[Molecular neuropharmacology of nociceptive transmission and opioid receptors].
This review summarizes our studies using pharmacological, neurochemical and molecular biological methods on the nociception in the CNS and opioid receptors (OPRs). We designed an in vitro fluorometric on-line monitoring system including an immobilized glutamate dehydrogenase column, and for the first time actually demonstrated that capsaicin induced the release of glutamate from rat dorsal horn slices containing the terminal area of primary afferents, in concentration-dependent, extracellular Ca(2+)-dependent and tetrodotoxin-resistant manners. Further, such a release was shown to be inhibited through mu- and delta-opioid receptors and alpha 2-adrenoceptors. On the other hand, we found that intracerebroventricular injections of interleukin (IL)-1 beta in rats produced biphasic effects on the mechanical nociception in rats (hyperalgesia in lower concentrations but analgesia in higher ones) and that similar injections of cytokine-induced neutrophil chemoattractant-1 (CINC-1) facilitated mechanical nociception in rats. The above described facts suggest that glutamate and some sorts of cytokines (IL-1 beta and CINC-1) contribute to nociception at least from the primary afferents to the spinal dorsal horn neurons and in higher brain, respectively. We have cloned rat kappa- and mu-opioid receptors. Using cloned cDNA for OPRs, we demonstrated (1) the distribution of mRNAs for OPRs in the rat central nervous system, (2) coexistence of each type of mRNA for mu-, delta- and kappa-OPRs and pre-protachykinin A mRNA in the dorsal root ganglion neurons, (3) an increased expression of mu- and kappa-OPR mRNAs in the I-II layers of rat lumbar dorsal horn with an adjuvant arthritis in the hind limb, (4) the inhibitions of N- and Q-types of Ca2+ channels by mu- and kappa-OPR agonists and (5) cross-desensitization of the inhibition through a common intracellular phosphorylation-independent mechanism, (6) pharmacological characterization of "antagonist analgesics" as partial agonists at every type of OPRs, and (7) the key-structure(s) of OPRs for discriminative binding of DAMGO to mu-OPR.
Satoh
M
M
Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Shimoadachi-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D002490:Central Nervous System / Q000502:physiology; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000494:pharmacology / Q000502:physiology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology; D009619:Nociceptors / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000502:physiology
D000701:Analgesics, Opioid; C475829:CXCL1 protein, human; D015220:Calcium Channels; D054360:Chemokine CXCL1; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; D005971:Glutamates; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D007375:Interleukin-1; D012333:RNA, Messenger; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-