Local Anesthetics

16 May

F. Yanagidate• G. R. Strichartz (✉)
Pain Research Center, BWH/MRB611, 75 Francis Street, Boston MA, 02115-6110, USA gstrichz@zeus.bwh.harvard.edu

Abstract Local anesthetics  are used broadly  to prevent  or reverse acute pain  and  treat symptoms  of chronic  pain.  This chapter,  on the analgesic aspects of local anesthetics, reviews their broad actions that affect many different molecular targets and disrupt their functions in pain processing. Application of local anesthetics to peripheral nerve primarily results in the blockade of propagating action potentials, through their inhibition of voltage- gated sodium channels. Such inhibition results from drug binding at a site in the channel’s inner pore, accessible from the cytoplasmic opening. Binding of drug molecules to these channels depends on their conformation, with the drugs generally having a higher affinity for the open and inactivated channel states that are induced by membrane depolarization. As a result, the effective potency of these drugs for blocking impulses increases during high-frequency  repetitive  firing and  also under  slow depolarization,  such as occurs  at a region of nerve injury, which is often the locus for generation of abnormal, pain-related ectopic impulses. At distal and central terminals  the inhibition  of voltage-gated calcium channels by local anesthetics  will suppress  neurogenic  inflammation  and the release of neurotransmitters. Actions on receptors that contribute  to nociceptive transduction, such as TRPV1 and the bradykinin B2 receptor, provide an independent mode of analgesia. In the spinal cord, where local anesthetics are present during epidural or intrathecal  anesthesia, inhibition of inotropic receptors, such as those for glutamate, by local anesthetics further

interferes with neuronal transmission. Activation of spinal cord mitogen-activated protein (MAP) kinases, which are essential for the hyperalgesia following injury or incision and occur in both neurons  and glia, is inhibited by spinal local anesthetics. Many G protein- coupled receptors are susceptible to local anesthetics, with particular  sensitivity of those

coupled via the Gq  α-subunit.  Local anesthetics  are also infused intravenously  to yield

plasma concentrations far below those that block normal  action potentials,  yet that are

frequently effective at reversing neuropathic  pain. Thus, local anesthetics modify a variety of neuronal  membrane  channels and receptors, leading to what is probably a synergistic mixture of analgesic mechanisms to achieve effective clinical analgesia.

Keywords  Ion channels · Action potentials · Nociception · G protein-coupled receptors · MAP kinases


Local anesthetics are widely used for the prevention and relief of both acute and chronic pain (Strichartz and Berde 2005). The reduction  or abolition of acute pain from accidental or intentional trauma (surgery) is accomplished by delivery of local anesthetics to the skin by topical application or subcutaneous infiltration, to peripheral nerve by percutaneous  injection, or to the neuraxis by administration into the epidural or intrathecal spaces (Gokin and Strichartz

1999). Chronic pain symptoms are also relieved, albeit mostly temporarily, by the “nerve blocking” procedures  just described. In contrast,  systemic local

anesthetics, administered  intravenously  and to much lower plasma concen- trations  than those used for direct nerve block, also relieve many forms of neuropathic  pain in humans  and in animal models, and with a therapeutic

benefit that  often endures  for weeks, months,  or longer, far outlasting  the presence of the drug in vivo (Boas et al. 1982; Mao and Chen 2000).

Mechanistic Overview

Whereas mechanisms for the nerve blocking actions of local anesthetics are relatively well understood,  those that underlie the neuraxial block are proba- bly more complex. The inhibition of neuronal voltage-gated sodium channels (VGSC) by direct  binding  of local anesthetics  (Nau and Wang 2004) leads to failure in the generation  or propagation  of action potentials, the primary mechanisms  for functional  deficits during peripheral  nerve blockade. After the delivery of local anesthetics to the epidural or intrathecal compartments, these drugs diffuse into the spinal cord where they can interact with a variety of other ion channels involved (1) in excitation/depolarization of presynaptic terminals,  (2) in regulating release of neurotransmitters, and (3) with both pre- and postsynaptic receptor proteins for small neurotransmitters and neu- ropeptides (Gokin and Strichartz 1999). These receptors include both inotropic

and metabotropic  receptors, membrane  macromolecules that are coupled to the activation of various intracellular signaling pathways using enzymes that themselves may be direct targets of local anesthetic  action. Since clinically used local anesthetics are relatively impotent  drugs, with inhibitory  actions dependent  on millimolar concentrations at their target molecule, and often have restricted  access to their desired target site, they are used clinically at high enough concentrations that many different molecular targets are likely to be modified by them.

