Secondary mechanical allodynia and hyperalgesia depend on descending facilitation mediated by spinal 5-HT₄, 5-HT₆ and 5-HT₇ receptors.
In the present study we determined the role of spinal 5-hydroxytriptamine (5-HT) and 5-HT(4/6/7) receptors in the long-term secondary mechanical allodynia and hyperalgesia induced by formalin in the rat. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia in both paws. In addition, formalin increased the tissue content of 5-HT in the ipsilateral, but not contralateral, dorsal part of the spinal cord compared to control animals. Intrathecal (i.t.) administration of 5,7-dihydroxytriptamine (5,7-DHT), a serotonergic neurotoxin, diminished tissue 5-HT content in the ipsilateral and contralateral dorsal parts of the spinal cord. Accordingly, i.t. 5,7-DHT prevented formalin-induced secondary allodynia and hyperalgesia in both paws. I.t. pre-treatment (-10 min) with ML-10302 (5-HT(4) agonist), EMD-386088 (5-HT(6) agonist) and LP-12 (5-HT(7) agonist) significantly increased secondary mechanical allodynia and hyperalgesia in both paws. In contrast, i.t. pre-treatment (-20 min) with GR-125487 (5-HT(4) antagonist), SB-258585 (5-HT(6) antagonist) and SB-269970 (5-HT(7) antagonist) significantly prevented formalin-induced long-term effects in both paws. In addition, these antagonists prevented the pro-nociceptive effect of ML-10302, EMD-386088 and LP-12, respectively. The i.t. post-treatment (6 days after formalin injection) with GR-125487, SB-258585 and SB-269970 reversed formalin-induced secondary allodynia and hyperalgesia in both paws. These results suggest that spinal 5-HT, released from the serotonergic projections in response to formalin injection, activates pre- or post-synaptic 5-HT(4/6/7) receptors at the dorsal root ganglion/spinal cord promoting the development and maintenance of secondary allodynia and hyperalgesia.
Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Sede Sur, México, DF, Mexico.
B
B
Godínez-Chaparro
F J
FJ
López-Santillán
P
P
Orduña
V
V
Granados-Soto
D015116:5,7-Dihydroxytryptamine / Q000494:pharmacology; D000818:Animals; D005260:Female; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D007278:Injections, Spinal; D010636:Phenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D013449:Sulfonamides / Q000494:pharmacology; D062366:para-Aminobenzoates / Q000494:pharmacology
C117947:2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate; C534240:5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole; D007211:Indoles; D010636:Phenols; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011985:Receptors, Serotonin; C418570:SB 258585; C404922:SB 269970; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D062366:para-Aminobenzoates; C097216:serotonin 6 receptor; C104425:serotonin 7 receptor; D044422:Receptors, Serotonin, 5-HT4; D005557:Formaldehyde; D015116:5,7-Dihydroxytryptamine; D012701:Serotonin; C082871:GR 113808