Neurobiological basis for selectivity of Na+ channel blockers in neuropathic pain

Commentary

Neurobiological Basis for Selectivity of Na+ Channel Blockers in Neuropathic Pain Marshall Devor

he Focus article by Tanelian and Victory outlined the basic scientific evidence that Na' channel-blocking agents selectively suppress ectopic neural firing in injured nerves, and the clinical evidence that this class of drugs is effective in controlling a broad range of neuropathic pain states. These two observations are not unrelated. Abundant evidence has accumulated over the past decade indicating that abnormal neural firing is a principal cause of neuropathic pain." Furthermore, the central role of Na" channel regulation in the genesis of this firing is becoming increasingly clear," As a result, the traditional lecture opening declaring neuropathic pain mechanisms to be a mystery is no longer as accurate as it used to be. Unfortunately, the same cannot be said of the traditional companion declaration that the clinical management of neuropathic pain is difficult and often unsatisfactory. Tanelian and Victory are correct in concluding that Na" channel blockers can be an effective clinical tool in some cases of neuropathic pain, and the evidence they muster certainly justifies the inference that this class of drugs should be tried more often. Nonetheless, considerable clinical experience with carbamazepine and phenytoin, and, if less so, with systemic local anesthetics (lidocaine, mexiletine) indicate that these agents are only sometimes effective at tolerable doses, and that they are associated with a range of unpleasant and dose-limiting side effects, such as vertigo, nausea, somnolence, tremor, slurred speech, etc.' Na" channels are ubiquitous, and play an essential role in virtually all neural functions, not just somatosensory processing and pain. Side effects due to nonspecific suppression of central nervous system (CNS) activity is an inevitable stumbling block. In order to bet-

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From the Department of Cell and Animal Biology, Life Sciences Institute, Hebrew University of Jerusalem, Jerusalem, Israel. Reprint requests: Marshall Devor, PhD, Department of Cell and Animal Biology, Life Sciences Institute, Hebrew University of Jerusalem, Jerusalem 91904, Israel.

Pain Forum 4(2): 83-86, 1995

ter exploit this treatment approach we need to understand the basis for the relative selectivity of Na" channel blockers in suppressing abnormal neural discharge, and to devise better means of targeting the offending ectopic sources without flooding the entire nervous system with powerful suppressive agents. The aim of this article is to discuss the neurobiological basis of the selectivity (why do Na' channel blockers suppress abnormal firing at concentrations so much lower than those required to block nerve conduction?) and also to explore potential strategies for avoiding unwanted central side effects.

THE DUAL ROLE OF ECTOPIA Ectopic firing (ectopia) is generated at several alternative locations in injured afferent neurons: the site of injury itself (neuroma pacemaker nodules), within the associated dorsal root ganglia, at sites of demyelination, in regenerating sprouts (freely outgrowing and arrested ones), and perhaps also in sensory terminals undergoing collateral sprouting due to the degeneration of neighbors." In the most excitable afferents it is expressed as spontaneous firing, but in many more it is expressed as hyperresponsiveness to depolarizing stimuli: chemical (inflammatory mediators, adrenoreceptor agonists, etc.), physical (mechanical deformation, temperature, etc.), and metabolic (hypoxia, ischemia, etc.). The role of ectopia in neuropathic pain is twofold. First, abnormal discharge injected into the CNS directly elicits abnormal sensations, including paresthesias and, when nociceptors are involved, dysesthesias and pain. These may be spontaneous, or evoked by movement, circulatory disturbances, or endogenous chemical events (e.g., changes in sympathetic outflow). In addition, ectopia may be the source of the background input that is apparently essential for the maintenance of "central sensifization''P" Central sensitization is a CNS hyperexcitability state in which afferent input entering along low-threshold AI3 fibers is interpreted by the brain as pain.'

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IMPULSE GENERATION (ELECTROGENESIS) VERSUS IMPULSE PROPAGATION Na' channel blockers (membrane stabilizers) prevent the generation of impulses at much lower concentrations than are required to block impulse propagation, because of the different "safety factors" of the two processes. As stimuli are delivered at gradually increasing intensity, a value is eventually reached that is just sufficient to generate an action potential (spike threshold). In some neurons there is a second, higher threshold at which impulse firing first becomes repetitive (thresho~d for rhythmogenesis). Since both of these electrogenic processes are threshold phenomena, even a small reduction in neuronal excitability is noticeable as threshold suppression. This is particularly so for rhythmoge~­ esis (Figure B, C). When the rhythmic firing threshold IS reached the neuron typically jumps from silence to a substantial minimum rhythmic firing frequency. Because of this nonlinearity in the stimulus-firing relation, even minimal suppression may take firing back from a high rate to silence (Figure A). This is the case for ectopic firing sources in injured nerves. Ectopia normally operates just above the rhythmic firing threshold. For this reason, minimal doses of suppressive drugs often produce maximal suppression of abnormal firinq." Propagating impulses, in contrast, are usually not threshold phenomena. Their safety factor is high. Even very substantial suppression of peripheral nerve excitability still leaves enough residual membrane current to support continued nerve conduction. When applied systemically, the amount of Na" channel blockers needed to stop nerve conduction is very high, and generally fatal. The only exception is at certain unique CNS locations, where peculiarities of geometry (branching, or a sudden shift in caliber), or membrane channel properties, reduce the axonal safety factor towards threshold. At these locations minor suppression may cause propagation block." Fortunately, the safety factor of the cardiac pacemaker system is also high, so analgesic doses of systemic Na' channel blockers are not expected to threaten cardiac function in otherwise healthy individuals.

