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Cardiovascular responses through spinal nicotinic receptors

Institution: University of California, San Diego
Investigator(s): Palmer Taylor, Ph.D.
Award Cycle: 2001 (Cycle 10) Grant #: 10RT-0107 Award: $448,941
Subject Area: Nicotine Dependence
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Tobacco use increases risk of both cardiovascular and neoplastic disease, but statistical studies show that former carries the far larger risk to the population. While cardiovascular risks can be attributed to tobacco smoke enhancing blood coagulation and clot formation, nicotine, the substance responsible for addiction to tobacco products, also has profound cardiovascular actions that appear to contribute to hypertension and, in so doing, enhance other cardiovascular risk factors. Our proposed research has a two-fold objective: (a) to examine nicotine's action in the central nervous system in influencing cardiovascular parameters such as blood pressure and heart rate and characterizing the receptors through which it acts, and (b) using the spinal cord as a model system to understand the mechanism of nicotine action in the central nervous system. To meet these objectives, we have developed a systematic approach extending from studies in the whole animal to molecular level investigations. Animal studies involve direct intrathecal (spinal) administration of nicotine, its congeners and nicotine antagonists into the conscious rat following prior placement of an intrathecal catheter. Our previous studies have documented an unusual sensitivity to nicotine in the spontaneously hypertensive rat strain enabling us to use the power of genetics and recombinant inbred strains to study nicotine sensitivity in the coming project period. Studies at the cellular level have revealed that the nicotinic receptor has a predominantly presynaptic location on nerve endings in the spinal cord, and nicotine stimulation releases other transmitters that exert a pharmacological action. Our cellular studies will be directed to examining the release mechanisms of peptides and other transmitters and assigning the subtypes of nicotinic receptors responsible for eliciting the release. These transmitters are responsible for transducing signals through the spinal cord and giving rise to the nociceptive and autonomic responses to nicotine. Studies at the molecular level will be devoted to identifying the subtypes of nicotinic receptors in the spinal cord and their localization in the dorsal, intermediary lateral and ventral horns of the spinal cord. A series of specific and high affinity antibodies directed to the individual receptor subunits have been generated in the last project period and will be employed for the receptor identification and localization studies. Specificity will be examined by the use of agents selective for receptor subtypes. Although the overall approach requires a long term commitment, we anticipate that the findings will lead to a more complete understanding of nicotine's action in eliciting cardiovascular responses, both acute and chronic, an understanding the molecular basis of nicotine's action in the central nervous system and the receptor targets through which nicotine acts.
Publications

Nicotinic receptor gene cluster on rat chromosome 8 in nociceptive and blood pressure hyperresponsiveness.
Periodical: Physiological Genomics Index Medicus:
Authors: Khan IM, Singeltary E, Alemayehu A, Stanislaus S, Printz MP, Taylor P ART
Yr: 2003 Vol: 11 Nbr: 65-82 Abs: Pg:

Nicotinic acetylcholine receptor distribution in relation to spinal neurotransmission pathways.
Periodical: Journal of Comparative Neurology Index Medicus:
Authors: Khan IM, Osaka H, Stanislaus S, Calvo R, Deernick T, Yaksh TL, Taylor P ART
Yr: 2003 Vol: 467 Nbr: Abs: Pg: 44 - 59

Ablation of primary afferent terminals reduces nicotinic receptor expression and the niciceptive responses to nicotinic agonists in the spinal cord.
Periodical: Journal Neurocytol. Index Medicus:
Authors: Khan I, Wennerholm M, Singletary E, Polston K, Zhang I, Deerinck T, Yaksh TL, Taylor P ART
Yr: 0 Vol: Nbr: Abs: Pg: