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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Pain hypersensitivity is characterized by an increase in the response to noxious stimuli (hyperalgesia) and a reduction in threshold such that innocuous stimuli begin to elicit pain (allodynia). These sensitivity changes can be produced by an increase in excitability of dorsal horn neurons; the phenomenon of central sensitization. We have now examined whether a reduction in local segmental inhibitory mechanisms produces similar changes. The model system used for studying touch-evoked allodynia has been the recruitment of a low-threshold mechanoreceptor input to the nociceptive flexion withdrawal reflex in the decerebrate-spinal rat. 2. Hamstring flexor alpha motoneurons are characterized by high-threshold cutaneous receptive fields. Mechanical stimuli (pinch or firm pressure) evoke a brisk firing response in these cells, whereas low-intensity stimuli (light touch or brush) produce little or no effect, as expected for the output neurons of the nociceptive flexion withdrawal reflex. 3. Primary afferent C fiber conditioning inputs have previously been shown to produce prolonged increases in the excitability of the flexion reflex, as measured by the augmentation of the response to high-intensity peripheral stimuli. We have now examined whether these conditioning inputs and segmental disinhibition modify the responsiveness of the reflex to low-threshold inputs. 4. Brief (20 s), low-frequency (1 Hz), C fiber conditioning stimuli to the sural nerve increased the response of the hamstring flexor motor neurons to low-intensity cutaneous touch stimuli, reduced the cutaneous mechanical threshold, and increased the response to A beta inputs from the sural nerve. 5. Intrathecal injections of subconvulsant doses of the glycine receptor antagonist, strychnine (7 nmol) or the gamma-aminobutyric acid-A (GABAA) receptor antagonist, bicuculline (8 nmol) produced similar but longer lasting changes. The GABAB antagonist P-(3-aminopropyl)-P-diethoxymethyl-phosphonic acid (CGP 35348) had no significant effects. 6. The nociceptive flexion withdrawal reflex is under the control, therefore, of segmental inhibitory mechanisms mediated by glycine and GABAA receptors. Removal of this inhibition enables the reflex to be activated by low-intensity cutaneous stimuli. Given the similarities between the stimulus-response profiles of the nociceptive flexion reflex and the production of pain in man, these findings indicate that a decrease in the efficacy of spinal inhibitory circuits may contribute to the touch-evoked allodynia that occurs in pain hypersensitivity states, where A beta inputs begin to produce pain.
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PMID:The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord. 796 3

An increase in the number of gamma-aminobutyric acid (GABA)-immunoreactive cells is reported in the superficial dorsal horn of the rat spinal cord upon unilateral inflammation of the hind foot caused by subcutaneous carrageenan injection. The rise of GABAergic cells was restricted to the ipsilateral dorsal horn, reaching a peak value of 23.4% over the contralateral side 4 days after carrageenan injection. Sciatic neurectomy or neonatal capsaicin treatment prevented this effect. These findings suggest that dorsal horn GABA is up-regulated by the increase of noxious inflow conveyed by unmyelinated C fibers from the inflamed tissues.
Pain 1994 Feb
PMID:Carrageenan-induced inflammation of the hind foot provokes a rise of GABA-immunoreactive cells in the rat spinal cord that is prevented by peripheral neurectomy or neonatal capsaicin treatment. 800 9

Injection of formalin into the hindpaw of a rat induces a biphasic response in pain-related behaviours, such that C-fibre activation during phase 1 triggers a state of central sensitization characterized by a longer lasting phase 2. As the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may participate in processing of nociceptive inputs, we hypothesized that pentobarbitone and propofol, i.v. anaesthetics with known GABAA agonist properties, would interfere with development of central sensitization and thereby modify the phase 2 hyperalgesic response. Pentobarbitone administered i.v. before injection of formalin produced dose-dependent suppression of phase 2, even though animals had recovered from anaesthesia, whereas it had substantially less effect when given after phase 1 had resolved. Picrotoxin, a GABAA antagonist, reversed the effect of pentobarbitone on phase 2 pain behaviour but was itself a mild analgesic. In contrast, propofol had no effect on phase 2 formalin-induced pain behaviour. Thus we conclude that pentobarbitone, but not propofol, produced pre-emptive analgesia in this model, presumably by suppressing noxious stimulation-induced central sensitization via activation of GABAA receptors.
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PMID:Pentobarbitone, but not propofol, produces pre-emptive analgesia in the rat formalin model. 802 13

