Effects of omega-agatoxin IVA, a P-type calcium channel antagonist, on the development of spinal neuronal hyperexcitability caused by knee inflammation in rats.
Both N- and P-type high-threshold calcium channels are located presynaptically in the CNS and are involved in the release of transmitters. To investigate the importance of P-type calcium channels in the generation of inflammation-evoked hyperexcitability of spinal cord neurons, electrophysiological recordings were made from wide-dynamic-range neurons with input from the knee joint in the anesthetized rat. The responses of each neuron to innocuous and noxious pressure onto the knee and the ankle were continuously assessed before and during the development 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 channels omega-agatoxin was administered into a 30-microl trough on the spinal cord surface above the recorded neuron. In most neurons the application of omega-agatoxin before induction of inflammation slightly enhanced the responses to pressure onto the knee and ankle or left them unchanged. Two different protocols were then followed. In the control group (13 rats) only Tyrode was administered to the spinal cord during and after induction of inflammation. In these neurons the responses to mechanical stimuli applied to both the inflamed knee and to the noninflamed ankle showed a significant increase over 4 h. In the experimental group (12 rats) omega-agatoxin was applied during knee injection and in five 15-min periods up to 180 min after kaolin. This prevented the increase of the neuronal responses to innocuous pressure onto the knee and to innocuous and noxious pressure onto the ankle; only the responses to noxious pressure onto the knee were significantly enhanced during development of inflammation. Thus the development of inflammation-evoked hyperexcitability was attenuated by omega-agatoxin, and this suggests that P-type calcium channels in the spinal cord are involved in the generation of inflammation-evoked hyperexcitability of spinal cord neurons. Finally, when omega-agatoxin was administered to the spinal cord 4 h after the kaolin injection, i.e., when inflammation-evoked hyperexcitability was fully established, the responses to innocuous and noxious pressure onto the knee were reduced by 20-30% on average. The shift in the effect of omega-agatoxin, from slight facilitation or no change of the responses before inflammation to inhibition in the state of hyperexcitability, indicates that P-type calcium channels are important for excitatory synaptic transmission involved in the maintenance of inflammation-evoked hyperexcitability.
Nebe
J
J
Physiologisches Institut der Universität Würzburg, D-97070 Würzburg, Germany.
Ebersberger
A
A
Vanegas
H
H
Schaible
H G
HG
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D020864:Calcium Channels, N-Type; D007596:Joints / Q000473:pathology / Q000503:physiopathology; D007616:Kaolin; D008297:Male; D009474:Neurons / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D013111:Spider Venoms / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D020867:omega-Agatoxin IVA
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D007616:Kaolin; D013111:Spider Venoms; D020867:omega-Agatoxin IVA