There appear to be multiple reasons driving this omission. First is the convent

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 There appear to be multiple reasons driving this omission. First is the convent Empty There appear to be multiple reasons driving this omission. First is the convent

Post  wangqian on Tue Apr 01, 2014 7:22 am

Phosphorylation and dephosphorylation reactions [You must be registered and logged in to see this link.] regu late TRPV1 receptor activity, which is crucial in promot ing inflammatory pain, There is clear evidence that the TRPV1 channel activation at the periphery is involved in the development of inflammatory thermal hyperalgesia and heat sensitivity, We have also pre viously reported that Cdk5 modulates thermal, nocicep tive signaling through the phosphorylation of TRPV1 at threonine 407, Another recent study points out that Cdk5 can control TRPV1 membrane trafficking, and thus regulate the heat sensitivity of the nociceptors, Furthermore, the systemic or intrathecal administration of TRPV1 antagonists is effective in reducing both ther mal hyperalgesia, as well as mechanical allodynia associ ated with chronic or neuropathic pain, which indicates that TRPV1 could play an important role in in tegrating multiple pain producing stimuli.

More recent studies have uncovered the involvement of TRPV1 in the central mechanical nociception together in connec tion with the other TRP channel TRPA1, Other studies speculate that the central mechanical hyperalge sia could be induced by the functional interaction be tween P2X3 or NMDA receptor and [You must be registered and logged in to see this link.] TRPV1. These studies provide the evidence that TRPV1 channels are important not only for the peripheral pain sensation, but they can also play an important role in the central mechanical nociception. An interesting possibility is that Cdk5 can mediate orofacial mechanical hyperalgesia through the regulation of the neurotransmitter release, thus indicating that this kinase could be an important presynaptic control par ameter.

Deregulation of its activity could affect nocicep tion via the [You must be registered and logged in to see this link.] presynaptic mechanism with the subsequent initiation of the pain sensation, Another possibil ity is that Cdk5 could mediate the orofacial mechanical hyperalgesia through the activation of other potential mechanotransducers. It is well known that the upregula tion of Cdk5 activity can lead to phosphorylation of delta opioid receptor, NMDA receptor, P2X3 receptor, and voltage gated calcium channels, Additionally, there are other potential candidates like TRPA1 or TREK channels that contain the Cdk5 phosphorylation consensus sequence and may be involved in the Cdk5 mediated activation and mechanotransduction in the orofacial area.

To under stand the precise mechanism through which Cdk5 regu lates orofacial mechanosensitisation will require further studies; including molecular, electrophysiological, and behavioral methods to map the functional role of Cdk5 in this type of the nociception. Conclusions We have adapted orofacial stimulation test for mice that could be used for orofacial pain studies, and using this test we have identified that Cdk5 activity has an import ant role in orofacial mechanical nociception. Moreover, our studies also demonstrate that genetically engineered mice with the altered Cdk5 p35 levels will prove to be valuable models to identify and characterize the inhibi tors of Cdk5 p35 as novel analgesics to treat orofacial pain. Methods Animals The p35 mice and the age matched, wild type con trols were maintained in C57BL6 129SVJ background. Tgp35 mice and the wild type littermate controls were maintained in FVBN background. All of the animals were housed and bred in standard cages, and they were maintained in climate and light controlled rooms with free access to food and water in accordance with the U. S. National Institutes of Health Guide for Care and Use of Laboratory Animals.


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