Like many “amphipathic” molecules, which contain both hydrophobic and hydrophilic—even ionized—regions, local anesthetics distribute into and have

effects upon the dynamic properties of membranes (Lissi et al. 1990). Almost all of the recognized targets of local anesthetics are membrane-intrinsic or membrane-associated macromolecules, and the partitioning  within and per-

meation through biomembranes is a feature of local anesthetics that is essential for their fundamental  actions and also governs their clinical effectiveness (de Paula and Schreier 1995).

In this chapter we will describe the various mechanisms and molecular and cellular targets for local anesthetics during neural blockade, as well present the phenomenon of and speculate on mechanisms for long-term relief of chronic pain by intravenous local anesthetics. Unlike the acute nerve-blocking actions

of local anesthetics, the mechanisms underlying the long-term effects of intra- venous drugs to relieve chronic pain symptoms remain a mystery. We will also consider the long-held possibility of using certain naturally occurring toxins to

effect analgesia by potent and specific binding to single classes of ion channels.

Finally, we will examine recently described nontraditional actions of local anesthetics, particularly their antiinflammatory effects, and relate the known mechanisms in neuronal tissues to those on immune cell functions.

Molecular Targets of Local Anesthetics

Blockade of Action Potentials: The Classic Local Anesthetic Action

Action potentials are the hallmark of excitable membranes,  and their occur- rence is absolutely dependent on ion channels that open in response to depo- larization and allow current to enter the cell. In most excitable membranes of nerve, skeletal, and cardiac cells, the major inward current that drives the fast depolarizing phase of the action potential is carried through VGSCs. In order to achieve the conditions  for an action potential  to occur, i.e., “threshold,” the cell membrane  must  be adequately  stimulated,  depolarized  sufficiently to open  enough  VGSCs to produce  inward  current  that  will overcome the

outward current  that flows through  the K+ and Cl− channels that coexist in

the membrane.  The initial sources of these impulse-generating  stimuli are physiological transducing  events, such as occur at distal sensory endings, or postsynaptic  “excitatory” receptors, such as occur in the CNS (spinal cord). Local circuit current from a depolarized membrane under an action potential flows to an unexcited adjacent region to stimulate it to threshold, accounting for the propagation  of the depolarizing wave of the action potential along an axon. This mode of propagating  stimulation  has a higher “margin of safety” than the other stimulation  modes, i.e., the current  supplied by the adjacent excited membrane  is about  5–10 times greater than  that  required  to reach threshold. At any one of these locations, impulse-generating  processes can be suppressed  by local anesthetics to prevent or abolish action potentials. Cor- responding to its higher margin of safety for conduction, propagating axonal action potentials are more resistant to treatments  that block inward current than are, for example, the initial generation of action potentials at sensory end- ings. It therefore takes lower concentrations of local anesthetics to suppress the initiation of an impulse than those necessary to abolish that impulse once it has started propagating (Raymond 1992). Furthermore, the margin of safety for conduction  is apparently  greatest in nonmyelinated  C-fibers (and in the smallest, i.e., slowest conducting, among these fibers) and is least in the small myelinated, A-delta and A-gamma fibers (Huang et al. 1997; Gokin et al. 2001). This accounts for the differential order of susceptibility to local anesthetics of axons documented  directly, in vitro and in vivo (small myelinated>large myelinated>non-myelinated). These observations  have been made by many experimentalists but are still challenged by the historical “size principle” that states that smaller fibers, regardless of micro-anatomy, are always more suscep- tible to local anesthetics than larger fibers, a principal extrapolated from very early observations  on compound  action potentials  at a time before C-fibers had been identified (Raymond and Gissen 1987).

Binding of Local Anesthetics to Voltage-Gated Na+ Channels

Blockade of action potentials relies on the inhibition of VGSCs. The regions of the VGSC that interact directly to bind local anesthetics have been identified, principally through  site-directed mutation  (Ragsdale et al. 1994; Wang et al.

