On dialog between clinicians and basic scientists.
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Interprofessional Relations↗
Biomedical subjects
M Devor
Publications and source records attributed to M Devor.
Hyperexcitability in sensory neurons of rats selected for high versus low neuropathic pain phenotype.
Selection line rats congenitally high or low for autotomy in the neuroma model of neuropathic pain (HA and LA rats) were found to be correspondingly high and low in a second type of neuropathic pain, the Chung model, which employs an alternative phenotypic endpoint, tactile allodynia. It has been proposed that both phenotypes reflect ectopic hyperexcitability in axotomized primary sensory neurons. To test this hypothesis we made in vitro recordings from sensory neurons in the L4 and 5 dorsal root ganglia. Baseline excitability was similar in HA and LA rats, and axotomy caused an increase in both lines. However, in the one neuronal subclass previously linked to neuropathic pain in these models the increase was significantly greater in HA than LA rats, and only at the time when pain scores in the two lines were diverging. Heritable differences in electrical response to axotomy in a specific afferent cell type appear to be a fundamental determinant of neuropathic pain.
Action Potentials↗
Neuropathic pain: what do we do with all these theories?
Only a generation ago there were few ideas as to what might cause neuropathic pain, and even fewer relevant data. In contrast, we can currently point to hundreds of distinct cellular changes that are triggered by nerve injury and that might be relevant to the emergence of pain symptomatology. The number may soon increase to thousands. It is essential, therefore, to redirect efforts towards the development of experimental strategies for testing which of these are essential parts of the pain process and which are tangential. In this paper I point out four such strategies: timing, deletion, prevention and genetic heterogeneity, and summarize how one neuropathic pain theory, the ectopic pacemaker hypothesis, holds up to scrutiny.
Humans↗
Dye coupling does not explain functional crosstalk within dorsal root ganglia.
Most primary sensory neurons in rat dorsal root ganglia (DRGs) are depolarized during repetitive impulse activity in neighboring neurons that share the same ganglion. We wondered whether this functional crosstalk might be mediated by a network of cytoplasmic bridges (gap junctions) between neighboring neurons and their satellite glia. Neurobiotin was injected intracellularly in whole excised DRGs. Some of the animals were intact, and others underwent transection of the ipsilateral sciatic nerve 7 to 21 days prior to injection. A total of 44 directly injected neurons were recovered histologically. There was little or no evidence of dye spread to neighboring satellite cells or neurons that would have indicated the presence of cytoplasmic bridges, certainly not enough to account for the nearly universal functional coupling that occurs among these neurons. Functional crosstalk within DRGs must therefore employ a different mechanism.
Animals↗
Preoperative open field behavior predicts levels of neuropathic pain-related behavior in mice.
Exploratory open field (OF) activity was assessed in seven different mouse strains and selection lines. We counted the number of beam interruptions made by three cagemate mice at a time. This assay tests reactivity to aversive stimuli, anxiety and emotionality. One hindlimb was then totally denervated by transecting the sciatic and saphenous nerves on one side, and autotomy, a behavior thought to be related to neuropathic pain, was quantified over 35 days. We report that OF activity and autotomy are highly variable across different strains/lines. These results reaffirm the genetic control of these behaviors. We also found that these behaviors are inversely and significantly correlated. We suggest that common genetically-determined neural mechanisms may underlie anxiety, emotionality and neuropathic pain in mice.
Animals↗
Functional cross-excitation between afferent A- and C-neurons in dorsal root ganglia.
Electrophysiological recordings were made in vitro from primary afferent neurons with unmyelinated axons (C-neurons) in excised rat dorsal root ganglia. Spike activity triggered in neurons with myelinated axons (A-neurons) by stimulation of the peripheral nerve or the dorsal root produced a transient depolarization in passive neighboring C-neurons that share the same ganglion. About 90% of neurons sampled responded with this "cross-depolarization". Cross-depolarization was associated with functional excitation as indicated by an increase in firing probability in response to previously subthreshold intracellular test pulses. Furthermore, it yielded a net increase of the input resistance of the affected C-neurons. We suggest that functional coupling among DRG neurons could serve a metabolic role, providing a functionally relevant feedback signal useful for controlling the excitability of nociceptive sensory endings. In addition, the results provide a novel mechanism whereby afferent nociceptors could be stimulated by activity in low-threshold mechanoreceptors, particularly in the event of nerve injury. Hence, the coupling between afferent A- and C-neurons in dorsal root ganglia provides a novel candidate mechanism for neuropathic pain.
Animals↗
Spinal nerve injury enhances subthreshold membrane potential oscillations in DRG neurons: relation to neuropathic pain.