DOES ANALGESIA RESULT FROM SUPPRESSION OF PERIPHERAL OR CENTRAL NERVOUS SYSTEM ACTIVITY? Central nervous system neurons typically spend most of their time near the border of firing and silence. Synaptic inputs continuously play on the somatic and dendritic membrane; only when the threshold is reached does the neuron fire. Hence, like ectopic impulse generation in the peripheral nervous system, even low concentrations

of Na" channel blockers are able to tilt the threshold balance toward silence. This is the reason that the plasma level of Na' channel blockers just sufficient to suppress peripheral nervous system ectopia is very near that which suppresses the firing of spinal cord neurons." It is also, of course, the plasma level that suppresses neuropathic pain. Even in cases where the origin of nerve impulses responsible for neuropathic pain is entirely peripheral, CNS suppression would be expected to provide pain relief. At clinically relevant doses these drugs almost certainly act in the peripheral nervous system and in the CNS simultaneously.

DOSE-LIMITING SIDE EFFECTS ORIGINATE IN THE CENTRAL NERVOUS SYSTEM The most disturbing side effects involved in the systemic use of Na" channel blockers are central. It is almost always dizziness and loss of alertness that prevent ?ne from titrating to higher, and presumably more effective, doses. This limitation might be overcome by regional infusion of a dilute solution of carbamazepine, lidocaine, etc., into a suspected source of ectopic electrogenesis, an injured brachial plexus, for example, or a few adjacent dorsal root ganglia. The use of concentrations well below those that block nerve conduction would ensure intact motor and residual sensory function. Another potential approach to avoiding dose-limiting CNS toxicity would be to produce a lidocaine- or carbamazepine-like agent in a form that does not cross the blood brain barrier. No such drug exists at present. Unfortunately, this is not a trivial matter. All of the agents used clinically act on the intracellular, cytoplasmic mouth of the Na" channel. They must enter the nerve cell in order to work. Chemical derivations that prevent entry into the brain are expected also to exclude entry into afferent neurons in the periphery and, therefore, to neutralize their analgesic effect. Strategies to overcome this problem, however, do exist. Pharmacological agents that block Na" channels by binding to the extracellular mouth of the channel are known and used widely as reagents in basic neuroscience research (e.g., tetrodotoxin and saxitoxin). To the best of my knowledge, these have never been tested in the context of neuropathic pain. In a first attempt, perhaps Helsinki approval could be obtained for use of these agents in a Bier block. Finally, mention should be made of the likelihood that nociceptive afferents use a complement of Na" channel molecules subtly different from those present in lowthreshold afferents, and those present in the heart and the brain. This difference might permit the creation of novel Na' channel blockers that selectively target and silence nociceptors.

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gNa+max (mS/cm 2 ) Figure. Computer simulation of repetitive firing in response to a prolonged depolarizing pulse (equivalent to prolonged stimulus application), based on the Hodgkin-Huxley equations for electrogenesis in the squid giant axon. (A) Frequency-current (t-l) relationship (encoding function). At threshold, firing rate increases stepwise from zero to the fiber's minimum rhythmic firing frequency (mRFF). Note that a small change in stimulus strength around the threshold (region a) has a much larger impact on firing frequency than the same change in region b. (8) A family of f-I curves using gradually increasing Na' channel density (gNa+max). As Na' channels are added, the repetitive firing threshold decreases, as does the mRFF. (C) The change in rhythmic firing threshold, and the threshold for evoking a single spike, as a function of gNa+max. Note that below about gNa+max = 81.7 miliiSiemens (mS}/cm 2 repetitive firing cannot be elicited, no matter how strong the stimulus. In all panels gK+max was held constant at 36 mS/cm 2 . Reprinted, with perrnlsslon."

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References 1. Campbell IN, Raja SN, Meyer RA, MacKinnon SE: Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 32:89-94, 1988 2. Devor M: Pathophysiology of injured nerve. pp. 79-100. In Wall PO, Melzack R (eds): Textbook of pain, 3rd ed. Churchill-Livingstone, London, 1994 3. Devor M, Lomazov P, Matzner 0: Na" channel accumulation in injured axons as a substrate for neuropathic pain. pp. 207-230. In Boivie J, Hansson P, Lindblom U (eds): Touch, temperature and pain in health and disease. Wenner-Gren Center Foundation Symposia, IASP Press, Seattle, 1994 4. Glazer S, Portnoy RK: Systemiclocal anesthetics in pain control. J Pain Symptom Manage 6:30-39, 1991 5. Gracely RH, Lynch SA, Bennett GJ: Painful neuropathy: altered central processing maintaineddynamically by peripheral input. Pain 51:175-194,1992

6. Matzner 0, Devor M: Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na" channels. J Neurophysiol 72:349-357, 1994 7. Sheen K, Chung JM: Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model. Brain Res 610:62-68, 1993 8. Sotgiu ML, Biella G, Castagna A, Lacerenza M, Marchettini P: Different time-courses of i.v. lidocaine effects on ganglionic and spinal units in neuropathic rats. Neuroreport 5:873-876, 1994 9. Wall PO, McMahon SB: Long ranging afferents in rat spinal cord. III. Failure of impulse transmission in axons and relief of the failure after rhizotomy of dorsal roots. Philos Trans R Soc London 343:211-223, 1994