The mechanism underlying the beneficial effect of electrical stimulation of the posterior surface of the spinal cord in chronic pain states are unknown. The prolonged pain relief following a short stimulation period is believed to imply the activation of long-lasting neurochemical processes, mainly in the spinal cord, but possibly also involving other parts of the central nervous system. Previous studies have demonstrated that substance P and serotonin are released in the cat dorsal horn during spinal cord stimulation (SCS) with electrical parameters similar to those used in the clinic. However, gamma-aminobutyric acid (GABA) has also been hypothesized to play a role in the effect of SCS, but there have been no studies of the possible effects of SCS on GABA release. The authors applied SCS to anesthetized rats and monitored the extracellular concentration of GABA in the lumbar dorsal horns by microdialysis and a sensitive reverse-phase high-performance liquid chromatography technique. After 30 minutes of SCS, the GABA level increased significantly (by almost 270%) in comparison with the basal level recorded before stimulation, from 3.6 +/- 1.0 nmol/L to 13.1 +/- 2.2 nmol/L (mean +/- the standard error of the mean; P < 0.05). The peak release was delayed and appeared in the 30-minute fraction collected after stimulation. Also, perfusion of the dialysis probes with potassium (100 mmol/L) induced an increase of the GABA level. In control experiments without electrical stimulation, slowly decreasing GABA levels were observed throughout the experiments. The present results may suggest an involvement of GABA in the mechanism of SCS-induced pain relief.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Gamma-aminobutyric acid is released in the dorsal horn by electrical spinal cord stimulation: an in vivo microdialysis study in the rat. 819 Feb 24

We have previously reported that transient spinal cord ischemia induced a behavioral hypersensitivity (allodynia) to innocuous cutaneous mechanical stimulation in rats. The spinal ischemia-induced allodynia was not relieved by morphine, but it was relieved by the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen, indicating that the allodynia may be related to dysfunction of the spinal GABA-ergic inhibitory system. In the present study we report that systemic application of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline (NBQX), an antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor for excitatory amino acids, dose-dependently relieved allodynia after spinal cord ischemia. The analgesic effect of NBQX at a low dose (7.5 mg/kg) was not accompanied by motor deficits or sedation. On the other hand, the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) only partially alleviated allodynia, even at doses that produced severe motor deficits. It is suggested that the abnormal, possibly painful, sensations elicited by innocuous mechanical stimulation observed after spinal cord ischemia may be mediated by excitatory amino acids, acting mainly on the AMPA receptor. Antagonists of excitatory amino acid receptors, especially at the AMPA site, may be effective in treating pain conditions where input from low threshold afferents triggers painful sensations.
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PMID:Systemic excitatory amino acid receptor antagonists of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and of the N-methyl-D-aspartate (NMDA) receptor relieve mechanical hypersensitivity after transient spinal cord ischemia in rats. 822 41

Baclofen (Lioresal) is a derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It is used to treat spasticity particularly for the relief of flexor spasms, pain, clonus, and muscular rigidity. There have been many rare neurologic side effects reported with its use. These side effects, in particular, hallucinations and seizures, have been observed predominantly following precipitous withdrawal of the drug. We present a case demonstrating a muscular dyskinetic side effect when baclofen treatment was first initiated. The mechanism by which baclofen affects spasticity and how the resulting side effect of dyskinesia developed in our patient is not known. They are, however, most probably related to dopamine receptor hypersensitivity and the resulting imbalance of the dopaminergic/cholinergic systems. Clinicians should be aware of this additional adverse effect of muscular dyskinesia, with the use of baclofen, and its reversibility when baclofen is discontinued.
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PMID:Baclofen-induced dyskinesia. 832 1

We tested the hypothesis that neurochemical changes in the spinal cord dorsal horn associated with neuropathic pain states differ from those seen in association with non-painful neuropathies. Immunohistochemistry was performed on spinal cord sections from rats with a chronic constriction injury (CCI), which develop hyperalgesia, and from animals with a nerve crush injury, which do not develop hyperalgesia or other signs of a painful syndrome. Immunohistochemistry was quantified by computer-assisted densitometry. Calcitonin gene-related peptide (CGRP) immunoreactivity and substance P (SP) immunoreactivity were decreased from 1 to 4 weeks after injury in CCI and from 2 to 6 weeks in crush. Gamma-aminobutyric acid immunoreactivity was unchanged in both conditions at all time points. Met-enkephalin (Met-enk) immunoreactivity was increased in CCI and unchanged in crush. Although SP and CGRP are involved in pain transmission, we conclude that their decrease in immunoreactivity is not specific for the CCI model, but rather a more general event in nerve de- and regeneration. The increase in immunoreactivity for the opioid peptide Met-ink, however, was only seen in the late phase of CCI, and may be specific for conditions associated with neuropathic pain and its resolution.
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PMID:Neurotransmitters in the spinal cord dorsal horn in a model of painful neuropathy and in nerve crush. 856 Sep 81

