Systemic QX-314 Reduces Bone Cancer Pain through Selective Inhibition of Transient Receptor Potential Vanilloid Subfamily 1–expressing Primary Afferents in Mice

• Published in: Anesthesiology (Philadelphia) Vol. 125; no. 1; pp. 204 - 218
• Main Authors: Fuseya, Satoshi, Yamamoto, Katsumi, Minemura, Hitoshi, Yamaori, Satoshi, Kawamata, Tomoyuki, Kawamata, Mikito
• Format: Journal Article
• Language: English
• Published: United States Copyright by , the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc 01-07-2016
• Subjects: Anesthetics, Local - therapeutic use; Animals; Behavior, Animal - drug effects; Bone Neoplasms - complications; Bone Neoplasms - pathology; Cyclic AMP Response Element-Binding Protein - antagonists & inhibitors; Cyclic AMP Response Element-Binding Protein - biosynthesis; Ganglia, Spinal - drug effects; Lidocaine - analogs & derivatives; Lidocaine - therapeutic use; Male; Mice; Mice, Inbred C3H; Movement; Pain - drug therapy; Pain - etiology; Pain - psychology; Pain Measurement - drug effects; Postural Balance - drug effects; Psychomotor Performance - drug effects; TRPV Cation Channels - antagonists & inhibitors; Weight-Bearing
• ISSN: 0003-3022; 1528-1175
• DOI: 10.1097/ALN.0000000000001152

BACKGROUND:The aim of this study was to determine whether systemic administration of QX-314 reduces bone cancer pain through selective inhibition of transient receptor potential vanilloid subfamily 1 (TRPV1)–expressing afferents.
METHODS:A mouse model of bone cancer pain was used. The authors examined the effects of bolus (0.01 to 3 mg/kg, n = 6 to 10) and continuous (5 mg kg h, n = 5) administration of QX-314 on both bone cancer pain–related behaviors and phosphorylated cyclic adenosine monophosphate response element–binding protein expression in dorsal root ganglion neurons (n = 3 or 6) and the effects of ablation of TRPV1-expressing afferents on bone cancer pain–related behaviors (n = 10).
RESULTS:The numbers of flinches indicative of ongoing pain in QX-314–treated mice were smaller than those in vehicle-treated mice at 10 min (3 mg/kg, 4 ± 3; 1 mg/kg, 5 ± 3 vs. 12 ± 3; P < 0.001; n = 8 to 9), 24 h (3 ± 2 vs. 13 ± 3, P < 0.001), and 48 h (4 ± 1 vs. 12 ± 2, P < 0.001; n = 5 in each group) after QX-314 administration, but impaired limb use, weight-bearing including that examined by the CatWalk system, and rotarod performance indicative of movement-evoked pain were comparable. QX-314 selectively inhibited the increase in phosphorylated cyclic adenosine monophosphate response element–binding protein expression in TRPV1-positive, but not in TRPV1-negative, dorsal root ganglion neurons compared to that in the case of vehicle administration (32.2 ± 3.0% vs. 52.6 ± 5.9%, P < 0.001; n = 6 in each group). Ablation of TRPV1-expressing afferents mimicked the effects of QX-314.
CONCLUSION:This study showed that systemic administration of QX-314 in mice inhibits some behavioral aspects of bone cancer pain through selective inhibition of TRPV1-expressing afferents without coadministration of TRPV1 agonists.