2000, 2001). The picture that emerges is of a dynamically altered drug binding site that varies with the state of the channel. Resting closed channels have the lowest affinity. Inactivated  closed channels are much higher in affinity, pri- marily because of a much slower dissociation rate (Chernoff 1990; Hille 1977), perhaps  because the drug must escape from a sterically occluded channel, blocked by an “inactivation moiety” that closes the pore’s cytoplasmic ending (Catterall 2000; Vedantham and Cannon 1999; Wang et al. 2004; Courtney and Strichartz 1987). Open channels also have a higher affinity, but bind the drugs much faster than inactivated  channels do (Hille 1977; Chernoff 1990). One

thermodynamic consequence of the differential binding affinity to different channel states is that the transitions  between these states, the so-called “gat- ing” of the channel, must be modified when local anesthetics are bound (Hille

1977; Balser et al. 1996).

Many of the amino acid side chains that appear to interact with the drug molecules are located around  the cytoplasmic vestibule that forms a portal to the channel’s narrow pore (Kondratiev and Tomaselli 2003; Ragsdale et al.

1994), although parts of the “inner pore domain,” located deeper in the channel, also seem to influence binding  (Sunami et al. 1997). Of the residues lining the vestibule, some are more influential in determining  drug affinity for the

resting state; others  are more important  for determining  inactivation  state binding (Li et al. 1999; Nau et al. 1999, 2003). From this we conclude that local anesthetic binding does not occur at a constant locus in the channel and, given

the conformational  flexibility of most local anesthetics, it is likely that they adjust their shape to fit the channel’s altered conformations.  The name that has been applied to this reciprocal adjustment  of drug and channel during

state-dependent binding is the “modulated receptor” (Hille 1977).

All VGSCs are composed of one large (ca. 180 kDa) α-subunit and 1 to 2 auxiliary β-subunits  (Catterall 2000). The ion pore of the channel  and the major gating machinery, including the loci for local anesthetic binding, are

located on the α piece, although combination  with β-subunits can influence the overall gating pattern and thus, through this modulation of state transitions, influence the state-dependent binding of these drugs (Wang et al. 1996; Wright

et al. 1997, 1999). Each α-subunit  carries four homologous  domains,  each domain contributing  one segment of the channel’s ion conducting pore and one part  of the overall gating apparatus  that couples membrane  voltage to

channel  states. Each domain  also contains  regions that  interact  with local anesthetics, although it is unclear whether a tightly bound  local anesthetic molecule simultaneously  interacts  with all four regions. Judging from their relatively low affinity, rarely having KD values below 10 μM, and their weak stereoselectivitytency ratios rarely exceeding 5 (Lee-Son et al. 1992; Valenzuela

et al. 1995; Brau et al. 2000; see review by Nau and  Strichartz  2002), the fit of local anesthetics to VGSCs is apparently  not very tight (Courtney and Strichartz 1987).

Local Anesthetic Binding to K+ and Ca2+ Channels

There is much structural similarity among the voltage-gated, cation-selective ion channels (Yu et al. 2005). The charged transmembrane regions that act as “voltage-sensors,” the hairpin segments that line the narrowest part of the pore to form the ion “selectivity filter,” and several of the other transmem- brane helices that support  these critical functional regions are homologous structures  among many of these ion channels. Not surprisingly,  then, they

also possess a similar pharmacology for drugs that interact with these regions, among which are the local anesthetics, although, in general, their affinity for these targets is less than that for the Na+ channels.

Both the transient  “A-type” and  the more  persistent  “delayed rectifier” types of K+ channels, both of which are activated by membrane  depolariza- tions, are blocked by local anesthetics (Courtney and Kendig 1988; Castle 1990; Josephson 1988; Olschewski et al. 1998; Komai and McDowell 2001). The ki-

netics of the block are most consistent with high-affinity binding to the open state, and the mechanistic picture that accompanies these kinetics portrays one local anesthetic molecule entering  an open channel’s pore and occlud- ing it, analogous to the mode for blocking open Na+  channels (Castle 1990; Valenzuela et al. 1995). Classical “inward rectifier” K+ channels are much less susceptible to local anesthetics (Castle 1990; Carmeliet et al. 1986), perhaps because they are not activated by voltage but instead may have a metal cation binding site in their pore that has few of the physicochemical properties  that bind a local anesthetic, e.g., hydrophobicity. However, other K+ channels that are not voltage-gated but are open at the resting potential  are potently  in- hibited by local anesthetics (Brau et al. 1995; Olschewski et al. 1996; Kindler

et al. 1999).