Primary sensory neurons with myelinated axons were examined in vitro in excised whole lumbar dorsal root ganglia (DRGs) taken from adult rats up to 9 days after tight ligation and transection of the L(5) spinal nerve (Chung model of neuropathic pain). Properties of subthreshold membrane potential oscillations, and of repetitive spike discharge, were examined. About 5% of the DRG neurons sampled in control DRGs exhibited high-frequency, subthreshold sinusoidal oscillations in their membrane potential at rest (V(r)), and an additional 4.4% developed such oscillations on depolarization. Virtually all had noninflected action potentials (A(0) neurons). Amplitude and frequency of subthreshold oscillations were voltage sensitive. A(0) neurons with oscillations at V(r) appear to constitute a population distinct from A(0) neurons that oscillate only on depolarization. Axotomy triggered a significant increase in the proportion of neurons exhibiting subthreshold oscillations both at V(r) and on depolarization. This change occurred within a narrow time window 16-24 h postoperative. Axotomy also shifted the membrane potential at which oscillation amplitude was maximal to more negative (hyperpolarized) values, and lowered oscillation frequency at any given membrane potential. Most neurons that had oscillations at V(r), or that developed them on depolarization, began to fire repetitively when further depolarized. Spikes were triggered by the depolarizing phase of oscillatory sinusoids. Neurons that did not develop subthreshold oscillations never discharged repetitively and rarely fired more than a single spike or a short burst, on step depolarization. The most prominent spike waveform parameters distinguishing neurons capable of generating subthreshold oscillations, and hence repetitive firing, was their brief postspike afterhyperpolarization (AHP) and their low single-spike threshold. Neurons that oscillated at V(r) tended to have a more prolonged spike, with slower rise- and fall-time kinetics, and lower spike threshold, than cells that oscillated only on depolarization. The main effects of axotomy were to increase spike duration, slow rise- and fall-time kinetics, and reduce single-spike threshold. Tactile allodynia following spinal nerve injury is thought to result from central amplification ("central sensitization") of afferent signals entering the spinal cord from residual intact afferents. The central sensitization, in turn, is thought to be triggered and maintained in the Chung model by ectopic firing originating in the axotomized afferent neurons. Axotomy by spinal nerve injury enhances subthreshold membrane potential oscillations in DRG neurons, augments ectopic discharge, and hence precipitates neuropathic pain.
Action Potentials↗
Membrane potential oscillations in dorsal root ganglion neurons: role in normal electrogenesis and neuropathic pain.
Abnormal afferent discharge originating at ectopic sites in injured primary sensory neurons is thought to be an important generator of paraesthesias, dysaesthesias, and chronic neuropathic pain. We report here that the ability of these neurons to sustain repetitive discharge depends on intrinsic resonant properties of the cell membrane and that the prevalence of this characteristic increases after nerve injury. Recording from primary sensory neurons in excised rat dorsal root ganglia, we found that some cells show subthreshold oscillations in their membrane potential. The amplitude, frequency, and coherence of these oscillations were voltage sensitive. Oscillations gave rise to action potentials when they reached threshold. Indeed, the presence of oscillations proved to be a necessary condition for sustained spiking both at resting membrane potential and on depolarization; neurons without them were incapable of sustained discharge even on deep depolarization. Previous nerve injury increased the proportion of neurons sampled that had subthreshold oscillations, and hence the proportion that generated ectopic spike discharge. Oscillatory behavior and ectopic spiking were eliminated by [Na(+)](o) substitution or bath application of lidocaine or tetrodotoxin (TTX), under conditions that preserved axonal spike propagation. This suggests that a TTX-sensitive Na(+) conductance contributes to the oscillations. Selective pharmacological suppression of subthreshold oscillations may offer a means of controlling neuropathic paraesthesias and pain without blocking afferent nerve conduction.
Afferent Pathways↗
Myelinated afferent fiber types that become spontaneously active and mechanosensitive following nerve transection in the rat.
It is difficult to know which afferent types preferentially develop ectopic firing characteristics following nerve injury because axotomy disconnects the sensory receptor ending from the remainder of the afferent neuron. We compared the prevalence of ectopic firing originating in nerve-end neuromas of nerves serving muscle and skin in the rat. Spontaneous firing was much more prevalent in the injured medial gastrocnemius nerve, a hindlimb muscle nerve, than in the saphenous and sural nerves which primarily innervate hindlimb skin. Ectopic mechanosensitivity, on the other hand, was more prominent in neuromas of the cutaneous nerves. In neuromas of the facial nerve, a cranial nerve which serves striated muscles of the face, there was no spontaneous discharge and very little ectopic mechanosensitivity. We conclude that the development of spontaneous ectopic discharge and ectopic mechanosensitivity depends on the type of myelinated afferent fiber involved.
Action Potentials↗
Effect of age and nerve injury on cross-excitation among sensory neurons in rat dorsal root ganglia.
Spike activity in dorsal root ganglion (DRG) neurons depolarizes passive neighbors that share the same ganglion. We asked whether age or prior nerve injury affect this 'cross-depolarization' signal. Intracellular recordings made from excised DRGs in vitro revealed that the prevalence and duration of cross-depolarization were no greater in adult than in young rats, and that its amplitude was significantly smaller in adults. The amplitude of cross-depolarization was not affected by nerve injury. The decrease in membrane input resistance (R(in)) observed during cross-depolarization was less than that expected from equivalent depolarization alone. This affirms prior evidence that the neural process underlying cross-depolarization causes a net increase in R(in).
