Spinal modulation of the induction of central sensitization

Peripheral tissue injury results in a change in the excitability of spinal dorsal horn neurons, central sensitization, and the behavioral correlate, hyperalgesia. It is proposed here that a dynamic balance exists between excitatory and inhibitory synaptic input to the spinal dorsal horn that functions to prevent central sensitization following brief, mild, noxious stimulation. Following more severe stimulation and injury, there is a loss of these inhibitory mechanisms that allow central sensitization to proceed. Single-unit recordings were made from L4-L5 deep dorsal horn neurons (wide dynamic range and nociceptive specific) from barbiturate-anesthetized rats that were non-inflamed or had a carrageenan-inflamed hindpaw. Baseline test responses to mechanical stimuli were obtained and normalized to 100%. An electrical conditioning stimulus (1 Hz, 20 s, C-fiber strength) was applied to the tibial nerve or the neuronal receptive field. Five seconds later the test stimulus was repeated and the magnitude of response compared to baseline. During the conditioning stimulus, 46% of the neurons from non-inflamed and inflamed rats showed wind-up although the magnitude of wind-up was significantly greater for inflamed rats. The remaining neurons showed no change (36-46%) or wind-down (8-18%). Five seconds following the end of the conditioning stimulus 67% of the neurons from non-inflamed rats had attenuated responses to mechanical stimuli (36% of baseline). The remaining neurons were either unaffected (30%) or facilitated (3%). Following inflammation significantly fewer neurons (28%) had attenuated responses and the magnitude of attenuation was significantly less than in non-inflamed rats (54% of baseline). The responses of the remaining neurons were unaffected (54%) or facilitated (18%). During subsequent test stimuli, the responses of 30% of the neurons from non-inflamed rats were facilitated to 140% of baseline. The responses of 46% of neurons from inflamed rats were facilitated to 160% of baseline. In these neurons there was significantly less initial attenuation following inflammation compared to non-inflamed rats. The response of the neuron during the electrical conditioning had no effect upon the response following conditioning. The conditioning stimulus given transcutaneously within the receptive field produced qualitatively similar results to tibial nerve stimulation. In non-inflamed rats, when the conditioning/test-stimulus interval was increased from 5 s to 10-30 s, the responses of 20% of the neurons were attenuated (compared to 67%) and the mean magnitude of attenuation was 52% of baseline (compared to 36% of baseline). However, the responses of only 33% of the neurons were ultimately facilitated (compared to 30%). The present study documents a short period following a low-frequency C-fiber input in which the response to natural stimuli is suppressed. It is suggested that this attenuation, whether or not expressed, prevents a significant portion of deep dorsal horn neurons from becoming sensitized to C-fiber input. This functions to prevent central sensitization when the noxious stimulus does not produce inflammation and it is not beneficial to the animal to become hyperalgesic (i.e., to alter its behavior in order to protect an injured limb and reduce painful sensations). Following injury-producing tissue damage and inflammation the mechanisms that produce the attenuation are reduced, with a concomitant increase in excitation to electrical and natural stimuli, suggesting that the attenuation is inhibitory modulation of nociceptive input and injury results in a disinhibition producing an increase in excitability and central sensitization.