Secondary mechanical allodynia and hyperalgesia depend on descending facilitation mediated by spinal 5-HT4, 5-HT6 and 5-HT7 receptors

Abstract

In the present study we determined the role of spinal 5-hydroxytriptamine (5-HT) and 5-HT4/6/7 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 (−10min) with ML-10302 (5-HT4 agonist), EMD-386088 (5-HT6 agonist) and LP-12 (5-HT7 agonist) significantly increased secondary mechanical allodynia and hyperalgesia in both paws. In contrast, i.t. pre-treatment (−20min) with GR-125487 (5-HT4 antagonist), SB-258585 (5-HT6 antagonist) and SB-269970 (5-HT7 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 (6days 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-HT4/6/7 receptors at the dorsal root ganglion/spinal cord promoting the development and maintenance of secondary allodynia and hyperalgesia.