This project will examine the spinal function of excitatory amino acids (EAAs) and substance P (SP) in the transmission of pain from primary afferent sensory fibers to secondary neurons in the spinal cord dorsal horn. The experiments will also explore mechanistic similarities, differences and interactions among three putative spinal analgesic systems, the mu and delta opioid and the alpha2 adrenergic systems. These systems may be involved both in endogenous forms of analgesia and in the actions of opiates and cocaine. The results will significantly improve our understanding of spinal pain transmission, spinal analgesic mechanisms and the spinal actions of opiates and cocaine. The overall goal of the proposed studies is to identify the neurotransmitters which mediate excitation and inhibition of rostrally projecting neurons, to examine the receptor mechanisms involved in the action of these agonists and in interactions between them, and to approach an understanding of the ionic events mediating their effects. The mechanisms involved will be investigated at the organismic, cellular and synaptic levels in both in vivo and in vitro experiments. At the level of neural systems, in vivo electrophysiological recording will examine the responses of sensory neurons to both natural stimulation and iontophoretic application of drugs. At the level of single neurons, voltage clamp studies in spinal cord slices in vitro will explore receptor identity, ion channel populations and synaptic interactions. Whole cell patch clamp recording from neonatal dissociated spinal cord neurons will explicitly examine postsynaptic receptor mechanisms in synaptically isolated spinal cord neurons. The contribution of receptors nerve terminals to nociception and antinociception will be explored using spinal cord homogenates selected for presence of particular receptors using immunomagnetophoresis. The first hypothesis to be tested is that the supra-additive interaction which has been observed between cocaine or alpha2 adrenergic agonists and mu or delta opioid agonists in antinociception, takes place at the level of single cells in the spinal cord. This adrenergic-opioid interaction is interesting both from the clinical analgesic viewpoint and at the molecular mechanistic level. The second hypothesis to be tested is that EAA-mediated excitation is selectively inhibited by mu opioid agonists. The very high potency of mu selective agonists on this component of nociception may also have both clinical and mechanistic importance. Understanding analgesic mechanisms at this level of resolution is crucial to the design of new manipulations with enhanced analgesic efficacy and reduced abuse liability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA001933-07A1
Application #
3207040
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
1978-09-30
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Riedl, Maureen S; Schnell, Stephen A; Overland, Aaron C et al. (2009) Coexpression of alpha 2A-adrenergic and delta-opioid receptors in substance P-containing terminals in rat dorsal horn. J Comp Neurol 513:385-98
Stone, Laura S; Wilcox, George L (2004) Alpha-2-adrenergic and opioid receptor additivity in rat locus coeruleus neurons. Neurosci Lett 361:265-8
Stone, Laura S; Vulchanova, Lucy; Riedl, Maureen S et al. (2004) Effects of peripheral nerve injury on delta opioid receptor (DOR) immunoreactivity in the rat spinal cord. Neurosci Lett 361:208-11
Laughlin, Tinna M; Tram, Kevin V; Wilcox, George L et al. (2002) Comparison of antiepileptic drugs tiagabine, lamotrigine, and gabapentin in mouse models of acute, prolonged, and chronic nociception. J Pharmacol Exp Ther 302:1168-75
Fairbanks, Carolyn A; Stone, Laura S; Kitto, Kelley F et al. (2002) alpha(2C)-Adrenergic receptors mediate spinal analgesia and adrenergic-opioid synergy. J Pharmacol Exp Ther 300:282-90
Laughlin, T M; Bethea, J R; Yezierski, R P et al. (2000) Cytokine involvement in dynorphin-induced allodynia. Pain 84:159-67
Fairbanks, C A; Nguyen, H O; Grocholski, B M et al. (2000) Moxonidine, a selective imidazoline-alpha2 -adrenergic receptor agonist, produces spinal synergistic antihyperalgesia with morphine in nerve-injured mice. Anesthesiology 93:765-73
Fairbanks, C A; Posthumus, I J; Kitto, K F et al. (2000) Moxonidine, a selective imidazoline/alpha(2) adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P-induced behavior in mice. Pain 84:13-20
Fairbanks, C A; Schreiber, K L; Brewer, K L et al. (2000) Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci U S A 97:10584-9
Fairbanks, C A; Wilcox, G L (1999) Moxonidine, a selective alpha2-adrenergic and imidazoline receptor agonist, produces spinal antinociception in mice. J Pharmacol Exp Ther 290:403-12

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