Glutamate, Substance P, and Calcitonin Gene-Related Peptide Cooperate in Inflammation-Induced Heat Hyperalgesia

Abstract

The transient receptor potential cation channel subfamily V member 1 (TRPV1) is known as a thermosensor and integrator of inflammation-induced hyperalgesia. TRPV1 is expressed in a subpopulation of primary afferent neurons that express several different neurotransmitters. The role of the TRPV1 channel in the development of hyperalgesia is established, but the role of the neurotransmitter glutamate, used partially by the same neuronal population and thus probably mediating the response, is still under investigation. We have used a Trpv1-Cre mouse line in which we either ablated Trpv1-Cre expressing neurons or induced vesicular glutamate transporter 2 (Vglut2) deficiency in Trpv1-Cre expressing neurons and investigated specific states of hyperalgesia after persistent inflammation. Furthermore, by pharmacologic inhibition of substance P (SP) or calcitonin gene-related peptide (CGRP) signaling in Vglut2-deficient mice, we also evaluated the contribution of SP or CGRP to inflammationinduced hyperalgesia, with or without the presence of vesicular glutamate transporter 2 (VGLUT2)-mediated glutamatergic transmission in Trpv1-Cre neurons. This examination, together with c-Fos analyses, showed that VGLUT2-mediated glutamatergic transmission in Trpv1-Cre afferents together with SP or CGRP is essential for the development of the heat hyperalgesia associated with persistent inflammation. Additionally, SP-, CGRP-, and VGLUT2-mediated transmission together were found to play a role in the development of mechanical hyperalgesia after persistent inflammation.

Multimodal Use of Calcitonin Gene-Related Peptide and Substance P in Itch and Acute Pain Uncovered by the Elimination of Vesicular Glutamate Transporter 2 from Transient Receptor Potential Cation Channel Subfamily V Member 1 Neurons

“…Mice heterozygous for the diphtheria toxin A (DTA) allele [Gt(ROSA)26Sor tm1(DTA)Jpmb ], hereafter called R26 DTA/wt (Ivanova et al, 2005), were crossed with mice heterozygous for the Trpv1-Cre allele (Lagerström et al, 2010) to generate mice lacking TRPV1-positive neurons (R26 DTA/w t ;Trpv1-Cre tg/wt ) and controls (R26 DTA/wt ;Trpv1-Cre w/w or R26 wt /wt ;Trpv1-Cre w/w ). The Trpv1-Cre mice were also crossed with Vglut2 f/f mice to generate mice in which Vglut2 was selectively removed from Trpv1-Creexpressing neurons (Vglut2 f/f ;Trpv1-Cre).…”

“…The neurons expressing the transient receptor potential cation channel subfamily V member 1 (TRPV1) constitute a population of somatosensory neurons involved in the transduction of various sensations, including acute heat, cold, and tissue injuryinduced pain and itch (Lagerström et al, 2010;Mishra et al, 2011). However, the neurotransmitters required for the sensation of these diverse sensations have not yet been established fully.…”

“…Conditional genetic deletion of vesicular glutamate transporters (VGLUTs) provides an approach to silence glutamatergic signaling in defined neuronal populations (Lagerström et al, 2010(Lagerström et al, , 2011Scherrer et al, 2010;Rogoz et al, 2012). This has allowed for studies of the role of glutamate-mediated neurotransmission in acute and chronic pain states, which has begun to unravel interactions between the peptidergic and the glutamatergic neurotransmitter systems (Koga et al, 2011;Lagerström et al, 2011;Rogoz et al, 2014).…”

“…This has allowed for studies of the role of glutamate-mediated neurotransmission in acute and chronic pain states, which has begun to unravel interactions between the peptidergic and the glutamatergic neurotransmitter systems (Koga et al, 2011;Lagerström et al, 2011;Rogoz et al, 2014).…”

“…Previously, substance P transmission has been connected mainly to the mediation of hyperalgesia associated with neuropathic or inflammatory conditions (Mansikka et al, 2000;Cahill and Coderre, 2002;Rogoz et al, 2014) but also contributes to the sensation of tissue-injury induced pain, as shown in studies of substance P-deficient mice (Zimmer et al, 1998). Whether substance P-or CGRP-positive primary afferents are required to sense acute thermal or mechanical stimuli has been unclear (McCoy et al, 2012), but it was reported recently that the CGRP-expressing population of neurons plays a role in encoding heat and can tonically cross-inhibit cold (McCoy et al, 2013).…”