Diisopropylfluorophosphate and tetanic stimulation fail to reverse mecamylamine antagonism of Renshaw cells

Mecamylamine-induced antagonism of Renshaw cells was studied in the spinal cord of DIAL anesthetized adult male or spayed female mongrel cats. Renshaw cell unit responses to 1- or 2-Hz supramaximal antidromic stimulation of lumbar segment 7 ventral root were recorded by conventional means from glass micropipettes (2.7 M NaCl, tip diameter 1.0 to 1.6 micron, 2.0 to 4.0 M omega resistance). Data were analyzed by computer. Mecamylamine (1.0 mg/kg iv) antagonizes the response to 1- or 2-Hz stimulation. The onset occurs within 60 sec, only the first one or two spikes remain after 2 min, and this antagonism is observed 30 min after injection. Persistence of action of acetylcholine (ACh) induced by diisopropylfluorophosphate (DFP 2.0 to 2.5 mg/kg iv) increases the spike frequency of the Renshaw cell burst and reduces the variability in the number of spikes per discharge in response to 1- or 2-Hz antidromic stimulation. Excess ACh generated by 2 min of 20-Hz antidromic stimulation fails to reverse the mecamylamine-induced antagonism to 1- or 2-Hz antidromic stimulation. Also, DFP-induced persistence of action of ACh or 20-Hz (2 min) antidromic stimulation to induce excess ACh in the presence of DFP, fails to reverse the mecamylamine-induced antagonism of response to 1- or 2-Hz antidromic stimulation. It is concluded that the data agree with a mechanism of action of mecamylamine as a noncompetitive open channel blocker of the nicotinic receptor ion-channel complex which renders it nonresponsive to the agonist ACh and to the open channel blocker, DFP.