NOVEL KAINATE DERIVATIVES - POTENT DEPOLARIZING ACTIONS ON SPINAL MOTONEURONS AND DORSAL-ROOT FIBERS IN NEWBORN RATS

1 Neuropharmacological actions of several kainate derivatives (kainoids) were examined for electrophysiological effects in the isolated spinal cord and the dorsal root fibre of the newborn rat. 2 Some kainoids caused depolarization of the motoneurone much more effectively than kainic acid or domoic acid and others were weaker. The rank order of the depolarizing activities of the kainoids tested here is as follows: 4-(2-methoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (MFPA) > acromelic acid A > domoic acid greater-than-or-equal-to 4-(2-hydroxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (HFPA) greater-than-or-equal-to acromelic acid B > kainic acid. 3 In the isolated dorsal root fibre, domoic acid caused the most significant depolarization. There were distinct differences with regard to the rank order of the depolarizing activity between the motoneurone and the dorsal root fibre. The rank order in the dorsal root fibre is domoic acid > acromelic acid B > 5-bromowillardine greater-than-or-equal-to MFPA > acromelic acid A > HFPA > kainic acid. 4 Significant desensitization of kainate receptors was observed in the isolated dorsal root fibre during prolonged application of L-glutamate, kainate and its derivatives. Cross desensitization was also observed among these excitatory amino acids. Receptors desensitized by kainate did not respond to MFPA, HFPA and acromelic acids, suggesting that these kainate derivatives activated common kainate receptors in the dorsal root fibre. 5 In both motoneurones and dorsal root fibres 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) effectively depressed the depolarization induced by kainoids, and neither 3-[(+/-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP) nor picrotoxin blocked or affected the depolarization, but there were some differences in pharmacological potencies of glutamate antagonists between both preparations. 6 MFPA, HFPA and acromelic acids should provide valuable pharmacological tools for analysis of physiological functions of excitatory amino acids, in particular, as specific agonists for some subtypes of kainate receptors.