Anesthesiology 2009; 111:12–4 Copyright © 2009, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Local Anesthetics A New Hydrophilic Pathway for the Drug-receptor Reaction WHERE, how, and by what pathway local anesthetics local anesthetic action: one involving Na channels and produce their effects, at least those related to inhibition the other involving conformational changes in lipopro- of action potentials in axons, have curiously only re- teins and membrane expansion.8 There was also a com- cently become established dogma in Anesthesia. Now ment that local anesthetics could produce their effects we are presented with data in the current issue of this “. internally or externally at the channel opening,” journal that support a challenge to some of our long- despite the lack of evidence to support an external site. standing assumptions about the pathways by which local In 1990, another review of local anesthetic pharmacol- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/1/12/248744/0000542-200907000-00008.pdf by guest on 30 September 2021 1,2 anesthetics may approach their binding site. ogy appeared in ANESTHESIOLOGY that again emphasized Shortly after Hodgkin and Huxley used voltage-clamp- the central importance of drug binding to Na channels.9 ing to posit the existence of specific Na channels in the Meanwhile, textbooks published in that decade contin- giant axon of the squid, Loligo, Weidmann observed ued to speculate about uncharged local anesthetics caus- cocaine- and procaine-induced reductions in the ampli- ing membrane expansion and, of all things, “decreasing tude and peak rate of rise of action potentials in isolated the diameter of the sodium channel.”10,11 Purkinje fibers.3 Weidmann speculated that cocaine and Presently, the local anesthetics in clinical use are (with procaine might promote inactivation of Na channels in the exception of the neutral compound benzocaine) cardiac muscle. Taylor reported that procaine had no tertiary amines that under physiologic conditions exist in effect on the resting membrane potential or on the Na a mixture of protonated and neutral forms. The charged equilibrium potential of squid axons.4 Rather, procaine forms appear to be more potent than the neutral forms specifically inhibited Na currents. Taylor also observed once they gain access to the local anesthetic binding site that procaine had a less robust action at inhibiting K on the cytoplasmic “side” of the conducting pore of the currents and commented that this latter action would Na channel.6,9 Quaternary, obligatorily charged local an- tend to counteract procaine “block” of nerves. esthetics have been used for 30 yr to define the site of These observations only slowly made there way into drug action and to determine the “active form” of local the anesthesia literature. A contemporary textbook1 anesthetics.6,9 The assumption has long been made that stated that local anesthetics might work through inter- if QX-314 (a compound similar to lidocaine in every way ference with electrical depolarization of nerves or “hu- except that it has a third ethyl moiety on its terminal moral actions” (competing with acetylcholine for recep- amine nitrogen that renders it positively charged under tor binding).5 Strichartz described use-dependent block all conditions) or any other quaternary compound is in 1973, and he reviewed local anesthetic pharmacology placed extracellularly, the positive charge will prevent it in ANESTHESIOLOGY in 1976, documenting the data that from permeating the plasma membrane. When applied discredited those theories of local anesthetic action that to the cytoplasmic side of neural membrane QX-314 will did not involve binding of the drugs to Na channels.6 A potently produce both tonic and frequency-dependent year later, Hille provided an explanation (and a drawing) block. Nevertheless, accepted dogma states that QX-314 of the pathways by which charged and neutral local should not have an effect if used for local or regional anesthetics might reach the drug receptor on the Na anesthesia in patients because there would be no way channel within the plasma membrane.7 Yet, a contem- for it to approach the local anesthetic receptor. porary textbook continued to provide two theories of We are now presented with strong evidence that our dogma regarding QX-314 is in conflict with the facts. First, there were two reports that extracellular quater- This Editorial View accompanies the following articles: 12,13 ᭜ Binshtok AM, Gerner P, Oh SB, Puopolo M, Suzuki S, Roberson nary local anesthetics could inhibit Na channels. DP, Herbert T, Wang C-F, Kim D, Chung G, Mitani AA, Wang GK, Vanilloid receptor agonists were observed to potentiate Bean BP, Woolf CJ: Co-application of lidocaine and the perma- local anesthesia.14,15 Next, Lim et al. reported that ap- nently charged sodium channel blocker QX-314 produces a long- plication of QX-314 could produce long-lasting nerve lasting blockade in rodents. ANESTHESIOLOGY 2009; 111:127–37; 16 and Ries CR, Pillai R, Chung CCW, Wang JTC, MacLeod BA, blocks in animals. Binshtok, Bean, and Woolf