Pharmacological characteristics and regulation of 5-HT receptor-stimulated phosphoinositide hydrolysis in the rat spinal cord

In slices from immature rat spinal cord, both 5-hydroxytryptamine (5-HT) and the 5-HT2A/C receptor agonists (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and alpha-methyl-5-HT (alpha-Me-5-HT) stimulate phosphoinositide (PI) hydrolysis. PI breakdown is also increased by the 5-HT3 receptor agonist 2-Me-5-HT but not by phenylbiguanide. The effect of either 5-HT or DOI is blocked by selective 5-HT2A receptor antagonists such as spiperone and ketanserin and more markedly by mixed 5-HT2 receptor antagonists, such as ritanserin, methysergide and mesulergine, with higher affinity at the 2C subtype. The effect of 2-Me-5-HT is blocked by 5-HT2 and not by 5-HT3 receptor antagonists, indicating that 5-HT3 receptors do not directly or indirectly take part in PI hydrolysis in the spinal cord. Moreover, lesion with neonatal capsaicin of thin primary afferents to the dorsal spinal cord enhances inositol phosphate formation stimulated by 5-HT or DOI but not by 2-Me-5-HT. This lesion also increases 5-HT2A and 5-HT2C receptor density. After neonatal injection of 5,7-dihydroxytryptamine, which results in a marked loss of 5-HT content in the cord, 5-HT and 5-HT2 receptor agonists also enhance PI breakdown without a concomitant change in receptor number. The results suggest that the 5-HT-stimulated PI response in the rat spinal cord is associated only with the 5-HT2 receptor class, in particular with the 5-HT2C subtype. (C) 1999 Elsevier Science Inc. All rights reserved.