Spinal 5-HT₃ Receptors Mediate Descending Facilitation and Contribute to Behavioral Hypersensitivity via a Reciprocal Neuron-Glial Signaling Cascade

Abstract

BackgroundIt has been recently recognized that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear.ResultsIn the present study, activation of spinal 5-HT3 receptors by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via the chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of NMDA receptors in the spinal dorsal horn. Glial hyperactivation in spinal dorsal horn after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference.ConclusionsThese findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neurons and glia.

Neural correlates of cough hypersensitivity in humans: evidence for central sensitisation and dysfunctional inhibitory control

“…This bimodal control occurs via distinct excitatory (on cells) and inhibitory (off cells) neurons residing in the rostral ventromedial medulla, which receive input commands from both the midbrain and the spinal cord, and in turn regulate output to the dorsal horn of the spinal cord where incoming nociceptive signals are first integrated 30. In animal studies, alterations in descending control can induce hyperalgesia in the absence of peripheral injury 31 32. Neural circuit tracing studies provide an anatomical framework for airway sensory pathways innervating the descending pain modulatory system25 33 which in turn regulate medullary brainstem regions that process airway sensory inputs 34.…”

Neuropathic Pain: Central vs. Peripheral Mechanisms

“…The ionotropic serotonin receptor 5-HT 3 in the dorsal horn is the target of descending serotonergic facilitation of pain from the rostral ventromedial medulla (RVM). Activation of spinal 5-HT 3 receptors is also associated with pro-inflammatory cytokine release and glial cell activation, changes that appear to be crucial for the maintenance of central sensitization [68]. Enhanced excitability is also brought about by a reduction in inhibitory tone.…”

Activity-triggered tetrapartite neuron–glial interactions following peripheral injury

“…1C), ATP released from primary afferent central terminals can engage P2X3R on neurons [see 26], P2X4R/P2Y12R on microglia [see 24,30], and P2X7R on astrocytes [51]. Microglia release CatS that cleaves CX3CL1 tethered to spinal neurons and TNF/interleukin (IL)-18 that acts on astrocytes [48*, 71**]. Astrocytes can interact with C-C chemokine receptor type 2 (CCR2) on microglia through release of Chemokine (C-C motif) ligand 7 (CCL7) [72], and with chemokine (C-X-C motif) receptor 2 (CXCR2) on neurons through CXCL1 [48*,62].…”

“…Spinal pain processing is subject to descending modulation. Descending serotonin produces facilitation by activating 5-HT 3 receptors on spinal neurons, followed by upregulation of glial markers and behavioral hyperalgesia in rats [71**]. These effects of 5-HT are mediated by a signaling cascade that involves neuronal CX3CL1, microglial IL-18, astrocytic IL-1β and their respective receptors CX3CR1 (microglia), IL18R (astrocytes) and IL-1R (neurons) (Fig.…”