Knock pain

FAAH was originally purified and cloned from rat liver microsomes and is able to catalyse the hydrolysis of anandamide and 2-AG, in addition to other long-chain fatty acid amides [25]. Studies into the structure and role of this enzyme have generated interest in the potential therapeutic applications of FAAH inhibitors [26-28]. FAAH knock-out mouse brains contained 15-fold higher levels of anandamide than their wild-type counterparts and these animals have also been shown to be more responsive to exogenously administered anandamide [29]. These animals also showed a reduced response to painful stimuli, supporting the hypothesis that FAAH inhibition may provide novel analgesics. Levels of 2-AG were not elevated in the FAAH knock-out animals, apparently due to the existence of alternative metabolic fates for this compound [30]. 

Soon after Otto Ambros first went to Oswiecem, Birkenau was established to house the people of the town whom Ambros had recommended to be "evacuated" and placed in a new concentration camp. In those days the main camp — still predominantly for political prisoners — was kept as "pure" as possible by having the Jews and Poles in the main camp transferred to Birkenau. The first killings at Birkenau were the explosive result of the mistreatment of Birkenau inmates enroute to and from the main camp and to and from the buna plant. From the center of the buna plant to the center of Camp Birkenau was almost five miles, and their return at night was extremely painful and dangerous. Over the whole distance they dragged tools, firewood, heavy caldrons, and the bodies of those who had died or been killed during the working day. Others who could not maintain the brisk pace of the march were knocked down and beaten to death. 

NGF has effects on the physiological responses of mature neurons. NGF acts as a target-derived trophic factor for pain neurons, which innervate peripheral tissues such as the skin. Inflammation of these peripheral tissues leads to local elevation of NGF synthesis and abundance. Elevated concentartions of NGF are responsible for the enhanced sensitivity to pain that accompanies inflammation. This is due to the ability of NGF to lower the sensory threshold of the pain fibers, leading to hyperalgesia. Nocioceptive sensory neurons mediating pain sensation are entirely dependent upon NGF for their survival as these cells are selectively lost in animal in which either the NGF or TrkA genes have been knocked out. These animals are insensitive to pain and live only a few weeks. 

EP1 receptor knock-out mice show reduced pain sensitivity, suggesting an important role for this receptor subtype in pain perception (Stock et al., 2001). Furthermore these mice show a significant reduction in systolic blood pressure and an increased renin angiotensin activity, suggesting a role also in cardiovascular homeostasis. 

Studies with CBi receptor knock-out mice suggest the existence of an as yet unknown neuronal cannabinoid receptor -potentially a new target for pain research... 

Further experimental evidence for the involvement of SP in pain perception came from knock-out animals. Mice, in which the preprotachykinin A gene was disrupted, showed significantly reduced responses in tests that involved more intense noxious stimuli (Cao et al., 1998). De Felipe et al. (1998) disrupted the N receptor, and found the characteristic amplification ( wind up ) and intensity coding of nociceptive reflexes to be absent. NK receptor knockout mice show no changes in acute nociception tests. In contrast, SP and NKi receptor knock-out mice show reduction in responses to inflammatory stimuli. Nerve injury-induced mechanical but not thermal hyperalgesia is attenuated in NKi receptor knock-out mice, when inducing chronic neuropathic pain by unilateral ligation of the L5 spinal nerve (Mansikka et al., 2000). 

The analgesic effect of NOS inhibitors refers to the inhibition of nNOS and, in the case of inflammation, iNOS. Knock-out experiments support this thesis mice lacking iNOS have a delay in the expression of neuropathic pain following a chronic constriction injury of nerves associated with neuropathic pain (Levy et al., 2001). For physiological changes observed in nNOS-, iNOS- and eNOS-knock-out mice, see Table 2. 

Antisense approaches for knock-down of pain relevant genes... 

Extreme pain, respiratory arrest, severe muscular contractions individual normally cannot let go unless knocked away by muscle action death is possible Ventricular fibrillation (the rhythmic pumping action of the heart ceases) muscular contraction and nerve damage occur death is most likely Cardiac arrest, severe bums, and probable death... 

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