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.