Opposite nociceptive effects of the arginine/NO/cGMP pathway stimulation in dermal and subcutaneous tissues.
1. Nitric oxide has been described either as pronociceptive or antinociceptive. In this investigation, using an electronic pressure-metre, the intradermal and the subcutaneous effects of prostaglandin E(2) (PGE(2)) and agents that mimic or inhibit the arginine/NO/cGMP pathway were compared. 2. The hypernociceptive effect of the intradermal injection of PGE(2) (100 ng) was immediate, peaking within 15-30 min and returning to basal values in 45-60 min. The subcutaneous injection of PGE(2) induced a hypernociception with a delayed peak (3 h) plateauing for 4-6 h. 3. Intradermal administration of 3-morpholino-sydnonimine-hydrochloride (SIN-1) enhanced, while its subcutaneous administration inhibited, subcutaneous hypernociception induced by PGE(2). This inhibition was prevented by ODQ (8 micro g) but not by NG-monomethyl-L-arginine (L-NMMA) (50 micro g). 4. Intradermal but not subcutaneous administration of L-arginine (1-100 micro g), SIN-1 (1-100 micro g) and dibutyrylguanosine 3':5'-cyclic monophosphate (db cGMP) (0.1-100 micro g) induced an early (15-30 min) dose-dependent hypernociceptive effect. Intradermal pretreatment with NG-monomethyl-L-arginine (L-NMMA; 50 micro g) inhibited the hypernociception induced by L-Arg (10 micro g), but not that induced by SIN-1 (10 micro g) or db cGMP (10 micro g). 5. Intradermal injection of ODQ (8 micro g) antagonized the hypernociception induced by L-arginine and SIN-1, but not that induced by db cGMP. 6. Considering (a) the different time course of intradermal and subcutaneous PGE(2)-induced hypernociception, (b) the opposite nociceptive effect of intradermal and subcutaneous administration of SIN-1 (db cGMP) as well as the arginine/NO/cGMP pathway, the existence of different subsets of nociceptive primary sensory neurons in which the arginine/NO/cGMP pathway plays opposing roles is suggested. This hypothesis would explain the apparent contradictory observations described in the literature.
Vivancos
Gustavo G
GG
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, 14049-900, Monte Alegre, Ribeirão Preto, São Paulo, Brazil.
Parada
Carlos A
CA
Ferreira
Sérgio H
SH
D000818:Animals; D001120:Arginine / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D003994:Bucladesine / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D006152:Cyclic GMP / Q000008:administration & dosage* / Q000502:physiology; D020405:Dermis / Q000503:physiopathology*; D015232:Dinoprostone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000139:chemically induced*; D007279:Injections, Subcutaneous; D008297:Male; D008981:Molsidomine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects* / Q000503:physiopathology*; D010069:Oxadiazoles / Q000008:administration & dosage; D010147:Pain Measurement / Q000187:drug effects*; D011810:Quinoxalines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D040521:Subcutaneous Tissue / Q000503:physiopathology*; D013997:Time Factors; D019323:omega-N-Methylarginine / Q000008:administration & dosage
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D010069:Oxadiazoles; D011810:Quinoxalines; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C002385:linsidomine; D003994:Bucladesine; D001120:Arginine; D008981:Molsidomine; D006152:Cyclic GMP; D015232:Dinoprostone