The specific contribution of different primary sensory neurons in producing pain and itch will be investigated by targeted delivery of an impermeant cationic sodium channel blocker (QX-314, a quaternary derivative of lidocaine) through large-pore ion channels differentially expressed on afferents.
The aim i s to electrically silence subsets of axons using combinations of QX-314 and large-pore ion channel agonists. We have validated this strategy for TRPV1-expressing nociceptors using capsaicin and QX-314 to produce a long lasting """"""""pain-specific"""""""" local anesthesia, and our pilot data suggest that TRPA1 and P2X3 activation by mustard oil and ATP also allow QX-314 permeation into DRG neurons. We will confirm this using whole cell patch clamp recordings in DRG neurons. The strategy will then be used in vivo to determine the functional effects on nociception of blocking TRPV1, TRPA1 and P2X3 expressing nociceptors in naive rats and mice, measuring behavioral deficits in response to specific mechanical, thermal and chemical stimuli. The afferent silencing strategy will also be used to identify which large-pore ion channel expressing primary afferents contribute to histaminergic and non-histaminergic itch. The presence of silenced afferents after administering QX-314 alone will be used to establish if large-pore ion channels are constitutively activated by endogenous agonists during peripheral inflammation, after nerve injury, in acute and chronic itch, when, and where. Our pilot data show that QX-314 blocks nociceptor terminals in the presence of inflammation but not in naive animals. We will now explore if QX314 administered to peripheral terminals or nerves alters different modalities of pain sensitivity in soft tissue, incisional, arthritic, and peripheral neuritic inflammatory models, as well as in neuropathic pain and pruritic atopic dermatitis models. These strategies will help both identify the cellular mechanisms of nociceptive, inflammatory and neuropathic pain, acute and chronic itch and develop opportunities for targeted novel therapeutic interventions to treat these conditions.
We propose to develop a new analgesic strategy;targeting the pain pathway in the periphery using large- pore lon channels specific to the system as a means of delivering a sodium channel blocker only into defined sets of neurons. The proposal will test the potential of this approach for acute and chronic pain therapy.
| Cheng, Longzhen; Duan, Bo; Huang, Tianwen et al. (2017) Identification of spinal circuits involved in touch-evoked dynamic mechanical pain. Nat Neurosci 20:804-814 |
| Jo, Sooyeon; Bean, Bruce P (2017) Lacosamide Inhibition of Nav1.7 Voltage-Gated Sodium Channels: Slow Binding to Fast-Inactivated States. Mol Pharmacol 91:277-286 |
| Blair, Nathaniel T; Philipson, Benjamin I; Richards, Paige M et al. (2016) Naturally Produced Defensive Alkenal Compounds Activate TRPA1. Chem Senses 41:281-92 |
| Vardeh, Daniel; Mannion, Richard J; Woolf, Clifford J (2016) Toward a Mechanism-Based Approach to Pain Diagnosis. J Pain 17:T50-69 |
| Talbot, Sébastien; Foster, Simmie L; Woolf, Clifford J (2016) Neuroimmunity: Physiology and Pathology. Annu Rev Immunol 34:421-47 |
| Andrews, Nick A; Latrémolière, Alban; Basbaum, Allan I et al. (2016) Ensuring transparency and minimization of methodologic bias in preclinical pain research: PPRECISE considerations. Pain 157:901-9 |
| Bean, Bruce P (2015) Pore dilation reconsidered. Nat Neurosci 18:1534-5 |
| Bourane, Steeve; Duan, Bo; Koch, Stephanie C et al. (2015) Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science 350:550-4 |
| Talbot, Sébastien; Abdulnour, Raja-Elie E; Burkett, Patrick R et al. (2015) Silencing Nociceptor Neurons Reduces Allergic Airway Inflammation. Neuron 87:341-54 |
| Brenneis, C; Kistner, K; Puopolo, M et al. (2014) Bupivacaine-induced cellular entry of QX-314 and its contribution to differential nerve block. Br J Pharmacol 171:438-51 |
Showing the most recent 10 out of 41 publications
