Neuronal nitric oxide synthase (NOS1) is a constitutive isoform of NOS predominantly found in the brain and spinal cord and is responsible for the production of nitric oxide, an important messenger in nociceptive signal transduction pathways. Researchers have shown that nitric oxide synthesis plays an important role in nociception. For example, in rats, NOS1 is upregulated in the spinal cord after the injection of capsaicin into the animals paw. The increased responses to noxious chemical stimulus to the paw of rats were blocked by inhibitors of NOS1. Mice genetically deficient in NOS1 have reduced late phase carrageenan-induced thermal hyperalgesia and NOS1 inhibitors inhibited inflammation-induced hyperalgesia in wild type mice. Also, in diabetic rats with diabetes-induced hyperalgesia, the expression of NOS1 is decreased compared to controls. Therefore, there is evidence to indicate that NOS1 plays an important role in nociception. However, the role of NOS1 in the transmission of pain is not entirely understood and it may vary according to the types of injury that produce pain. The purpose of the present study is to investigate the role of NOS1 on pain thresholds in mice. We are studying wild type and NOS1 genetically deficient mice and using a non injurious and neurospecific method to measure pain threshold. We define vocalization as the pain avoiding behavior end point of this study and measured current vocalization threshold to electrical stimulus delivered at different frequencies. In order to study the role of NOS1 in the transmission of noxious stimulus via specific nerve fibers, we deliver electrical stimuli to the skin (tail) at increasing intensities at different frequencies, 5-Hz, 250-Hz and 2000-Hz that specifically stimulate C, Aa, and Aa fibers respectively. The intensity of the electrical stimulus that elicits pain avoiding behavior (here defined as vocalization) is defined as current vocalization threshold for each frequency. Once baseline pain thresholds are obtained, we will study the mechanisms by which NOS1 impacts on pain transmission. We have designed a protocol to study the impact of NOS1 inhibitors on the transmission of pain as well.
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| Finkel, Julia C; Besch, Virginia G; Hergen, Adrienne et al. (2006) Effects of aging on current vocalization threshold in mice measured by a novel nociception assay. Anesthesiology 105:360-9 |
