THE CONTRIBUTION OF GABA(A) AND GLYCINE RECEPTORS TO CENTRAL SENSITIZATION - DISINHIBITION AND TOUCH-EVOKED ALLODYNIA IN THE SPINAL-CORD

1. Pain hypersensitivity is characterized by an increase in the respon se to noxious stimuli (hyperalgesia) and a reduction in threshold such that innocuous stimuli begin to elicit pain (allodynia). These sensit ivity changes can be produced by an increase in excitability of dorsal horn neurons; the phenomenon of central sensitization. We have now ex amined whether a reduction in local segmental inhibitory mechanisms pr oduces similar changes. The model system used for studying touch-evoke d allodynia has been the recruitment of a low-threshold mechanorecepto r input to the nociceptive flexion withdrawal reflex in the decerebrat e-spinal rat. 2. Hamstring flexor cu 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 effe ct, as expected for the output neurons of the nociceptive flexion with drawal reflex. 3. Primary afferent C fiber conditioning inputs have pr eviously been shown to produce prolonged increases in the excitability of the flexion reflex, as measured by the augmentation of the respons e to high-intensity peripheral stimuli. We have now examined whether t hese conditioning inputs and segmental disinhibition modify the respon siveness of the reflex to low-threshold inputs. 4. Brief (20 s), low-f requency (1 Hz), C fiber conditioning stimuli to the sural nerve incre ased the response of the hamstring flexor motor neurons to low-intensi ty 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 (GAB A(A)) receptor antagonist, bicuculline (8 nmol) produced similar but l onger lasting changes. The GABA(B) antagonist P-(3-aminopropyl)-P-diet hoxymethyl-phosphonic acid (CGP 35348) had no significant effects. 6. The nociceptive flexion withdrawal reflex is under the control, theref ore, of segmental inhibitory mechanisms mediated by glycine and GABA(A ) receptors. Removal of this inhibition enables the reflex to be activ ated by low-intensity cutaneous stimuli. Given the similarities betwee n the stimulus-response profiles of the nociceptive flexion reflex and the production of pain in man, these findings indicate that a decreas e in the efficacy of spinal inhibitory circuits may contribute to the touch-evoked allodynia that occurs in pain hypersensitivity states, wh ere A beta inputs begin to produce pain.