Wide-dynamic-range neurons are heterogeneous in windup responsiveness to changes in stimulus intensity and isoflurane...

The windup phenomenon in wide-dynamic-range (WDR) neurons represents a short-term neuronal sensitization to repetitive noxious inputs that may share similar mechanisms with those that trigger the development of persistent pain and hyperalgesia. Some WDR cells are readily sensitized and express prominent windup (windup(+)), whereas others do not (windup(-)). We recorded extracellular single-unit activity of deep laminae WDR neurons (350-700 microm) in C57BL/6 mice to determine how changes in stimulus intensity (1x and >2x C-component threshold, n = 53) and concentrations of isoflurane anesthesia (2.0% and 1.0%, n = 30) might differently modulate windup responsiveness in windup(+) and windup(-) cells. Two principally different analysis methods [absolute windup (the number of action potentials) and relative windup (the percentage of action potentials evoked by the first stimulus of the train)] were used to interpret windup data. We observed that increasing the stimulus intensity and decreasing the isoflurane concentration: 1) facilitated windup generation at 0.2-Hz stimulation and significantly enhanced absolute windup at both 0.2-Hz and 0.5-Hz stimulation predominantly in windup(+) cells but did not confer windup capability on windup(-) cells and 2) significantly increased relative windup at 0.2-Hz, but not 0.5-Hz, stimulation in windup(+) cells. Our findings advance our understanding of the neurobiology of deep WDR neurons in mice and demonstrate that two populations of cells differ in their windup responsiveness to changes in experimental conditions. We also elucidate the usefulness and potential limitations of two widely used methods for calculating and presenting windup data.