Ameliorative effect of chlorpromazine hydrochloride on visceral hypersensitivity in rats: possible involvement of 5‐HT_2A receptor

Abstract

BACKGROUND AND PURPOSEVisceral hypersensitivity is responsible for pathogenesis of irritable bowel syndrome (IBS). Therefore, its prevention can help avoid abdominal pain and discomfort in IBS. To find candidate drugs for visceral hypersensitivity, we screened existing medicines for their ability to prevent visceral sensitivity induced by colorectal distension (CRD) in rats and identified chlorpromazine, a typical antipsychotic drug, as a candidate compound. In this study, we investigated the effect of chlorpromazine on visceral hypersensitivity. EXPERIMENTAL APPROACHVisceral sensitivity (visceromotor response) was monitored by measuring the electrical activity of the abdominal external oblique muscle contraction in response to CRD using a barostat apparatus. Visceral hypersensitivity was induced by a colonic instillation of sodium butyrate or acetic acid in neonates. KEY RESULTSOral administration of chlorpromazine suppressed butyrate-induced visceral hypersensitivity to CRD. Interestingly, atypical antipsychotic drugs, quetiapine and risperidone, ameliorated butyrate-induced visceral hypersensitivity, whereas the typical antipsychotic drugs, haloperidol and sulpiride, did not. Pharmacological analysis using specific inhibitors showed that a selective 5-HT 2A receptor antagonist, ketanserin, suppressed butyrate-induced visceral hypersensitivity, whereas a selective dopamine D 2 receptor antagonist, L-741626, did not. Furthermore, the 5-HT 2A receptor agonist AL-34662 stimulated visceral sensitivity to CRD in healthy control rats but not in butyrate-treated rats. These findings suggest that increased 5-HT levels in the colon contribute to the induction of visceral hypersensitivity. CONCLUSIONS AND IMPLICATIONSOur results indicate that chlorpromazine ameliorates visceral hypersensitivity and that the 5-HT 2A receptor is a potential therapeutic target for treating abdominal pain and discomfort in IBS. Abbreviations7OH-Cpz, 7-hydroxy chlorpromazine; ASIC, acid-sensing ion channel; CRD, colorectal distension; DRG, dorsal root ganglion; IBS, irritable bowel syndrome; p-CPA, p-chlorphenylalanine; TRPV1, transient receptor potential vanilloid 1; VMR, visceromotor response

Effects of Bepridil and Pimozide, Existing Medicines Capable of Blocking T-Type Ca²⁺ Channels, on Visceral Pain in Mice

“…19) On the other hand, chlorpromazine, another typical antipsychotic drug, ameliorated the colonic hypersensitivity in the same rat models. 19) Of interest is that chlorpromazine as well as pimozide, but not haloperidol, blocks T-channel currents. 5,20) There is also evidence for the involvement of serotonin 5-HT 2A receptor blockade in the effect of chlorpromazine on visceral pain.…”

“…Many of voltage-sensitive ion channels, such as N-type Ca 2+ channels as well as T-channels, Na + channels and also hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, regulate neuronal excitability and/or neurotransmitter release in the central and peripheral nervous systems including nociceptors, and participate in pain processing. 16) Thus, bepridil, capable of blocking those multiple voltage-sensitive cation channels including Ca v 3.2, 4,17,18) may be beneficial to treat human pain, because multi-channel inhibition is expected to cause synergistic suppression of nociceptor excitation. Nonetheless, the T-channel blockade is considered to play a major role in the induction of the antinociceptive effect of bepridil at least in laboratory animals, considering the IC 50 values, 0.4-10.6 µM in blocking T-channels at holding potentials between −70 and −100 mV, 4) and 80 and 4.9 µM in blocking voltage-sensitive Na + channels and HCN channels, respectively.…”

“…Nonetheless, the T-channel blockade is considered to play a major role in the induction of the antinociceptive effect of bepridil at least in laboratory animals, considering the IC 50 values, 0.4-10.6 µM in blocking T-channels at holding potentials between −70 and −100 mV, 4) and 80 and 4.9 µM in blocking voltage-sensitive Na + channels and HCN channels, respectively. 17,18) On the other hand, the alleviation of colonic and bladder pain by pimozide, a neuroleptic, in the present study may be attributable predominantly to T-channel inhibition, but not D 2 receptor blockade, considering the reports showing that typical antipsychotic drugs, haloperidol and sulpiride, or a selective D 2 receptor antagonist, L-741626, did not attenuate visceral hypersensitivity to colorectal distention in rats that had received a colonic instillation of butyrate or acetic acid in the neonatal period. 19) On the other hand, chlorpromazine, another typical antipsychotic drug, ameliorated the colonic hypersensitivity in the same rat models.…”

“…17,18) On the other hand, the alleviation of colonic and bladder pain by pimozide, a neuroleptic, in the present study may be attributable predominantly to T-channel inhibition, but not D 2 receptor blockade, considering the reports showing that typical antipsychotic drugs, haloperidol and sulpiride, or a selective D 2 receptor antagonist, L-741626, did not attenuate visceral hypersensitivity to colorectal distention in rats that had received a colonic instillation of butyrate or acetic acid in the neonatal period. 19) On the other hand, chlorpromazine, another typical antipsychotic drug, ameliorated the colonic hypersensitivity in the same rat models. 19) Of interest is that chlorpromazine as well as pimozide, but not haloperidol, blocks T-channel currents.…”

Shaoyao‐Gancao Decoction Relieves Visceral Hyperalgesia in TNBS‐Induced Postinflammatory Irritable Bowel Syndrome via Inactivating Transient Receptor Potential Vanilloid Type 1 and Reducing Serotonin Synthesis

“…5-HT is synthesized from tryptophan by tryptophan hydroxylase (TPH) in enterochromaffin (EC) cells and aromatic amino acid decarboxylase [ 10 ]. The 5-HT released from EC cells may activate serotonergic receptors and be taken up into the enterocytes by serotonin reuptake transporter (SERT).…”