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The vanilloid receptor 1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel expressed by peripheral sensory neurons. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Here, we describe the in vitro and in vivo pharmacology of a novel TRPV1 antagonist, AMG 9810,AMG 9810 is a competitive antagonist of capsaicin activation (IC 50 value for human TRPV1, 24.5 Ϯ 15.7 nM; rat TRPV1, 85.6 Ϯ 39.4 nM) and blocks all known modes of TRPV1 activation, including protons (IC 50 value for rat TRPV1, 294 Ϯ 192 nM; human TRPV1, 92.7 Ϯ 72.8 nM), heat (IC 50 value for rat TRPV1, 21 Ϯ 17 nM; human TRPV1, 15.8 Ϯ 10.8 nM), and endogenous ligands, such as anandamide, N-arachidonyl dopamine, and oleoyldopamine. AMG 9810 blocks capsaicin-evoked depolarization and calcitonin gene-related peptide release in cultures of rat dorsal root ganglion primary neurons. Screening of AMG 9810 against a panel of G protein-coupled receptors and ion channels indicated selectivity toward TRPV1. In vivo, AMG 9810 is effective at preventing capsaicin-induced eye wiping in a dose-dependent manner, and it reverses thermal and mechanical hyperalgesia in a model of inflammatory pain induced by intraplantar injection of complete Freund's adjuvant. At effective doses, AMG 9810 did not show any significant effects on motor function, as measured by open field locomotor activity and motor coordination tests. AMG 9810 is the first cinnamide TRPV1 antagonist reported to block capsaicin-induced eye wiping behavior and reverse hyperalgesia in an animal model of inflammatory pain.Activation of peripheral nociceptors in humans by capsaicin results in burning pain (Park et al., 1995). Capsaicin, and its ultrapotent analog resiniferatoxin, aided the identification and characterization of the vanilloid receptor 1 (aka VR1 and TRPV1). TRPV1 is a nonselective cation channel with high permeability to calcium (Caterina et al., 1997) and belongs to a superfamily of ion channels known as the transient receptor potential channels or TRPs (Clapham et al., 2001). In addition to activation by exogenous agonists such as capsaicin and resiniferatoxin, TRPV1 can be activated by physical stimuli, such as heat (Ͼ42°C) and protons (pH 5). Based on their structural similarity to capsaicin, several endogenous ligands have been proposed that include anandamide (AEA), 12-hydroperoxy-5,8,10,14-eicosatetraenoic acid,N-arachidonyl dopamine (NADA), N-oleoyldopamine (OLDA), and products of lipoxygenases (Hwang et al., 2000;Olah et al., 2001;Huang et al., 2002;Chu et al., 2003). TRPV1 is up-regulated during inflammation (Ji et al., 2002), and channel activity is modulated by the action of inflammaArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org.doi :

Therapeutic agents that block the calcitonin gene-related peptide (CGRP) signaling pathway are a highly anticipated and promising new drug class for migraine therapy, especially after reports that small-molecule CGRP-receptor antagonists are efficacious for both acute migraine treatment and migraine prevention. Using XenoMouse technology, we successfully generated AMG 334, a fully human monoclonal antibody against the CGRP receptor. Here we show that AMG 334 competes with [ 125 I]-CGRP binding to the human CGRP receptor, with a K i of 0.02 nM. AMG 334 fully inhibited CGRP-stimulated cAMP production with an IC 50 of 2.3 nM in cell-based functional assays (human CGRP receptor) and was 5000-fold more selective for the CGRP receptor than other human calcitonin family receptors, including adrenomedullin, calcitonin, and amylin receptors. The potency of AMG 334 at the cynomolgus monkey (cyno) CGRP receptor was similar to that at the human receptor, with an IC 50 of 5.7 nM, but its potency at dog, rabbit, and rat receptors was significantly reduced (.5000-fold). Therefore, in vivo target coverage of AMG 334 was assessed in cynos using the capsaicin-induced increase in dermal blood flow model. AMG 334 dose-dependently prevented capsaicin-induced increases in dermal blood flow on days 2 and 4 postdosing. These results indicate AMG 334 is a potent, selective, full antagonist of the CGRP receptor and show in vivo dose-dependent target coverage in cynos. AMG 334 is currently in clinical development for the prevention of migraine.

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A considerable body of evidence implicates endogenous nerve growth factor (NGF) in conditions in which pain is a prominent feature, including neuropathic pain. However, previous studies of NGF antagonism in animal models of neuropathic pain have examined only the prevention of hyperalgesia and allodynia after injury, whereas the more relevant issue is whether treatment can provide relief of established pain, particularly without tolerance. In the current work, we studied the effects of potent, neutralizing anti-NGF antibodies on the reversal of tactile allodynia and thermal hyperalgesia in established models of neuropathic and inflammatory pain in rats and mice. In the complete Freund's adjuvant-induced hind-paw inflammation, spinal nerve ligation and streptozotocin-induced neuropathic pain models, a single intraperitoneal injection of a polyclonal anti-NGF antibody reversed established tactile allodynia from approximately day 3 to day 7 after treatment. Effects on thermal hyperalgesia were variable with a significant effect observed only in the spinal nerve ligation model. In the mouse chronic constriction injury (CCI) model, a mouse monoclonal anti-NGF antibody reversed tactile allodynia when administered 2 weeks after surgery. Repeated administration of this antibody to CCI mice for 3 weeks produced a sustained reversal (days 4 to 21) of tactile allodynia that returned 5 days after the end of dosing. In conclusion, NGF seems to play a critical role in models of established neuropathic and inflammatory pain in both rats and mice, with no development of tolerance to antagonism. Antagonists of NGF, such as fully human monoclonal anti-NGF antibodies, may have therapeutic utility in analogous human pain conditions.