Mediation of serotonin hyperalgesia by the cAMP second messenger system.
In this study we have evaluated the second messenger system that might couple 5-HT1A receptor activation to produce peripheral hyperalgesia. The intradermal injection of the serotonin (5-hydroxytryptamine; 5-HT) receptor agonist for the 1A receptor subset (5-HT1A), (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide (8-OH DPAT) produces a dose-dependent hyperalgesia which was attenuated by a cAMP kinase inhibitor (the R-isomer of cyclic adenosine-3'-5'-monophosphate), but prolonged by the inhibition of endogenous phosphodiesterase by rolipram, supporting a role for the cAMP second messenger system. The 5-HT1A receptor agonist, 8-OH-DPAT, and the adenyl cyclase activator, forskolin administered together, produced an additive hyperalgesia, suggesting that the 5-HT1A receptor in peripheral terminals of the primary afferent neurons is positively coupled to the cAMP second messenger system in producing hyperalgesia. The inability of pertussis toxin to inhibit 8-OH DPAT-induced hyperalgesia further supports this hypothesis. The coupling of the 5-HT1A receptor to the cAMP second messenger system appears to be through guanine regulatory proteins since guanosine 5'-O-(3-thiotriphosphate) and cholera toxin both markedly enhanced 8-OH DPAT hyperalgesia. In further support of the role of guanine nucleotide regulatory proteins, guanosine 5'-O-(2-thiodiphosphate), as well as activators of inhibitory guanine regulatory proteins (the mu-opioid agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, and the adenosine A1 agonist, N6-cyclopentyladenosine, significantly attenuated 8-OH DPAT hyperalgesia.
Taiwo
Y O
YO
Department of Medicine, University of California, San Francisco 94143-0452A.
Heller
P H
PH
Levine
J D
JD
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006930:Hyperalgesia / Q000503:physiopathology*; D007536:Isomerism; D008297:Male; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D020889:Rolipram; D015290:Second Messenger Systems; D012701:Serotonin / Q000494:pharmacology* / Q000502:physiology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D000700:Analgesics; D004745:Enkephalins; D047428:Protein Kinase Inhibitors; D011759:Pyrrolidines; D011760:Pyrrolidinones; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D005576:Colforsin; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C048599:N(6)-cyclopentyladenosine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D020881:Enkephalin, D-Penicillamine (2,5)-; D000242:Cyclic AMP; D020889:Rolipram; D000241:Adenosine