The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord

Abstract

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.