Effects of omega-agatoxin IVA, a P-type calcium channel antagonist, on thedevelopment of spinal neuronal hyperexcitability caused by knee inflammation in rats

Effects of omega-agatoxin IVA, a P-type calcium channel antagonist, on the development of spinal neuronal hyperexcitability caused by knee inflammatio n in rats. J. Neurophysiol. 81: 2620-2626, 1999. Both N- and P-type high-th reshold calcium channels are located presynaptically in the CNS and are inv olved in the release of transmitters. To investigate the importance of P-ty pe calcium channels in the generation of inflammation-evoked hyperxcitabili ty of spinal cord neurons, electrophysiological recordings were made from w ide-dynamic-range neurons with input from the knee joint in the anesthetize d rat. The responses of each neuron to innocuous and noxious pressure onto the knee and the ankle were continuously assessed before and during the dev elopment of an inflammation in the knee joint induced by the injections of K/C into the joint cavity. The specific antagonist at P-type calcium channe ls w-agatoxin was administered into a 30-mu l trough on the spinal cord sur face above the recorded neuron. In most neurons the application of omega-ag atoxin before induction of inflammation slightly enhanced the responses to pressure onto the knee and ankle or left them unchanged. Two different prot ocols were then followed. In the control group (13 rats) only Tyrode was ad ministered to the spinal cord during and after induction of inflammation. I n these neurons the responses to mechanical stimuli applied to both the inf lamed knee and to the noninflamed ankle showed a significant increase over 4 h. In the experimental group (12 rats) w-agatoxin was applied during knee injection and in five 15-min periods up to 180 min after kaolin. This prev ented the increase of the neuronal responses to innocuous pressure onto the knee and to innocuous and noxious pressure onto the ankle; only the respon ses to noxious pressure onto the knee were significantly enhanced during de velopment of inflammation. Thus the development of inflammation-evoked hype rexcitability was attenuated by omega-agatoxin, and this suggests that P-ty pe calcium channels in the spinal cord are involved in the generation of in flammation-evoked hyperexcitability of spinal cord neurons. Finally, when o mega-agatoxin was administered to thr spinal cord 4 h after the kaolin inje ction, i,e., when inflammation-evoked hyperexcitability was fully establish ed, the responses to innocuous and noxious pressure onto the knee were redu ced by 20-30% on average. The shift in the effect of omega-agatoxin, from s light facilitation or no change of the responses before inflammation to inh ibition in the state of hyperexcitability, indicates that P-type calcium ch annels an important for excitatory synaptic transmission involved in the ma intenance of inflammation-evoked hyperexcitability.