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CENTRAL INHIBITORY DYSFUNCTIONS: MECHANISMS AND CLINICAL IMPLICATIONS

Wiesenfeld-Hallin, Z. , Aldskogius, H., Grant, G., Hao, J.-X., Hškfelt, T. and Xu, X.-J. (1997) CENTRAL INHIBITORY DYSFUNCTIONS: MECHANISMS AND CLINICAL IMPLICATIONS.

Short Abstract:

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved by the g-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic pain of peripheral and central origin is often not relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the upregulation of endogenous anti-opioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section both CCK and CCK-R are upregulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, upregulation of CCK and CCK-R in the CNS may also underly opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue.

Long Abstract:

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved by the g-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic pain of peripheral and central origin is often not relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the upregulation of endogenous anti-opioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section both CCK and CCK-R are upregulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, upregulation of CCK and CCK-R in the CNS may also underly opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue.

Keywords:	pain; neuropathy; axotomy; ischaemia; spinal cord; g-aminobutyric acid; GABA; cholecystokinin; morphine; opioids; dysinhibition
Subjects:	Neuroscience: Behavioral Neuroscience Neuroscience: Neurochemistry Neuroscience: Neuroendocrinology Neuroscience: Neurology Neuroscience: Neuropharmacology Neuroscience: Neurophysiology Psychology: Psychobiology
ID code:	bbs00000462
Deposited by:	Z Wiesenfeld-Hallin on 01 May 2001