Elevated serotonin in mouse spinal dorsal horn is pronociceptive

Abstract

AbstractSerotonergic neurons in the rostral ventral medulla (RVM) contribute to bidirectional control of pain through modulation of spinal and trigeminal nociceptive networks. Deficits in this pathway are believed to contribute to pathological pain states, but whether changes in serotonergic mechanisms are pro or anti-nociceptive are debated. We used a combination of optogenetics and fiber photometry to examine these mechanisms more closely. We find that optogenetic activation of RVM serotonergic afferents in the spinal cord of naïve mice produces mechanical hypersensitivity and conditioned place aversion. Neuropathic pain, produced by chronic constriction injury of the infraorbital nerve (CCI-ION), evoked a tonic increase in serotonin concentrations within the spinal trigeminal nucleus caudalis (SpVc), measured with liquid chromatography-tandem mass spectroscopy (LC-MS/MS). By contract, CCI-ION had no effect on the phasic serotonin transients in SpVc, evoked by noxious pinch, and measured with fiber photometry of a serotonin sensor. These findings suggest that serotonin release in the spinal cord is pronociceptive and that an increase is sustained serotonin signaling, rather than phasic or event driven increases, potentiate nociception in models of chronic pain.Significance StatementSerotonergic neurons of the rostral ventral medulla participate in descending pain modulation by regulating spinal and trigeminal nociceptive circuits. Whether changes in serotonergic mechanisms are pro or anti-nociceptive is debated. We show that serotonin release within the spinal trigeminal nucleus is pronociceptive and that enhanced tonic, but not phasic serotonin release may contribute to sensitization in mouse models of chronic pain. These results further clarify the role of serotonin in nociception and suggest that local inhibition of serotonin release or increase of uptake may be a viable therapeutic approach in treating chronic pain.