We investigated the interaction between gamma-aminobutyric acid (GABA)-immunoreactive (IR) elements and substance P (SP)-IR central terminals in synaptic glomeruli in lamina II of the chicken spinal cord in order to ascertain how pain information is modulated in the spinal dorsal horn. We combined the peroxidase-antiperoxidase (PAP) technique and the protein A-gold (PAG) technique to observe the synaptic relationship between these two components. At the light microscopic level, we observed both GABA-IR and SP-IR elements in the lamina II. GABA-IR elements were also observed in the lamina III. At the electron microscopic level, the following three GABA-IR elements formed synapses with the SP-IR central terminals in synaptic glomeruli: (1) elements which appeared to be axon terminals containing tightly-packed pleomorphic clear vesicles; (2) elements which appeared to be vesicle-containing dendrites with loosely-packed clear and dense-cored vesicles (DCVs); and (3) dendrites without synaptic vesicles. The first type of element was always presynaptic to the SP-IR central terminal. The second type was postsynaptic, presynaptic or in some cases reciprocal to the SP-IR central terminals. The third type was postsynaptic to the SP-IR central terminal. These results suggest that the SP-containing primary afferents activate GABA-containing dendrites and that the SP-containing primary afferents are inhibited presynaptically by GABA-containing neurons through axo-axonic and dendro-axonic synapses.
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PMID:Interaction between substance P-immunoreactive central terminals and gamma-aminobutyric acid-immunoreactive elements in synaptic glomeruli in the lamina II of the chicken spinal cord. 860 72

Most of the previous experimental studies on the antinociceptive effects of electrical spinal cord stimulation (SCS) have focused on short-lasting effects mainly depending on spinal mechanisms. However, patients treated with SCS for chronic pain often report pain relief exceeding the period of stimulation for several hours. The long lasting effect of SCS might not only involve spinal, but also supraspinal mechanisms. A supraspinal region of major importance for the coordination of descending pain inhibition is the periaqueductal grey matter (PAG). The aim of the present microdialysis study, performed in awake freely moving rats, was to investigate if repeated SCS (two 30 min periods separated by a 90 min resting period) alters the extracellular neurotransmitter concentrations in the ventrolateral PAG. In a first series of experiments significantly decreased (-30%; P < 0.05; n = 7) gamma-aminobutyric acid (GABA) levels were detected immediately after the second SCS session. Neither the concentration of serotonin nor that of substance P-like immunoreactivity (SP-LI) was affected by SCS. The decrease of GABA after two SCS sessions was confirmed in a second series of experiments (-30%; P < 0.05; n = 7). No spontaneous decline of GABA was observed in sham-stimulated animals (n = 6). The glutamate concentration was also determined in this latter series of experiments and a significant decrease (-23%; P < 0.05; n = 5) was observed after the second SCS session. As GABA-neurons in the PAG exert a tonic depressive effect on the activity in descending pain inhibitory pathways, a decreased extracellular GABA level in this region, as detected following repeated SCS, might indicate an increased pain inhibition.
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PMID:Repeated spinal cord stimulation decreases the extracellular level of gamma-aminobutyric acid in the periaqueductal gray matter of freely moving rats. 861 26

Opioids are generally believed to activate descending pain inhibitory pathways from the periaqueductal gray matter (PAG). Since opioids exert an inhibitory effect on neural excitability and transmitter release, an opioid-mediated inhibition of tonically active inhibitory gamma-aminobutyric acid (GABA) neurons has been suggested to mediate this effect. The aim of the present microdialysis study was to investigate the effect of local administration of morphine on the extracellular GABA level in the PAG of awake rats. The recently developed and highly sensitive method of capillary electrophoresis with laser-induced fluorescence detection was used for GABA determination in microdialysate samples obtained from the PAG of freely moving rats. The basal GABA level was 54.5 +/- 6.6 nM (n = 8; mean +/- SEM). Perfusion of the dialysis probe with morphine (100 microM) for 30 min significantly decreased the GABA level to 28.2 +/- 4.2 nM (n = 8; P < 0.05). The effect of morphine was reversed by coperfusion with naloxone (100 microM in the perfusion fluid). The present results thus provide direct experimental evidence for an opioid-induced inhibition of tonic GABA release in the PAG, which may in turn lead to a disinhibition of descending pain inhibitory pathways.
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PMID:Local administration of morphine decreases the extracellular level of GABA in the periaqueductal gray matter of freely moving rats. 873 36


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