TOLERANCE TO OPIOID ACTIONS ON SENSORY NEURONS

Project: Research project

Description

It is widely accepted that intrathecal injection of opioids and alpha2
adrenergic drugs produce antinociception in animal models of pain and in
man. The sites and mechanism of action of these drugs at the level of
the spinal cord, however remains unknown. one possible mechanism to
explain this spinal action of opioids and alpha2-agonists is by
inhibition of neurotransmitter release from nociceptive sensory neurons.
The purpose of this work is to determine whether tolerance and
cross-tolerance develop to the inhibitory effects of opioids and
alpha2-agonists on transmitter release from sensory neurons. Two
techniques will be used to study tolerance and cross-tolerance, release
evoked from spinal cord slices and release from rat sensory neurons.
Regulation of release of substance P and calcitonin gene-related peptide
are the endpoints of the studies. The use of spinal cord slices will
allow correlation between tolerance to antinociception and tolerance to
inhibition of transmitter release. Use of sensory neurons in culture
will provide a model for studying tolerance mechanisms. Regulation of
potassium-stimulated release will be measured in spinal cords from
non-tolerant rats and rats tolerant to the antinociceptive effects of
opioids or alpha2 agonists. Dose-response curves for inhibition of
release will be generated for both groups and will be compared to
determine if tolerance and cross-tolerance develop. Similar experiments
will be performed in rat sensory grown in cells in grown culture.
Regulation of release of peptides in cells chronically exposed to
morphine will be compared with naive cells. In addition, selective
studies will be performed on cells in culture to determine if G-proteins
and/or cyclic AMP are involved in acute regulation of transmitter release
and in the development of tolerance. From these studies we will gain
knowledge as to the sites and mechanisms by which opioids and
alpha2-agonists produce antinociception and on the mechanisms of
tolerance development.
StatusFinished
Effective start/end date6/1/915/31/95

Funding

  • National Institutes of Health
  • National Institutes of Health: $138,456.00
  • National Institutes of Health

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Sensory Receptor Cells
Opioid Analgesics
Spinal Cord
Spinal Injections
Nociceptors
Calcitonin
Substance P
Pharmaceutical Preparations
Cyclic AMP
Neurotransmitter Agents
Animal Models
Cell Culture Techniques
Pain
Peptides
Genes

ASJC

  • Medicine(all)