Development of Novel Local Analgesics for Management of Acute Tissue Injury Pain
Abstract
The goal of this project is to develop a completely new approach to the management of the acute pain that results from injury and battle wounds, one that can be applied quickly, safely, and by untrained personnel, and that does not have the problems associated with morphine or similar opiate drugs. The specific objective is to block the electrical activity of all those pain neurons that supply an injured area for a prolonged period by targeting a drug into these fibers where it will get trapped for some time. The rationale for this approach is based on the driver for the electrical activity in neurons being sodium channels and our discovery of a way of delivering a blocker of these channels selectively into pain fibers. A typical example of a sodium channel blocker is the local anesthetic lidocaine. When injected close to nerve fibers, it diffuses into the nerve fibers where it acts on a particular site on the sodium channel found only on the inside of cells. This blocks all nerve fibers including those that carry pain or touch signals, causing complete numbness, and those fibers that supply muscles, causing paralysis. An essential feature of such local anesthetic agents is that in order to get into the nerve fiber, they need to be able to diffuse through the cell membrane -- something they can do because they can readily dissolve in lipids (a property called lipophilic), which is what the membrane is composed of. However, once they are in the nerve fiber, they diffuse right out and their action is then both non-selective (affecting sensory and motor nerve fibers) and short-lasting (a few hours). If a sodium channel blocker is changed chemically so that it is charged, it can now no longer diffuse through cell membranes to get into a nerve fiber (it is not lipid soluble -- but lipophobic) and is ineffective as a local anesthetic. One such chemical is QX-314, which is a permanently charged form of lidocaine. If QX-314 is introduced experimentally into a nerve cell through a glass electrode, it blocks excitability, but if it is administered outside a cell, it has no such action. Our major discovery reported in a paper published Nature in 2007 was that if a charged sodium channel blocker is small enough, it can enter cells though neuronal channels that have large pores or holes in them. One such channel is TRPV1, which is only expressed by pain fibers and produces heat pain. TRPV1 is also activated by capsaicin, the pungent ingredient in a hot chili. When TRPV1 is activated by heat, capsaicin, or by the inflammation accompanying tissue injury, it allows QX-314 into pain fibers where it now blocks sodium channels to produce local analgesia. Because touch fibers and those supplying muscles do not express TRPV1, they are not blocked, the effect is specific for pain. In addition, once the blocker is in the cell, it is trapped there for some time and so produces a pain block that lasts more than 10 times longer than lidocaine. Furthermore, because of the blocker s charge, it, unlike lidocaine-like drugs, cannot readily be distributed around the body and will therefore have reduced actions on the heart or brain, increasing its safety profile. Our plan now is to discover a suitable candidate charged sodium channel blocker to push this strategy forward for use in wounded Soldiers. To do this, we have designed a set of 72 new compounds -- all charged sodium channel blockers -- and will now test which is the most potent in blocking sodium channels when inside a cell but ineffective outside the cell and which is still small enough to enter cells when TRPV1 channels are activated. We will then test those compounds with such a profile for their efficacy in rodent tissue injury pain models, looking for compounds that have minimal action in non-injured tissue but a strong and long-lasting analgesic action in damaged tissue. The best of these will be assessed for local or systemic toxicity to nominate a candidate, on co
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510480
Entities
People
- Clifford J. Woolf
Organizations
- United States Army