Effects of recurrent withdrawal on spinal GABA release during chronic morphine infusion in the rat

Chronic opioid administration is associated with altered nociception. The mechanisms underlying these changes are not fully understood. Nociceptive transmission within the spinal cord is modulated by both excitatory and inhibitory neurotransmitters. Using spinal microdialysis, the effects of recurrent withdrawal on the release of gamma-aminobutyric acid (GABA), at rest or after naloxone stimulation, was investigated in rats chronically exposed to morphine. For comparison purpose, the release of glutamate was investigated in parallel. We observed that chronic morphine treatment alone significantly inhibited resting GABA release; and recurrent withdrawal appeared to reverse this effect. Recurrent withdrawal also significantly elevated resting glutamate levels. In addition, we observed that only acute withdrawal moderately increased stimulated GABA release. In contrast, both acute and recurrent withdrawal markedly increased stimulated glutamate release. These observed changes in GABA release offer direct evidence that GABA may contribute to the altered nociceptive response mediated by opioids.