Voltage-gated Ca2+ channels also are blocked by local anesthetics (Palade and Almers 1985; Oyama et al. 1988; Guo et al. 1991; Sugiyama and Muteki

1994; Xiong and Strichartz 1998; Liu et al. 2001). Interestingly, in the case of the slowly inactivating L-type Ca2+ channels, the primary mode of block seems to be a promotion  of the inactivated state (Carmeliet et al. 1986; Xiong and Strichartz 1998), like one of the actions of local anesthetics (LAs) on VGSCs

and  also like the dihydropyridine drugs, e.g., nifedipine,  that  are classical inhibitors  of L-type channels.  The LAs do not, however, bind  at the dihy- dropyridine  binding  site on these channels  (Hirota  et al. 1997; Xiong and Strichartz 1998).

Pacemaker currents in neurons (and in cardiac muscle), Ih , carried by the hyperpolarization-activated, cyclic nucleotide-gated (HCN) class of channels which conduct Na+ and K+ about equally well, are LA sensitive too (Bischoff et al. 2003). Concentrations  of bupivacaine and lidocaine to half block these channels, ca. 50 and 100 μM, respectively, are actually lower than those re-

ported  to block Na+  channels in the same sensory neurons  (Bischoff et al.

2003). Membrane-impermeant derivatives  of local anesthetic—such  as the permanently charged quaternary homolog of lidocaine, QX314—which block most cation channels from the intracellular direction, do not attenuate  pace- maker currents when applied to the cell’s exterior, suggesting that there is also an intracellular  route to the local anesthetic binding site of these channels. Inasmuch  as pacemaker  channels  are found in many neurons  (Doan et al.

2004) and have been implicated as sources that drive the repetitive firing often associated with abnormal  pain (Chaplan  et al. 2003; Yao et al. 2003)—and

because selective inhibitors  of Ih delivered systemically are known to relieve

certain neuropathic  pain symptoms (Chaplan et al. 2003; Lee et al. 2005; cf. Raes et al. 1998)—their relative susceptibility to blockade by local anesthetics nominates  them as likely targets for some of the clinical analgesic actions of these drugs.

The physiological,  functional  consequences  of blocking  these  different channels will obviously depend on that channel’s role in neural activity. Potas- sium channel block is often synergistic with the Na+ channel blocking activity for effecting impulse blockade by local anesthetics (Drachman and Strichartz

1991). Blocking K+ channels can depolarize the resting membrane and usually slows the repolarization  of the action potential. In the absence of an accom-

panying Na+ channel blockade by the drug, these actions will often enhance excitability, bringing the resting membrane  closer to threshold and prolong- ing the duration  of the action potential, an action that raises the margin of

safety for impulse propagation and increases the likelihood of repetitive firing after a single stimulus (Raymond et al. 1990). When conjoined with the Na+ channel blocking properties of local anesthetics, however, K+ channel block- ade has a remarkably synergistic action on action potentials. Both the steady depolarization of the resting potential and the prolonged depolarization of the action potential potentiate impulse blockade by increasing the presence of the open and inactivated Na+ channels that bind LAs with high affinity. This over- all effect illustrates  an important pharmacological  principle: the integrated actions of an agent that acts on several, physiologically coupled targets may differ from the action that would be predicted from the actions of that agent on the separate targets. Since the nervous system almost always utilizes plural ion

channels and receptors in neural conduction and synaptic transmission (Hille

2001), the net effect of local anesthetics cannot always be predicted directly from their actions on only one of these targets.

Inhibition of the Ca2+ channels at nerve terminals by local anesthetics has dramatic  physiological effects, disproportionally greater than the inhibition of action potentials through Na+ channel blockade. Transmitter  release from

nerve terminals  depends on the free cytosolic concentration of Ca2+  in the presynaptic  ending, raised to the third  power or higher. Therefore, if half the Ca2+  channels are blocked, the release of transmitter might be reduced

to about  10% of the control  value in drug-free conditions.  By comparison, the margin of safety for impulse propagation  is so large for most peripheral nerve axons that about 80% of the channels must be blocked before impulse

conduction fails. These calculations are not intended to indicate the functional potency relationships  for local anesthetics  acting at different ion channels, but rather  to emphasize the different forms of nonlinear  relations  between blockade of ion channels  and the inhibition  of the physiological functions

to which they are coupled. Ultimately, it is these final physiological actions that are most directly related to analgesia, and the toxic side effects of local anesthetics.

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