reported Schwarz SKW: QX-314 produces long-lasting local anesthesia that extracellular application of QX-314 with capsaicin, a modulated by transient receptor potential vanilloid receptors in compound that promotes opening of transient receptor mice. ANESTHESIOLOGY 2009; 111:122–6. potential vanilloid subtype I (TRPV1) channels, pro- duced greater inhibition of membrane Na currents than either compound administered by itself.17 Local anes- Accepted for publication March 20, 2009. The authors are not supported by, thetics were added to the list of drugs and conditions nor maintain any financial interest in, any commercial activity that may be 18 associated with the topic of this article. that activate TRPV1 channels. Anesthesiology, V 111, No 1, Jul 2009 12 EDITORIAL VIEWS 13 In this edition of ANESTHESIOLOGY Binshtok et al. extend dination of ions with but a very few residues in a “selectiv- these observations with a report that coapplication of ity filter” all remain components of ion selectivity in the lidocaine with QX-314 promotes a long-persisting re- revised models of K channels. The similarities between gional anesthesia, presumably by lidocaine’s promoting TRPV1 and Kv channel structures implied by experimental activation of TRPV1 channels through which QX-314 and theoretical comparisons naturally led to the view that gains entry to the cytoplasm.17 Meanwhile Ries et al. ion selectivity in TRPV1 is also a relatively static feature used activators and inhibitors of TRPV1 to provide reflecting rigid structural domains of the channel. This strong evidence that this channel represents the most view, however, is challenged by recent observations of likely pathway by which QX-314 might breach the anomalous permeation of TRPV1 by much larger mole- plasma membrane.18 But, are these reports consistent cules. Moreover, evidence also suggests that Kv channels with what is known about the biophysical characteris- can exhibit dynamic ion selectivity under certain condi- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/111/1/12/248744/0000542-200907000-00008.pdf by guest on 30 September 2021 tics of TRPV1 channels? tions, suggesting the general view of a static immutable It has long been known that capsaicin, the pungent selectivity filter needs rethinking. principal of hot chili peppers, can induce burning pain The first report that anomalously large molecules when injected into the skin and, paradoxically, can serve could pass through TRPV1 came from a chance obser- as an analgesic.19 Furthermore, embryonic exposure to vation that the styryl dye FM1-43 could gain entry into a capsaicin leads to failure of development of small diam- variety of sensory cells and neurons through TRP chan- eter nociceptor sensory afferent neurons and an inability nels.22 Only cell lines heterologously expressing TRPV1 to express pain-related behaviors. For these reasons, the would accumulate the dye in response to activation. 1997 cloning of the capsaicin receptor, now termed Since that report, other investigators have documented TRPV1, represented a major breakthrough in understand- that molecules ranging from large dyes (YO-PRO1, ing the transduction of noxious stimuli in the periphery.20 MQAE), antibiotics (gentamycin), and large organic cat- Since that time, a superfamily of TRP channels (now includ- ions (NMDG, tetraethylammonium) will permeate TRPV1 ing six vanilloid-type receptor-channels [TRPV1-6]) has channels.23–25 Inspired by these observations, Chung et al. been recognized to transduce a variety of physical and made comprehensive biophysical assessments of TRPV1 chemical stimuli, including heat, cold, osmotic strength, permeability and selectivity under conditions of pro- mechanical force, and Ca2ϩ ion depletion. Several of the longed activation by capsaicin, heat, and other ago- TRPV channels along with TRPM8 and TRPA1 have been nists.26 These authors documented a progressive de- implicated in thermal sensation; however, evidence from crease in channel selectivity with increasing activation two lines of TRPV1-null mice suggest that TRPV1 is re- time and/or agonist concentration yielding passage of quired for certain pathologic hyperalgesic states, but not large dyes and organic cations through TRPV1. Thus, for physiologic thermal sensation. This apparent segrega- extended activation of TRPV1 as might occur during tion of pathologic and physiologic pain responses has re- conjoint application of capsaicin (or lidocaine or thermal newed interest in the development of both selective stimulation) and QX-314 could readily result in perme- TRPV1 antagonists and agonists as potential novel analgesic ation of QX-314 to the cytoplasmic compartment, where agents.19 it potently blocks Na channels. Much is now known about TRPV1 structure-function Based on atomic radii, the limiting size of the selectiv- relationships. Identified domains of TRPV1 bind capsa- ity filter of TRPV1 under acute activation has been esti- icin, sense heat, respond to activation by protons, and mated at 6–10 A˚, whereas the crystal structure of lido- respond to inflammatory signals.