The research proposed here expands our effort to establish methods for the selective control of painful sensations using local anesthetics. We plan to elaborate from our present emphasis on axonal phenomena in vitro to record from the peripheral and central projections of neurons in vivo whose physiological role will be identified by unit recording during a spectrum of natural stimuli and motor activities. We will then characterize the actions of anesthetics on these functionally classified nerve fibers using methods developed in our present work. Effects on the CNS of peripheral nerve blocks will be studied by comparing unit responses from the dorsal horn of the spinal cord, and from several mode-selective ascending pathways. The neurophysiological consequences of epidural and intrathecal application of local anesthetics also will be investigated by measuring the relationship between impulses incoming via peripheral nerves, and the responses of spinal units, ventral roots, and centrally projecting pathways. To restrict the diffusion of anesthetic molecules within the spinal cord and epidural space, they will be leashed to macromolecules or synthesized into biologically active polymers. Quaternary amine derivatives of local anesthetics, which inhibit synaptic transmission while sparing axonal conduction, will also be injected intrathecally to help define alternative mechanisms for spinal anesthesia. Recording sites and radioactively-tagged free anesthetics, as well as those leashed to macromolecules or present as polymers, will be localized using light microscopy and radio-autography. To further specify the mechanism of action of anesthetics on spinal neurons we will study such cells in tissue culture by standard intracellular and path-clamp methods, examining the effects of anesthetics and derivatives on single-channel events activated by neuro-transmitters and on transmission between synaptically coupled cells. Studies on isolated peripheral nerve will be extended or physiologically characterized single units further refining the role of changes in pH, pCO2 and temperature on local anesthetic block of functionally characterized fibers.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM035647-02
Application #
3288589
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1985-02-01
Project End
1988-01-31
Budget Start
1986-02-01
Budget End
1987-01-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Leeson, Stanley; Strichartz, Gary (2013) Kinetics of uptake and washout of lidocaine in rat sciatic nerve in vitro. Anesth Analg 116:694-702
Barreveld, Antje; Witte, J├╝rgen; Chahal, Harkirat et al. (2013) Preventive analgesia by local anesthetics: the reduction of postoperative pain by peripheral nerve blocks and intravenous drugs. Anesth Analg 116:1141-61
Sinnott, Catherine J; Cogswell III, Lawrence P; Johnson, Anthony et al. (2003) On the mechanism by which epinephrine potentiates lidocaine's peripheral nerve block. Anesthesiology 98:181-8
Sinnott, Catherine J; Strichartz, Gary R (2003) Levobupivacaine versus ropivacaine for sciatic nerve block in the rat. Reg Anesth Pain Med 28:294-303
Nakamura, Tadashi; Popitz-Bergez, Frederique; Birknes, John et al. (2003) The critical role of concentration for lidocaine block of peripheral nerve in vivo: studies of function and drug uptake in the rat. Anesthesiology 99:1189-97
Taheri, Saeed; Cogswell 3rd, Lawrence P; Gent, Alison et al. (2003) Hydrophobic and ionic factors in the binding of local anesthetics to the major variant of human alpha1-acid glycoprotein. J Pharmacol Exp Ther 304:71-80
Araujo, Marco C; Sinnott, Catherine J; Strichartz, Gary R (2003) Multiple phases of relief from experimental mechanical allodynia by systemic lidocaine: responses to early and late infusions. Pain 103:21-9
Strichartz, Gary R; Zhou, Zhongren; Sinnott, Catherine et al. (2002) Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain. Novartis Found Symp 241:189-201; discussion 202-5, 226-
Nau, Carla; Strichartz, Gary R (2002) Drug chirality in anesthesia. Anesthesiology 97:497-502
Khodorova, A; Meissner, K; Leeson, S et al. (2001) Lidocaine selectively blocks abnormal impulses arising from noninactivating Na channels. Muscle Nerve 24:634-47

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