Pain is signaled by generation of action potentials in a specific population of primary sensory neurons known as nociceptors. The most effective form of pain relief without loss of consciousness is provided by administration of local anesthetics, which act by inhibiting voltage-dependent sodium channels and thereby depressing electrical excitability. Clinically-used local anesthetics are molecules that exist at least partially in a hydrophobic, uncharged form that can enter neurons through the cell membrane. These anesthetics enter and inhibit excitability in all neurons, not just nociceptors, and thus can have many undesirable effects (including paralysis and block of autonomic signaling) in addition to blocking pain. The proposed research is based on a recent finding that sodium channel blocking drugs can be targeted selectively to nociceptors by co-applying a permanently charged derivative of lidocaine (QX- 314) with capsaicin, an agonist for TRPV1 channels. The underlying hypothesis, supported by the preliminary data in the proposal, is that QX-314 can enter nociceptors by passing through the pore formed by TRPV1 channels. The overall goal of the proposed research is to identify combinations of TRPV1 activators and charged sodium channel blockers that optimize the block of excitability of nociceptive sensory neurons. Specific questions to be addressed include: What is the size limit for effective entry of charged sodium channel blockers? How does the time course of blocker entry depend on the nature and concentration of the TRPV1 agonist? Can blocker entry and accumulation be enhanced by activation of protein kinase C? Are there TRPV1 agonists that allow QX-314 entry without first stimulating firing of action potentials? What is the relative potency of intracellular QX-314 for blocking the different types of sodium channels known to be important for excitability of nociceptors? These questions will be addressed using patch clamp experiments on native TRPV1 channels and sodium channels in rat dorsal root ganglion neurons, with additional experiments using heterologous expression of cloned TRPV1 channels. Characterizing these mechanisms should facilitate the development of new clinical treatments for pain relief based on the targeted entry of charged sodium channel blockers into pain-sensing neurons. Such treatments should be highly advantageous for more selective pain relief in childbirth, surgery, and dental procedures and possibly for some forms of chronic neurogenic pain.

Public Health Relevance

The goal of the research is to develop a new treatment for pain based on selective targeting of sodium channel blocking drugs to pain-sensing neurons. By co-applying a permanently charged lidocaine derivative with capsaicin, an agonist for TRPV1 channels, it is possible to block electrical excitability in pain-sensing neurons but not in other types of neurons, thus avoiding the motor paralysis and block of autonomic fibers that occurs with conventional local anesthesia. Besides allowing pain-specific local anesthesia (e.g. for dental procedures and minor surgery), this may lead to improved epidural anesthesia in childbirth and thoracic surgery and possibly improved treatments for some forms of chronic neuropathic pain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Babcock, Debra J
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Harvard University
Schools of Medicine
United States
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Ellis, Samantha; Kalinowski, Danuta S; Leotta, Lisa et al. (2014) Potent antimycobacterial activity of the pyridoxal isonicotinoyl hydrazone analog 2-pyridylcarboxaldehyde isonicotinoyl hydrazone: a lipophilic transport vehicle for isonicotinic acid hydrazide. Mol Pharmacol 85:269-78
Jo, Sooyeon; Bean, Bruce P (2014) Sidedness of carbamazepine accessibility to voltage-gated sodium channels. Mol Pharmacol 85:381-7
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
Brenneis, Christian; Kistner, Katrin; Puopolo, Michelino et al. (2013) Phenotyping the function of TRPV1-expressing sensory neurons by targeted axonal silencing. J Neurosci 33:315-26
Puopolo, Michelino; Binshtok, Alexander M; Yao, Gui-Lan et al. (2013) Permeation and block of TRPV1 channels by the cationic lidocaine derivative QX-314. J Neurophysiol 109:1704-12
Liu, Pin; Jo, Sooyeon; Bean, Bruce P (2012) Modulation of neuronal sodium channels by the sea anemone peptide BDS-I. J Neurophysiol 107:3155-67
Jo, Sooyeon; Bean, Bruce P (2011) Inhibition of neuronal voltage-gated sodium channels by brilliant blue G. Mol Pharmacol 80:247-57
Bosmans, Frank; Puopolo, Michelino; Martin-Eauclaire, Marie-France et al. (2011) Functional properties and toxin pharmacology of a dorsal root ganglion sodium channel viewed through its voltage sensors. J Gen Physiol 138:59-72
Roberson, D P; Binshtok, A M; Blasl, F et al. (2011) Targeting of sodium channel blockers into nociceptors to produce long-duration analgesia: a systematic study and review. Br J Pharmacol 164:48-58
Kim, Hyun Yeong; Kim, Kihwan; Li, Hai Ying et al. (2010) Selectively targeting pain in the trigeminal system. Pain 150:29-40