Activation of descending pain-facilitatory pathways from the rostral ventromedial medulla by cholecystokinin elicits release of prostaglandin-E2 in the spinal cord

Abstract

Cholecystokinin (CCK) has been suggested to be both pro-nociceptive and anti-opioid by actions on pain modulatory cells within the RVM. One consequence of activation of RVM CCK2 receptors may be enhanced spinal nociceptive transmission but how this might occur, especially in states of pathological pain is unknown. Here, in vivo microdialysis was used to demonstrate that levels of RVM CCK increased by approximately 2-fold following ligation of L5/L6 spinal nerves (SNL). Microinjection of CCK into the RVM of naïve rats elicited hypersensitivity to tactile stimulation of the hindpaw. Additionally, RVM CCK elicited a time-related increase in PGE2 measured in cerebrospinal fluid from the lumbar spinal cord. The peak increase in spinal PGE2 was approximately 5-fold and was observed at approximately 80-min post-RVM CCK, a time coincident with maximal RVM CCK-induced mechanical hypersensitivity. Spinal administration of naproxen, a non-selective COX-inhibitor, significantly attenuated RVM CCK-induced hindpaw tactile hypersensitivity. RVM-CCK also resulted in a 2-fold increase in spinal 5-HIAA, a 5-HT metabolite, as compared to controls, and mechanical hypersensitivity that was attenuated by spinal application of ondansetron, a 5-HT3 antagonist. The present studies suggest that chronic nerve injury can result in activation of descending facilitatory mechanisms that may promote hyperalgesia via ultimate release of PGE2 and 5-HT in the spinal cord.

Role of spinal 5-HT5A, and 5-HT1A/1B/1D, receptors in neuropathic pain induced by spinal nerve ligation in rats

“…Some studies have shown an increase of 5-HT levels in the dorsal spinal cord of rats submitted to spinal nerve injury (Wei et al, 2010;Marshall et al, 2012). Those results imply that nerve injury promotes the participation of the central serotonergic system that then leads to the increase of 5-HT levels at the spinal level.…”

“…Previous studies have shown that stimulation of spinal 5-HT 1A (Colpaert et al, 2004;Aira et al, 2010) and 5-HT 1B/1D (Kayser et al, 2002(Kayser et al, , 2011 receptors produces antiallodynic effects, whereas activation of spinal 5-HT 2 (Aira (Rahman et al, 2006;Chen et al, 2009;Wei et al, 2010;Marshall et al, 2012), 5-HT 4 and 5-HT 6 (Rocha-González, personal communication) and 5-HT 7 (Amaya-Castellanos et al, 2011) receptors instead elicits pronociceptive effects. Nevertheless, to the best of our knowledge, no study has investigated directly the role of spinal 5-HT 5A receptors in neuropathic pain models in rats.…”

“…Accordingly, lesions to descending serotonergic projections, by 5,7-dihydroxytryptamine or RNAi for tryptophan hydroxylase-2, reduce 5-HT tissue content and mechanical allodynia in rats with spinal nerve injury (Rahman et al, 2006;Wei et al, 2010;Leong et al, 2011). There is evidence that activation of spinal 5-HT 2 (Aira et al, 2010;Rahman et al, 2011), 5-HT 3 (Rahman et al, 2006;Chen et al, 2009;Wei et al, 2010;Marshall et al, 2012), 5-HT 4 , 5-HT 6 (Rocha-González, personal communication) and 5-HT 7 (Amaya-Castellanos et al, 2011) receptors has been associated with a descending facilitatory role of 5-HT in neuropathic pain models. In contrast, the descending inhibitory role of 5-HT in neuropathic pain models has not been systematically studied.…”

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

“…RVM sends projections to the spinal cord through the dorsolateral funiculus Burgess et al, 2002) which releases cholecystokinin, dynorphin, calcitonin gene-related peptide (CGRP) and serotonin (5-hydroxytriptamine, 5-HT), among other neurotransmitters, to promote development and maintenance of long-term nociception (Kovelowski et al, 2000;Gardell et al, 2003;Heinricher and Neubert, 2004;AmbrizTututi et al, 2011). It is thought that activation of RVM ON cells, by cholecystokinin, leads to behavioral allodynia and hyperalgesia (Kovelowski et al, 2000;Heinricher and Neubert, 2004;Xie et al, 2005;Marshall et al, 2012) and a time-dependent dynorphin A (Wagner et al, 1993;Laughlin et al, 1997;Malan et al, 2000;Burgess et al, 2002), cholecystokinin (Gustafsson et al, 1998;Xu et al, 2001;Kim et al, 2009) and 5-HT (Wei et al, 2010;Marshall et al, 2012) increase in the spinal cord.…”

“…However, the role of 5-HT in pain processing is complex as it may inhibit and/or facilitate nociceptive transmission depending on the type of nociceptive stimuli and the nature of the 5-HT receptors. In the case of the formalin test, it seems that serotonergic descending inhibition is important to develop primary hyperalgesia while descending facilitation participates in secondary hyperalgesia (Vanegas and Schaible, 2004 descending system is involved in the facilitation of the spinal nociceptive transmission (Suzuki et al, 2004;Wei et al, 2010;Leong et al, 2011;Marshall et al, 2012). For instance, spinal nerve ligation leads to a loss (one third) of serotonergic neurons (Leong et al, 2011).…”