5-HT3 and 5-HT4 receptors and cholinergic and tachykininergic neurotransmission in the guinea-pig proximal colon

Eur J Pharmacol. 1996 Jul 18;308(2):173-80. doi: 10.1016/0014-2999(96)00297-x.


The pathways and possible transmitters involved in the contractile response to selective 5-HT3 and 5-HT4 receptor stimulation in the guinea-pig proximal colon were studied. In the presence of methysergide, 5-HT induced contractions, yielding a biphasic concentration-response curve that was changed into a monophasic curve in the presence of the 5-HT3 receptor antagonist, granisetron (1 microM) (low-affinity phase blocked), or the 5-HT4 receptor antagonist, SB 204070 ((1-butyl-4-piperidinyl methyl)-8-amino-7-chloro-1,4-benzodioxan-5-carboxylate) (10 nM) (high-affinity phase blocked) combination of the two antagonists abolished the contraction to 5-HT. The effectiveness and selectivity of both antagonists was confirmed by testing them against contractions in response to the 5-HT3 receptor-selective agonist, 2-methyl-5-HT, and the 5-HT4 receptor-selective agonist, 5-methoxytryptamine. Hexamethonium (100 microM) did not affect the 5-HT3 receptor-mediated contractions, whereas tetrodotoxin (0.3 microM) caused only slight inhibition. Both in the absence and presence of tetrodotoxin, atropine (0.3 microM) inhibited the 5-HT3 receptor-mediated contractions. Hence, the contractions to 5-HT are partly mediated by 5-HT3 receptors that are localized on the nerve endings of the motor neurons. Hexamethonium halved the 5-HT4 receptor-mediated contractions, whereas tetrodotoxin abolished them. The 5-HT4 receptor-mediated contractions were inhibited by atropine (0.3 microM). Thus, the 5-HT4 receptors seem to be localized in the soma of the motor neurons; they also occur on interneurons. The remaining contractions induced by 5-HT3 and 5-HT4 receptor stimulation in the presence of atropine were almost completely inhibited by the tachykinin NK1 receptor antagonist, CP 96345 ((2S,3S)-cis-2-(diphenyl methyl)-N-[(2-methoxy phenyl)-methyl]-1-azabicyclo-[2.2.2]-octan-3-amine) (0.1 microM). CP 96345 also abolished or strongly inhibited contractions in response to substance P (10 nM) and to neurokinin A (30 nM), but neither granisetron nor SB 204070 affected them. Hence, stimulation of either 5-HT3 or 5-HT4 receptors induced contractions that are partially mediated by acetylcholine, and partially by a tachykinin NK1 receptor-stimulating neurotransmitter, probably substance P and/or neurokinin A.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Biphenyl Compounds / pharmacology*
  • Colon / drug effects*
  • Colon / innervation
  • Dioxanes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Female
  • Granisetron / pharmacology*
  • Guinea Pigs
  • In Vitro Techniques
  • Interneurons / metabolism
  • Male
  • Motor Neurons / metabolism
  • Muscle Contraction
  • Neurokinin-1 Receptor Antagonists*
  • Piperidines / pharmacology*
  • Receptors, Neurokinin-1 / physiology
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / physiology
  • Serotonin / pharmacology*
  • Serotonin Receptor Agonists / pharmacology*


  • Biphenyl Compounds
  • Dioxanes
  • Neurokinin-1 Receptor Antagonists
  • Piperidines
  • Receptors, Neurokinin-1
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • SB 204070A
  • Serotonin
  • CP 96345
  • Granisetron