Formalin-induced nociception activates a monoaminergic descending inhibitory system

Neural plasticity of afferent pain pathways that is induced by prolonged or repeated noxious stimuli may contribute to activate intrinsic inhibitory mechanisms in CNS. In order to clarify the role of the monoaminergic descending inhibitory system in acute nociception and inflammatory pain, we examined if this inhibitory system would modulate the tonic response to formalin-induced nociception. Yohimbine, α2 adrenergic antagonist, or methysergide, serotonin antagonist was administered intrathecally before or after subcutaneous 2% formalin injection into the plantar of the hind paw in rats. In another series of the experiment, the tissue of the spinal dorsal half of the untreated rats and post-formalin-treated rats were sampled and analyses of monoamine levels were carried out by HPLC. The subcutaneous formalin evoked biphasic flinching behavior of the injected paw. Intrathecal pretreatment with yohimbine and methysergide produced a significantly greater increase in the number of flinches than in the control in phase 1, intermediate period and phase 2. Posttreatment with yohimbine and methysergide showed a significantly greater increase in the number of flinches in phase 2. Furthermore, formalin injection induced significant increases in noradrenaline, MHPG, serotonin (5-hydroxytryptamine; 5-HT) and 5-HIAA concentrations in both the ipsi- and contralateral dorsal halves. These results suggest that the pain state produced by formalin-induced chemical and/or inflammatory nociception is under the modulation of the monoaminergic (noradrenergic and serotonergic) descending inhibitory system.