Effect of temperature on limitation by MK-801 of firing of action potentials by spinal cord neurons in cell culture.

The anticonvulsant, MK-801, limited sustained high frequency repetitive firing of sodium-dependent action potentials by mouse spinal cord neurons in monolayer dissociated cell culture. Limitation was voltage- and temperature-dependent and was accompanied by decreasing rate of rise of action potentials until firing ceased during the 400 ms depolarizations. The IC50 for limitation was 2 x 10(-7) M at 37 degrees C, 6.4 x 10(-7) M at 35 degrees C, and 4 x 10(-5) M at 23 degrees C. The relationship between the percentage of neurons capable of sustained repetitive firing and MK-801 concentration at 33 degrees C was biphasic. The first phase (about 50%) of limitation had IC50a = 1.5 x 10(-7) M, and the second had IC50b = 2 x 10(-4) M; the midpoint of the connecting plateau was 10(-5) M. At temperatures below 37 degrees C, the current needed to achieve maximal firing increased. The maximal rate of rise, maximal firing frequency and sensitivity to MK-801 of action potentials elicited by 1 ms stimuli decreased at temperatures below 37 degrees C. Passive membrane properties were unchanged. Slow firing and a temperature-sensitive conformational change in voltage-activated sodium channels could account for the higher concentrations of MK-801 required to block sodium-dependent action potentials at temperatures below 37 degrees C.