Natural Sciences Foundation of China (No. 30271500).
文摘Summary: To investigate the effects of WIN 55,212-2 on I K in cultured rat trigeminal ganglion (TG) neurons, whole-cell patch clamp techniques were used to record the I K before and after WIN 55,212-2 perfusion at different concentrations. 30 μmol/L WIN 55,212-2 markedly (35 7 %± 7 3 %, P<0.01, n=8) inhibited I K currents, and the currents were partially recovered after washing. 30 μmol/L WIN 55,212-2 also induced a significant depolarizing shift in conductance-voltage parameters (control: V 0 5=10 43 ± 4.25 mV, k=16 27±3 86; WIN 55,212-2: V 0.5=24.71±3.91 mV, k =16.69±2.75; n = 8, P<0.01 for V 0.5). 0.01 μmol/L WIN 55,212-2 slightly (27.0 %± 7.9 %, P<0.05, n=7) increased I K currents, but had no significant change in conductance–voltage parameters (control: V 0.5=10.74±5.27 mV, k=17.33±2.96; WIN 55,212-2: V 0.5=11.06±2.05 mV, k=19.69±6.60; n=7, P>0.05 for V 0.5 and k). These results suggested that WIN 55,212-2 has dual action, which might be through different receptors.
