5‐HT_2B Receptor Antagonists Reduce Nerve Injury‐Induced Tactile Allodynia and Expression of 5‐HT_2B Receptors

Abstract

Preclinical Research This work was performed to assess the effects of intrathecal serotonin 2B (5-HT ) receptor antagonists in rats with neuropathic pain. With RS-127445, its effect was also determined on 5-HT receptor expression. Neuropathic pain was induced by L5/L6 spinal nerve ligation. Western blotting was used to determine 5-HT receptor expression. Dose-response curves with the 5-HT receptor antagonists 2-amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyridine (RS-127445, 1-100 nmol) and 1-[(2-chloro-3,4-dimethoxyphenyl)methyl]-2,3,4,9-tetrahydro-6-methyl-1H-pyrido[3,4-b]indole hydrochloride (LY-266097, 1-100 nmol) were performed in rats. Tactile allodynia of the left hind paw (ipsilateral) was assessed for 8 h after compound administration. Intrathecal injection of the 5-HT receptor antagonists RS-127445 and LY-266097 diminished spinal nerve ligation-induced allodynia. In contrast, intrathecal injection of the 5-HT receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI, 10 nmol) did not modify tactile allodynia induced by nerve ligation. L5/L6 nerve ligation increased expression of the 5-HT receptors in the ipsilateral, but not contralateral, dorsal root ganglia. Furthermore, nerve injury also enhanced 5-HT receptor expression in the ipsilateral dorsal part of the spinal cord. Intrathecal treatment with RS-127445 (100 nmol) diminished spinal nerve injury-induced increased expression of 5-HT receptors in dorsal root ganglia and spinal cord. Our results imply that spinal 5-HT receptors are present on sites related to nociception and participate in neuropathic pain. © 2014 Wiley Periodicals, Inc.

Antiallodynic effect induced by [6]‐gingerol in neuropathic rats is mediated by activation of the serotoninergic system and the nitric oxide–cyclic guanosine monophosphate–adenosine triphosphate‐sensitive K+ channel pathway

“…Several studies have demonstrated that activation of spinal 5‐HT 1A/1B (Colpaert et al, ) and 5‐HT 5 (Avila‐Rojas et al, ) receptors reduced the behavioral or electrophysiological measures related to neuropathic pain. On the other hand, behavioral or electrophysiological studies demonstrated that the activation of the 5‐HT 2/3/4/6/7 receptor produced a pronociceptive effect (Pineda‐Farias, Velázquez‐Lagunas, Barragán‐Iglesias, Cervantes‐Durán, & Granados‐Soto, ), and these receptors are expressed in the dorsal horn of the spinal cord (Bardin, Bardin, Lavarenne, & Eschalier, ). Accordingly, we found that pretreatment with WAY‐100635 (6 μg per rat), SB‐224289 (5 μg per rat), BRL‐15572 (4 μg per rat), and SB‐699551(6 μg per rat) via intrathecal administration prevented the [6]‐gingerol‐induced antiallodynic effect in neuropathic rats.…”

Ethenzamide Exerts Analgesic Effect at the Spinal Cord <i>via</i> Multiple Mechanisms of Action Including the 5HT_2B Receptor Blockade in the Rat Formalin Test

“…Similarly, in another study, spinal administration of RS-127445 prevented the development and maintenance of the long-lasting hyperalgesia induced by formalin injection into the rat hindpaw 24) . Furthermore, in the spinal nerve ligation model of neuropathic pain in rats, thermal or mechanical allodynia was shown to be attenuated by spinal 5HT 2B receptor inhibition induced by the 5HT 2B receptor antagonists RS-127445 25) , LY-266097 25) , and SB204741 26) . As a mechanistic perspective, Aira et al proposed convergent synaptic input from a descending serotonergic varicosity and a primary C afferent fiber onto neurons at spinal superficial dorsal horn, and that activation of postsynaptic 5HT 2B receptor at the superficial dorsal horn by increased activity of descending serotonergic pathway would lead to dorsal horn hyperexcitablity to input from primary afferent fibers in the spinal nerve ligation model of neuropathic pain 26) .…”

Putative role of 5-HT2B receptors in migraine pathophysiology

“…In the rat brain 5-HT 2B receptors are slightly expressed in neurons located in the cerebellum, the posterior hypothalamus, the lateral septum and the medial amygdala but these data, which are derived from immunohistochemical staining (IHS) (20), are considered controversial. Other studies using IHS and molecular biological methods showed expression in motoneurons (21), in rat spinal cord and in dorsal root ganglion (DRG) (22)(23)(24). The subcellular localization of the receptor in blood vessels is not evident from the literature; however, it has been suggested that it is localized on the luminal side of vascular endothelial cells (11).…”