Serotonin Receptors are Involved in the Spinal Mediation of Descending Facilitation of Surgical Incision-Induced Increase of Fos-Like Immunoreactivity in Rats

Abstract

BackgroundDescending pronociceptive pathways may be implicated in states of persistent pain. Paw skin incision is a well-established postoperative pain model that causes behavioral nociceptive responses and enhanced excitability of spinal dorsal horn neurons. The number of spinal c-Fos positive neurons of rats treated intrathecally with serotonin, noradrenaline or acetylcholine antagonists where evaluated to study the descending pathways activated by a surgical paw incision.ResultsThe number of c-Fos positive neurons in laminae I/II ipsilateral, lamina V bilateral to the incised paw, and in lamina X significantly increased after the incision. These changes: remained unchanged in phenoxybenzamine-treated rats; were increased in the contralateral lamina V of atropine-treated rats; were inhibited in the ipsilateral lamina I/II by 5-HT1/2B/2C (methysergide), 5-HT2A (ketanserin) or 5-HT1/2A/2C/5/6/7 (methiothepin) receptors antagonists, in the ipsilateral lamina V by methysergide or methiothepin, in the contralateral lamina V by all the serotonergic antagonists and in the lamina X by LY 278,584, ketanserin or methiothepin.ConclusionsWe conclude: (1) muscarinic cholinergic mechanisms reduce incision-induced response of spinal neurons inputs from the contralateral paw; (2) 5-HT1/2A/2C/3 receptors-mediate mechanisms increase the activity of descending pathways that facilitates the response of spinal neurons to noxious inputs from the contralateral paw; (3) 5-HT1/2A/2C and 5-HT1/2C receptors increases the descending facilitation mechanisms induced by incision in the ipsilateral paw; (4) 5-HT2A/3 receptors contribute to descending pronociceptive pathways conveyed by lamina X spinal neurons; (5) α-adrenergic receptors are unlikely to participate in the incision-induced facilitation of the spinal neurons.

Associations between serotonin transporter gene polymorphisms and heat pain perception in adults with chronic pain

“…For instance, decreases in 5-HT basal release have been observed in preclinical studies using a neuropathic pain model [39,40], but increases in 5-HT release have been reported in chronic inflammatory models of pain [41,42]. Neuroplastic changes in descending 5-HT pathways may also occur at the receptor level where alterations in 5-HT 2A and 5-HT 3 receptor function have been observed in both central and peripheral tissues [43,44], and upregulation of 5-HT 1 , 5-HT 2 , 5-HT 3 receptor subtypes have been reported in the spinal cord [44-46]. Neuroplastic changes in 5-HT pathways have also been associated with alterations in 5-HTT expression [47], which is consistent with previous studies that document a role for 5-HTT in thermal nociception [8,9].…”

TRPV1 Antagonist Attenuates Postoperative Hypersensitivity by Central and Peripheral Mechanisms

“…In the peripheral tissues, neutrophils [ 8 ], acidosis [ 9 ], nerve growth factor (NGF) [ 10 , 11 ], EP 1 receptor [ 12 ], B 1 and B 2 bradykinin receptors, P2X purinoceptors, transient receptor potential vanilloid 1 (TRPV1) receptor, nitric oxide (NO) synthase, lipoxygenase [ 13 ], insulin-like growth factor 1 (IGF-1) [ 14 ], acid-sensing ion channel 3 [ 15 ], the activation of AMP-activated protein kinase that inhibits IL-6 mediated signaling to ERK [ 16 ] and others could contribute to postoperative pain. In the spinal cord cyclooxygenase (COX) [ 17 , 18 ], the EP 1 receptor for a product of COX metabolism - prostaglandin E 2 [ 19 ], brain derived neurotrophic factor (BDNF) [ 20 ], glial cell activation and interleukin-1 beta (IL-1β) [ 21 ], the chemokine CCL2 [ 22 ], serotonin receptors [ 23 ], GABA A and GABA B receptors [ 24 ], calcium/calmodulin-dependent protein kinase IIα [ 5 ], p38 mitogen-activated protein kinase (p38 MAPK) [ 25 ], phosphatidylinositol 3-kinase (PI3K) [ 26 ] and others could contribute to the hypersensitivity induced by plantar incision.…”

The Vanilloid Agonist Resiniferatoxin for Interventional-Based Pain Control

“…This suggests that a subpopulation of trigeminal neurons have calcium clearance mechanisms that render them relatively resistant to the toxic effects of RTX [9,11]. Nonetheless, in the rat, RTX injections administered peripherally produce a profound loss of responsiveness to noxious thermal stimulation, which is consistent with the idea of a broad-spectrum sensitivity of noxious thermally-responsive nerve endings to RTX-induced calcium cytotoxicity [39]. …”