Potentiation of transient receptor potential V1 functions by the activation of metabotropic 5-HT receptors in rat primary sensory neurons.
5-Hydroxytryptamine (5-HT) is one of the major chemical mediators released in injured and inflamed tissue and is capable of inducing hyperalgesia in vivo. However, the cellular mechanisms of 5-HT-induced hyperalgesia remain unclear. Transient receptor potential V1 (TRPV1) plays a pivotal role in nociceptive receptors. In the present study, we determined whether 5-HT changes TRPV1 functions in cultured dorsal root ganglion (DRG) neurons isolated from neonatal rats, using Ca(2+) imaging and whole-cell patch-clamp techniques. In more than 70% of DRG neurons, 5-HT potentiated the increases of [Ca(2+)](i) induced by capsaicin, protons and noxious heat. Capsaicin-induced current and depolarizing responses, and proton-induced currents were also augmented by 5-HT. RT-PCR analysis revealed the expression of 5-HT(2A) and 5-HT(7) receptors in rat DRG neurons. Agonists for 5-HT(2A) and 5-HT(7) receptors mimicked the potentiating effect of 5-HT, and their antagonists decreased it. In DRG ipsilateral to the complete Freund's adjuvant-injected inflammation side, expression levels of 5-HT(2A) and 5-HT(7) mRNAs increased, and the potentiating effect of 5-HT was more prominent than in the contralateral control side. These results suggest that the PKC- and PKA-mediated signalling pathways are involved in the potentiating effect of 5-HT on TRPV1 functions through the activation of 5-HT(2A) and 5-HT(7) receptors, respectively. Under inflammatory conditions, the increases of the biosynthesis of these 5-HT receptors may lead to further potentiation of TRPV1 functions, resulting in the generation of inflammatory hyperalgesia in vivo.
Ohta
Toshio
T
Laboratory of Pharmacology, Department of Biochemical Sciences, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan. tohta@vetmed.hokudai.ac.jp
Ikemi
Yuki
Y
Murakami
Matsuka
M
Imagawa
Toshiaki
T
Otsuguro
Ken-Ichi
K
Ito
Shigeo
S
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006930:Hyperalgesia / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009475:Neurons, Afferent / Q000166:cytology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000502:physiology*; D011985:Receptors, Serotonin / Q000235:genetics / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D018490:Serotonin Agents / Q000494:pharmacology; D013569:Synapses / Q000502:physiology; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology*
D018712:Analgesics, Non-Narcotic; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C104425:serotonin 7 receptor; D012701:Serotonin; D011494:Protein Kinases; D002211:Capsaicin