ROLE OF GABA IN MECHANISMS OF OPIATE ANALGESIA

The rostral ventromedial medulla (RVM) has a well-documented
role in modulation of nociceptive transmission, and several
independent lines of evidence support a major contribution of this
brainstem region to opiate antinociception. One approach to the
analysis of opiate action is at the level of single unit
neurophysiology. Neurons of the RVM can be divided into three
classes based on the relationship of cell discharge to the
occurrence of nocifensive reflexes such as the tail flick (TF).
Cells of one class, termed "off-cells," pause just prior to
withdrawal reflexes induced by noxious stimulation, and there is
good evidence that these neurons are the RVM output neurons
that inhibit nociceptive transmission and contribute to opiate
antinociception. Off-cells are activated by morphine in doses which are sufficient
to produce antinociception. This off-cell excitation is probably
due to suppression of the activity of an inhibitory interneuron,
since the direct cellular effects of opiates are generally effects
of opiates are generally inhibitory. One likely candidate for the
substance released by this inhibitory interneuron is the ubiquitous
inhibitory neurotransmitter GABA. GABA is found in cell bodies
and terminals in the RVM, and may contribute to the nociceptive
modulating functions of this region. The overall aim of the
proposed research is to determine the significance of GABA in
inhibitory control of activity of these putative nociceptive
modulating neurons in the RVM, specifically its role in opiate
antinociception. Three general approaches will be used. First, the effects of RVM
microinjection of GABA agonists and antagonists on the TF reflex
and on morphine-induced antinociception will be determined in
lightly-anesthetized rats. Second, extracellular single unit
recording and iontophoresis will be used to determine the role of
GABA-ergic inputs to physiologically-characterized RVM neurons.
Blockade of the TF-related pause or spontaneously-occurring
periods of quiescence in the off-cell by GABA antagonists would
favor a role for GABA in inhibitory control of off-cells. Reversal
of opiate-induced activation of off-cells by GABA agonists would
be consistent with the notion that opiates activate off-cells by
reducing GABA-mediated inhibition. Finally, recordings from
single off-cells before and after pressure ejection of GABA
antagonists in doses sufficient to block the TF will reveal any
changes in cell activity that are correlated with changes in
nocifensive responses. These studies will further our knowledge of intrinsic brain
mechanisms for controlling nociceptive transmission. In
particular, they will expand our understanding of opioid analgesia
and the physiological role of endogenous opioid peptides.