Spinal 5-HT₃Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Abstract

Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in 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. In the present study, activation of spinal 5-HT3 receptor 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 chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of GluN (NMDA) receptors in the spinal dorsal horn. In addition, exogenous BDNF-induced descending pain facilitation was accompanied with up-regulation of CD11b and GFAP expression in the spinal dorsal horn after microinjection in the RVM, which were significantly prevented by functional blockade of spinal 5-HT3 receptors. Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, these 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 neuron and glia.

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

“…Currently there are reports for the participation of spinal 5-HT 3/7 receptors in the maintenance of chronic neuropathic pain (Rahman et al, 2006;Amaya-Castellanos et al, 2011;Gu et al, 2011;Bravo-Herna´ndez et al, 2012; although see Dogrul et al, 2009;Brenchat et al, 2012). Our study provides evidence that spinal 5-HT 4/6/7 receptors located on DRG, central terminals of primary afferents and/or dorsal spinal cord also promote maintenance of pain as i.t.…”

Serotonin enhances urinary bladder nociceptive processing via a 5-HT3 receptor mechanism

“…The 5-HT 3 receptor is the only ligand-gated ion channel with excitatory functions in the serotonin family, and ample evidence suggests that 5-HT 3 receptor-dependent nociceptive facilitation is involved in persistent pain states. Thermal and mechanical sensitivity induced by spinal nerve ligation was blocked by intrathecal administration of the specific 5-HT 3 receptor antagonist Y25130[33]. Intrathecal ondansetron attenuated mechanical hyperalgesia and allodynia[34] and inhibited mechanical and thermal evoked responses of spinal dorsal horn neurons in this same model.…”

Loss of neurons in rostral ventromedial medulla that express neurokinin-1 receptors decreases the development of hyperalgesia

“…It has been established that serotonin, acting through 5-HT3 receptors in the spinal cord, contributes to descending facilitation of nociceptive transmission and hyperalgesia (Suzuki et al, 2002, 2004a, b, 2005; Rahman et al, 2004; Donovan-Rodriguez et al, 2006; Dogrul et al, 2009; Gu et al, 2011; Sikandar et al, 2012). Importantly, descending serotonergic mechanisms and spinal 5-HT3 receptors contribute to descending facilitation produced by activation of NK-1Rs in the RVM (Lagraize et al, 2010).…”