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CGRP antagonists

Pranav Prasoon, Shivani Gupta, Rahul Kumar, Mayank Gautam, Saroj Kaler, Subrata Basu Ray
OBJECTIVES: Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substance P (SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine...
July 2016: Indian Journal of Pharmacology
Tilmann Ditting, Kristina Rodionova, Sonja Heinlein, Karl Friedrich Hilgers, Christian Ott, Roland Schmieder, Kerstin Amann, Roland Veelken
OBJECTIVE: Afferent renal nerves exhibit a dual function. They influence intrarenal immunological processes by release of neurokinins like CGRP and control central sympathetic outflow via afferent electrical activity. The former seems to be important in renal inflammation whereas the sympathetic modulation by afferent electrical activity is not fully understood in cardiovascular disease and hypertension. Hence, we hypothesized that augmented effects of CGRP in renal inflammation occur with increased afferent renal nerve activity...
September 2016: Journal of Hypertension
Lauren E Cornelison, Jordan L Hawkins, Paul L Durham
Orofacial pain conditions including temporomandibular joint disorder (TMD) and migraine are characterized by peripheral and central sensitization of trigeminal nociceptive neurons. Although calcitonin gene-related peptide (CGRP) is implicated in the development of central sensitization, the pathway by which elevated spinal cord CGRP levels promote peripheral sensitization of primary trigeminal nociceptive neurons is not well understood. The goal of this study was to investigate the role of CGRP in promoting bidirectional signaling within the trigeminal system to mediate sensitization of primary trigeminal ganglion nociceptive neurons...
October 13, 2016: Neuroscience
Tilmann Ditting, Kristina Rodionova, Sonja Heinlein, Karl Friedrich Hilgers, Christian Ott, Roland Schmieder, Kerstin Amann, Roland Veelken
OBJECTIVE: Afferent renal nerves exhibit a dual function. They influence intrarenal immunological processes by release of neurokinins like CGRP and control central sympathetic outflow via afferent electrical activity. The former seems to be important in renal inflammation whereas the sympathetic modulation by afferent electrical activity is not fully understood in cardiovascular disease and hypertension. Hence, we hypothesized that augmented effects of CGRP in renal inflammation occur with increased afferent renal nerve activity...
September 2016: Journal of Hypertension
Olga Kuzawińska, Krzysztof Lis, Grzegorz Cessak, Dagmara Mirowska-Guzel, Ewa Bałkowiec-Iskra
Migraine is a chronic, recurrent disorder, characterized by attacks of severe pain, affecting around 1% of adult population. Many studies suggest, that trigeminovascular system plays a key role in pathogenesis of migraine and other primary headaches. Calcitonin gene-related peptide (CGRP) is an endogenous substance, which is regarded a key mediator released from trigeminovascular system after stimulation of sensory nerve endings, responsible for dilatation of peripheral vessels and sensory transmission. CGRP is and extensively studied peptide as one of the most promising targets in migraine drug research...
August 10, 2016: Neurologia i Neurochirurgia Polska
Zsófia Hajna, Éva Sághy, Maja Payrits, Aisah A Aubdool, Éva Szőke, Gábor Pozsgai, István Z Bátai, Lívia Nagy, Dániel Filotás, Zsuzsanna Helyes, Susan D Brain, Erika Pintér
It is supposed that TRPA1 receptor can be activated by hydrogen sulphide (H2S). Here, we have investigated the role of TRPA1 receptor in H2S-induced [Ca(2+)]i increase in trigeminal ganglia (TRG) neurons, and the involvement of capsaicin-sensitive sensory nerves in H2S-evoked cutaneous vasodilatation. [Ca(2+)]i was measured with ratiometric technique on TRG neurons of TRPA1(+/+) and TRPA1(-/-) mice after NaHS, Na2S, allylisothiocyanate (AITC) or KCl treatment. Microcirculatory changes in the ear were detected by laser Doppler imaging in response to topical NaHS, AITC, NaOH, NaSO3 or NaCl...
October 2016: Journal of Molecular Neuroscience: MN
Noriko Kawashima-Takeda, Yoshiya Ito, Nobuyuki Nishizawa, Rei Kawashima, Kiyoshi Tanaka, Kazutake Tsujikawa, Masahiko Watanabe, Masataka Majima
BACKGROUND AND AIMS: Calcitonin gene-related peptide (CGRP) is thought be involved in the modulation of intestinal motility. CGRP receptor is composed of receptor activity-modifying protein (RAMP) 1 combined with calcitonin receptor-like receptor (CRLR) for CGRP. We investigated the role of CGRP in mice with experimentally induced colitis. METHODS: We used dextran sodium sulfate (DSS) to induce colitis in mice. We compared the severity of colitis in wild-type (WT) mice, mice treated with a CGRP receptor antagonist (CGRP8-37 ), and RAMP1 knockout ((-/-) ) mice...
