Hiroshi Ueda
Department of Molecular Pharmacology and Neuroscience, Nagasaki University
School of Pharmaceutical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521,
Japan
Abstract: Although we have obtained a number of pharmacological
tools and mutant mice lacking specific genes related to the pain, the distinct
molecular basis of the pain-producing mechanism has remained to be fully
clarified since we have been using conventional paradigms of the nociception
test that may drive multiple endogenous molecules affecting nociception
at the same time. Here, I will introduce a new paradigm of the nociception
test. In this test, we focused on polymodal C-fibers by measuring nociceptive
flexor responses induced by the peripheral application of a single species
of nociceptive molecule. In addition, we identified the site of drug actions
on nociceptor endings by the fact that the nociception was abolished by
the intrathecal pretreatment with antisense oligodeoxynucleotide for receptors.
Throughout experiments using this paradigm of the nociception test, it was
firstly revealed that substance P, a major neurotransmitter of polymodal
C-fibers, directly stimulates nociceptor endings through activation of Gq/11
and phospholipase C, followed by Ca2+ influx through plasma membrane-bound
inositol trisphosphate receptors, and that bradykinin and histamine, both
endogenous representative pain-producing substances, share this mechanism.
Another unique mechanism is through Gi-coupled receptors such
as receptors for nociceptin (orphanin FQ) or kyotorphin (tyrosine-arginine).
The latter mechanism was found to be mediated through a substance P release
from nociceptor endings. Future studies including some modifications of
this paradigm should be also clinically useful for neuropathic pain research
as well as understanding of pain physiology.
Keywords: Nociceptin, Substance P, Nociceptor, Pain, Inositol trisphosphate
receptor