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Letters to the Editor / PAIN 155 (2014) 2204–2208 antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides. Neurogastroenterol Motil 2014;26:470–81. [3] Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther 2010;126:21–38. [4] Margolis KG, Stevanovic K, Li Z, Yang QM, Oravecz T, Zambrowicz B, Jhaver KG, Diacou A, Gershon MD. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut 2014;63: 928–37.

Maciej Salaga Department of Biochemistry, Medical University of Lodz, Lodz, Poland Martin Storr Division of Gastroenterology, Department of Medicine, University of Munich, Munich, Germany



Jakub Fichna Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, Lodz 92-215, Poland ⇑ Tel.: +48 42 272 57 07; fax: +48 42 272 56 94. E-mail address: jakub.fi[email protected]

http://dx.doi.org/10.1016/j.pain.2014.08.002 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Response to Letter to the Editor

To the Editor: We appreciate the opportunity to respond to the letter by Salaga et al. regarding our study [1]. Salaga et al. agree that our data are consistent with previous studies showing that enhanced endocannabinoid (CB) signaling may abolish abdominal pain in animals and humans and that the decrease in anandamide (AEA) levels may cause enhanced visceromotor response (VMR) to colorectal distention due to weakened activation of CB receptors [2,6]. They also agree that based on our study, acute treatment with serotonin (5-HT) may serve as a CB signaling activator. They propose that our data showing that exogenous AEA attenuates chronic luminal 5-HT-induced visceral hyperalgesia supports the hypothesis that pharmacological blockade of fatty acid amide hydrolase (FAAH) may reverse 5-HT-induced pronociception. Moreover, they discuss, based on our study, the potential of inhibitors targeting tryptophan hydroxylase (THP) 2 in the gut in the treatment of 5-HT-related visceral pain. This letter addresses the following question: if CB sites are reportedly able to form functional heterodimers with other types of receptors such as opioid receptors [5,6], can they form heterodimers with 5-HT 3 receptors (5-HT3Rs)? As CB sites belong to G protein–coupled receptors, while 5-HT3Rs are members of ligand-gated ion channels, it seems unlikely that CB receptors and 5-HT3Rs form such structures. Thus, the cross-talk between 5-HT and CB systems seems to be inexplicable. We noticed the evidence showing that 5-HT3Rs and CB1 receptors colocalize in neuronal cells [4,8]. Moreover, it should be noted that CBs are synthesized on demand at the cell surface membrane, a phenomenon triggered by an elevation of intracellular calcium. CBs can be released into the extracellular space, where they act locally as paracrine or autocrine factors [6,7,9]. Therefore, the interactions between 5-HT and CB systems in our study, ie, 5-HT stimulation of AEA release, may occur without forming CB1/5-HT3 receptor heterodimers. The underlying mechanisms for these interactions are unclear. Of note, activation of 5-HT3Rs evokes a rapid (within 50 s) rise in cytoplasmic calcium concentration [3]; this may be sufficient to trigger AEA synthesis [6,7]. Moreover, acute 5-HT

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treatment may increase the activity of AEA-synthesizing enzymes, such as N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), resulting in increased AEA synthesis. Although we believe that our study offers new insights into the interactions between CB and 5-HT signaling in the gut, we acknowledge that, as Salaga et al. point out, the underlying mechanisms remain poorly understood; future studies focused on an in-depth analysis of these interactions are thus urgently needed. Conflict of interest statement The authors report no conflict of interest. References [1] Feng CC, Yan XJ, Chen X, Wang EM, Liu Q, Zhang LY, Chen J, Fang JY, Chen SL. Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats. PAINÒ 2014;155:1591–604. [2] Fichna J, Salaga M, Stuart J, Saur D, Sobczak M, Zatorski H, Timmermans JP, Bradshaw HB, Ahn K, Storr MA. Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides. Neurogastroenterol Motil 2014;26:470–81. [3] Hargreaves AC, Lummis SC, Taylor CW. Ca2+ permeability of cloned and native 5-hydroxytryptamine type 3 receptors. Mol Pharmacol 1994;46:1120–8. [4] Hermann H, Marsicano G, Lutz B. Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain. Neuroscience 2002;109:451–60. [5] Hojo M, Sudo Y, Ando Y, Minami K, Takada M, Matsubara T, Kanaide M, Taniyama K, Sumikawa K, Uezono Y. l-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis. J Pharmacol Sci 2008;108:308–19. [6] Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther 2010;126:21–38. [7] Lutz B. On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures. Biochem Pharmacol 2004;68:1691–8. [8] Morales M, Bäckman C. Coexistence of serotonin 3 (5-HT3) and CB1 cannabinoid receptors in interneurons of hippocampus and dentate gyrus. Hippocampus 2002;12:756–64. [9] Storr MA, Sharkey KA. The endocannabinoid system and gut-brain signalling. Curr Opin Pharmacol 2007;7:575–82.

Xiu-Juan Yan ⇑ Sheng-Liang Chen Department of Gastroenterology, Ren Ji Hospital, Shanghai, China School of Medicine, Shanghai Jiao Tong University, Shanghai, China Shanghai Institute of Digestive Disease, Shanghai, China ⇑ Corresponding author. E-mail address: [email protected] (S.-L. Chen)

DOI of original article: http://dx.doi.org/10.1016/j.pain.2014.08.002 http://dx.doi.org/10.1016/j.pain.2014.08.032 0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Peripheral origin of phantom limb pain: Is it all resolved?

To the Editor: The neuroscientific investigation of mechanisms behind phantom limb pain (PLP) has implicated changes in both the central and peripheral nervous system. Centrally, functional adaptations to the amputation have been connected to PLP [2,4], while at the same time both residual limb pain and PLP have been associated

Response to letter to the editor.

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