August 11, 2016: Journal of Gastroenterology and Hepatology
Esther Sastre, Laura Caracuel, Isabel Prieto, Pablo Llévenes, M Ángeles Aller, Jaime Arias, Gloria Balfagón, Javier Blanco-Rivero
We evaluated the possible alterations produced by liver cholestasis (LC), a model of decompensated liver cirrhosis in sympathetic, sensory and nitrergic nerve function in rat superior mesenteric arteries (SMA). The vasoconstrictor response to electrical field stimulation (EFS) was greater in LC animals. Alpha-adrenoceptor antagonist phentolamine and P2 purinoceptor antagonist suramin decreased this response in LC animals more than in control animals. Both non-specific nitric oxide synthase (NOS) L-NAME and calcitonin gene related peptide (CGRP) (8-37) increased the vasoconstrictor response to EFS more strongly in LC than in control segments...
2016: Scientific Reports
Carlos M Villalón, Antoinette Maassen VanDenBrink
Migraine is a highly prevalent neurovascular disorder. Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5 HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder...
July 28, 2016: Mini Reviews in Medicinal Chemistry
Jennifer T Malon, Ling Cao
The role of calcitonin gene related peptide (CGRP) in neuropathic pain was investigated in a mouse model of neuropathic pain, spinal nerve L5 transection (L5Tx). Intrathecal injection (i.t.) of CGRP8-37, a CGRP antagonist, significantly reduced L5Tx-induced mechanical hypersensitivity and lumbar spinal cord CCL5 expression. i.t. injection of a CCL5 neutralizing antibody significantly inhibited L5Tx-induced mechanical hypersensitivity. Further, pre-treatment with a p38-inhibitor, SB203580, was able to reduce CGRP-induced mechanical hypersensitivity, but not CGRP-induced CCL5 production...
August 15, 2016: Journal of Neuroimmunology
Yan Wang, Yanli Li, Minyan Wang
BACKGROUND: Cortical spreading depression (CSD) is a transient propagating excitation of synaptic activity followed by depression, which is implicated in migraine with aura and is regarded as the underlying cause of migraine. Calcitonin-gene related peptide (CGRP) receptors play a crucial role in mediating the magnitude of CSD in rat cortical slice. This study aimed to examine whether CGRP receptors are involved in retinal spreading depression (RSD) in chicks. METHODS: Western blot was used for detection of calcitonin-receptor like receptor (CALCRL) and intrinsic optical imaging was used for pharmacological investigation...
October 2016: Pharmacological Reports: PR
Beatrice Girard, Abbey Peterson, Susan Malley, Margaret A Vizzard
The mechanisms underlying the postnatal maturation of micturition from a somatovesical to a vesicovesical reflex are not known but may involve neuropeptides in the lower urinary tract. A transgenic mouse model with chronic urothelial overexpression (OE) of NGF exhibited increased voiding frequency, increased number of non-voiding contractions, altered morphology and hyperinnervation of the urinary bladder by peptidergic (e.g., Sub P and CGRP) nerve fibers in the adult. In early postnatal and adult NGF-OE mice we have now examined: (1) micturition onset using filter paper void assays and open-outlet, continuous fill, conscious cystometry; (2) innervation and neurochemical coding of the suburothelial plexus of the urinary bladder using immunohistochemistry and semi-quantitative image analyses; (3) neuropeptide protein and transcript expression in urinary bladder of postnatal and adult NGF-OE mice using Q-PCR and ELISAs and (4) the effects of intravesical instillation of a neurokinin (NK)-1 receptor antagonist on bladder function in postnatal and adult NGF-OE mice using conscious cystometry...
June 21, 2016: Experimental Neurology
Maria Adele Giamberardino, Giannapia Affaitati, Martina Curto, Andrea Negro, Raffaele Costantini, Paolo Martelletti
Migraine is a highly disabling neurological pain disorder in which management is frequently problematic. Most abortive and preventative treatments employed are classically non-specific, and their efficacy and safety and tolerability are often unsatisfactory. Mechanism-based therapies are, therefore, needed. Calcitonin gene-related peptide (CGRP) is recognized as crucial in the pathophysiology of migraine, and new compounds that target the peptide have been increasingly explored in recent years. First tested were CGRP receptor antagonists; they proved effective in acute migraine treatment in several trials, but were discontinued due to liver toxicity in long-term administration...
