Neuroscience Letters 441 (2008) 129–133 Contents lists available at ScienceDirect Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet The VGF-derived peptide TLQP-21: A new modulatory peptide for inflammatory pain Roberto Rizzi a,1 , Alessandro Bartolomucci a,1,2 , Anna Moles a , Francesca D’Amato a , Paola Sacerdote b , Andrea Levi c , Giorgio La Corte c , Maria Teresa Ciotti c , Roberta Possenti c,d , Flaminia Pavone a,∗ a CNR, Institute of Neuroscience, Roma, Italy b Department of Pharmacology, University of Milano, Milano, Italy c CNR, Institute of Neurobiology and Molecular Medicine, Roma, Italy d Department of Neuroscience, University of Tor Vergata, Roma, Italy article info Article history: Received 28 January 2008 Received in revised form 23 May 2008 Accepted 2 June 2008 Keywords: Immunofluorescence DRG Substance P Formalin pain Behaviour Mice abstract Vgf, is a neuro-endocrine specific gene encoding for a large protein precursor of different peptides. A role for VGF in pain modulation has been suggested from immunohistochemical studies showing VGF mRNA widely expressed in primary sensory neurons. In this study, the presence of VGF on the primary sensory afferents in mice was confirmed by showing its immunostaining in cultured neurons of dorsal root ganglia in secretory granule varicosities colocalized with Substance P. Moreover, the functional role of a C-terminal internal VGF-derived peptide, i.e. TLQP-21, was assessed by investigating its peripheral (1, 2, 4, 8 mM) and central (1, 2, 4 mM) effects on inflammatory pain in the formalin test. A significant increase of pain-related licking response following peripheral injection of TLQP-21 (4 and 8mM) was observed in the second inflammatory phase of the test. In addition, an increase in licking response was detected when 4 mM of the peptide was injected alone without formalin. On the other hand, the central administration of TLQP-21 induced an U-shaped curve, with the dose of 2 mM being analgesic during the second phase. This study shows for the first time that a VGF-derived peptide may be involved in inflammatory pain in vivo and demonstrates a different action for TLQP21 at the peripheral and central levels of the nociceptive pathways. © 2008 Elsevier Ireland Ltd. All rights reserved. The Vgf gene was originally identified as a nerve growth factor responsive gene [10]. VGF has a tissue-specific pattern of expres- sion limited to neurons within the central (CNS) and peripheral nervous system (PNS) and to various endocrine cells [12]. In the adult rat brain, VGF mRNA is abundant in the olfactory system, cere- bral cortex, hypothalamus and hippocampus, and in a number of thalamic, septal, amygdaloid and brainstem nuclei. Endocrine cell types that express VGF include pituitary, gastroenteric endocrine cells, adrenal medulla cells and pancreatic  cells. The Vgf gene encodes a 617 amino acid protein in rodents that yields a number of peptides, stored in dense core granules and secreted through ∗ Corresponding author at: CNR, Institute of Neuroscience, Psychobiology & Psy- chopharmacology, Via del Fosso di Fiorano 64/65, 00143 Roma, Italy. Tel.: +39 06 501703271; fax: +39 06 501703304. E-mail address: f.pavone@ipsifar.rm.cnr.it (F. Pavone). 1 These authors considered as cofirst authors. 2 Present address: Department of Evolutionary and Functional Biology, University of Parma, Italy. the regulated pathway [21,28]. More than 10 different VGF pep- tides were detected in rat brain, bovine hypophysis and human CSF [2,12,13,25,28]. Notably, in the PNS, VGF is highly expressed in both neurons of sympathetic ganglia and primary sensory neurons [6]. Posi- tive immunostaining for VGF was observed in the spinal cord, particularly in the superficial dorsal horn and in the region sur- rounding the central canal, and in many neuronal cell bodies of the spinal ganglia [6]. Recently, increase of VGF mRNA in the dorsal root ganglia (DRG) after sciatic nerve transection was observed [5,29], while a 3.5-fold induction of VGF after spinal cord injury was determined in the surrounding spinal cord area [24]. Our attention was focused on the C-terminal region of the VGF polypeptide. In particular, the 21 amino acid-long peptide named TLQP-21 (from residue 557 to 576 of VGF) was recently identified in the rat brain [3]. Moreover, its biological role was characterized in the context of gut contraction, with a prostaglandin-mediated mechanism (Severini et al., unpublished data), while experiments 0304-3940/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2008.06.018