June 23, 2016: Internal and Emergency Medicine
Yu Zhang, Jinhua Yang, Peng Zhang, Tao Liu, Jianwei Xu, Zhihai Fan, Yixin Shen, Wenjie Li, Huanxiang Zhang
Mesenchymal stem cells (MSCs) can be used to treat many diseases, including spinal cord injury (SCI). Treatment relies mostly on the precise navigation of cells to the injury site for rebuilding the damaged spinal cord. However, the key factors guiding MSCs to the epicenter of SCI remain unknown. Here, we demonstrated that calcitonin gene-related peptide (CGRP), a neural peptide synthesized in spinal cord, can dramatically aid the homing of human umbilical cord mesenchymal stem cells (HUMSCs) in spinal cord-transected SCI rats...
2016: Scientific Reports
Tiffini Voss, Richard B Lipton, David W Dodick, Nicole Dupre, Joy Yang Ge, Robert Bachman, Christopher Assaid, Sheena K Aurora, David Michelson
AIM: The aim of this trial was to evaluate the efficacy and tolerability of ubrogepant (MK-1602), a calcitonin gene-related peptide receptor antagonist (CGRP-RA), for the acute treatment of migraine. METHODS: This double-blind, placebo-controlled study randomized 834 participants to treat one migraine attack with ubrogepant 1 mg, 10 mg, 25 mg, 50 mg, 100 mg, or placebo in a 1:1 ratio. The co-primary endpoints were pain freedom and headache response at two hours...
August 2016: Cephalalgia: An International Journal of Headache
C S Potes, A C Pestana, M Pontes, A S Caramelo, F L Neto
BACKGROUND: Amylin is a peptide from the calcitonin gene-related peptides (CGRP) family that is expressed by nociceptors. Amylin may modulate pain via a spinal action. METHODS: The effect of amylin's administration on the formalin test of acute and tonic pain was evaluated. Amylin's ability to modulate neuronal activity was analysed by c-Fos expression at the spinal cord lumbar 4-5 region (L4-5) and brain. RESULTS: Amylin subcutaneous administration 20 min prior, but not immediately before formalin, shortened the interphase and anticipated the beginning of the tonic pain phase...
June 5, 2016: European Journal of Pain: EJP
Yuwei Pan, Si Huang, Zejian Cai, Hai Lan, Yi Tong, Xuan Yu, Guoping Zhao, Fengguo Chen
Oxaliplatin is a widely used chemotherapeutic agent that induces both acute and chronic peripheral neuropathy. Based on previous research indicating that estrogen replacement may attenuate some forms of pain in ovariectomized animals, we examined the effects of 17β-estradiol in OXAIPN. We discovered that local cold exposure induces an abnormal vascular response in both acute and chronic models of OXAIPN (oxaliplatin-induced peripheral neuropathy) that may be used as an easy and non-invasive method to predict which patients may be susceptible to the development of severe, chronic OXAIPN...
June 1, 2016: Current Neurovascular Research
R Czekaj, J Majka, A Ptak-Belowska, A Szlachcic, A Targosz, K Magierowska, M Strzalka, M Magierowski, T Brzozowski
The antioxidizing properties of curcumin, a highly pleiotropic substance used for centuries in traditional medicine has been confirmed by numerous experimental and clinical studies. Curcumin exhibits anti-inflammatory, antiproliferative and anti-angiogenic actions inhibiting the development and progression of tumors but the efficacy of this compound to influence gastric acid secretion n in the stomach and to affect the gastric mucosal damage induced by non-topical ulcerogenes such as stress has been little studied...
April 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
Amy Y Chang, Tracy S Mann, Peter K McFawn, Liang Han, Xinzhong Dong, Peter J Henry
BACKGROUND: The hexapeptide SLIGRL-amide activates protease-activated receptor-2 (PAR-2) and mas-related G protein-coupled receptor C11 (MRGPRC11), both of which are known to be expressed on populations of sensory nerves. SLIGRL-amide has recently been reported to inhibit influenza A (IAV) infection in mice independently of PAR-2 activation, however the explicit roles of MRGPRC11 and sensory nerves in this process are unknown. Thus, the principal aim of this study was to determine whether SLIGRL-amide-induced inhibition of influenza infection is mediated by MRGPRC11 and/or by capsaicin-sensitive sensory nerves...
2016: Respiratory Research
Mária Dux, Éva Deák, Noémi Tassi, Péter Sántha, Gábor Jancsó
BACKGROUND: In the dura mater encephali a significant population of trigeminal afferents coexpress the nociceptive ion channel transient receptor potential vanilloid type 1 (TRPV1) receptor and calcitonin gene-related peptide (CGRP). Release of CGRP serves the central transmission of sensory information, initiates local tissue reactions and may also sensitize the nociceptive pathway. To reveal the possible activation of meningeal TRPV1 receptors by endogenously synthetized agonists, the effects of arachidonylethanolamide (anandamide) and N-arachidonoyl-dopamine (NADA) were studied on dural vascular reactions and meningeal CGRP release...
2016: Journal of Headache and Pain
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