Age Factors↗
Heritability of nociception II. 'Types' of nociception revealed by genetic correlation analysis.
Clinical pain syndromes, and experimental assays of nociception, are differentially affected by manipulations such as drug administration and exposure to environmental stress. This suggests that there are different 'types' of pain. We exploited genetic differences among inbred strains of mice in an attempt to define these primary 'types'; that is, to identify the fundamental parameters of pain processing. Eleven randomly-chosen inbred mouse strains were tested for their basal sensitivity on 12 common measures of nociception. These measures provided for a range of different nociceptive dimensions including noxious stimulus modality, location, duration and etiology, among others. Since individual members of inbred strains are identical at all genetic loci, the observation of correlated strain means in any given pair of nociceptive assays is an index of genetic correlation between these assays, and hence an indication of common physiological mediation. Obtained correlation matrices were subjected to multivariate analyses to identify constellations of nociceptive assays with common genetic mediation. This analysis revealed three major clusters of nociception: (1) baseline thermal nociception, (2) spontaneously-emitted responses to chemical stimuli, and (3) baseline mechanical sensitivity and cutaneous hypersensitivity. Many other nociceptive parameters that might a priori have been considered closely related proved to be genetically divergent.
Animals↗
Heritability of nociception I: responses of 11 inbred mouse strains on 12 measures of nociception.
It is generally acknowledged that humans display highly variable sensitivity to pain, including variable responses to identical injuries or pathologies. The possible contribution of genetic factors has, however, been largely overlooked. An emerging rodent literature documents the importance of genotype in mediating basal nociceptive sensitivity, in establishing a predisposition to neuropathic pain following neural injury, and in determining sensitivity to pharmacological agents and endogenous antinociception. One clear finding from these studies is that the effect of genotype is at least partially specific to the nociceptive assay being considered. In this report we begin to systematically describe and characterize genetic variability of nociception in a mammalian species, Mus musculus. We tested 11 readily-available inbred mouse strains (129/J, A/J, AKR/J, BALB/cJ, C3H/HeJ, C57BL/6J, C58/J, CBA/J, DBA/2J, RIIIS/J and SM/J) using 12 common measures of nociception. These included assays for thermal nociception (hot plate, Hargreaves' test, tail withdrawal), mechanical nociception (von Frey filaments), chemical nociception (abdominal constriction, carrageenan, formalin), and neuropathic pain (autotomy, Chung model peripheral nerve injury). We demonstrate the existence of clear strain differences in each assay, with 1.2 to 54-fold ranges of sensitivity. All nociceptive assays display moderate-to-high heritability (h2 = 0.30-0.76) and mediation by a limited number of apparent genetic loci. Data comparing inbred strains have considerable utility as a tool for understanding the genetics of nociception, and a particular relevance to transgenic studies.
Animals↗
Structural basis of sympathetic-sensory coupling in rat and human dorsal root ganglia following peripheral nerve injury.
Tyrosine hydroxylase immunocytochemistry was used to reveal the sympathetic postganglionic axons that sprout to form basket-like skeins around the somata of some primary sensory neurons in dorsal root ganglia (DRGs) following sciatic nerve injury. Ultrastructural observations in rats revealed that these sprouts grow on the surface of glial lamellae that form on the neurons. Sciatic nerve injury triggers glial cell proliferation in the DRG, and the formation of multilamellar pericellular onion bulb sheaths, primarily around large diameter DRG neurons. We infer that these glia participate in the sprouting process by releasing neurotrophins and expressing growth supportive cell surface molecules. Many DRG cell somata, and their axons in intact nerves and nerve end neuromas, express alpha2A adrenoreceptors intracytoplasmically and on their membrane surface. However, sympathetic axons never make direct contacts with the soma membrane. The functional coupling known to occur between sympathetic efferents and DRG neurons must therefore be mediated by the diffusion of neurotransmitter molecules in the extracellular space. Sympathetic basket-skeins were observed in DRGs removed from human neuropathic pain patients, but the possibility of a functional relation between these structures and sensory symptoms remains speculative.
Adult↗
The effect of preemptive analgesia on subacute postoperative pain.
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Analgesics↗
Cross-excitation in dorsal root ganglia does not depend on close cell-to-cell apposition.
About 90% of neurons in dorsal root ganglia (DRGs) of rats 2-5 weeks of age are depolarized and excited by impulse activity in neighboring neurons that share the same DRG. Synaptic contacts are extremely rare in DRGs, but instances of close membrane apposition between pairs of neuronal somata are not uncommon, especially in prenatal rats. Close membrane apposition could permit electrotonic interactions among neighboring DRG neurons. We carried out an ultrastructural examination of DRGs taken from rats 2-5 weeks of age and found that by this age < 2% of cells remain in close apposition with neighbors. The remainder are separated by one or two layers of satellite glial cytoplasm. It is, therefore, unlikely that close apposition between adjacent neurons contributes significantly to functional cross-excitation in the DRG.
Animals↗
Ectopic mechanosensitivity in injured sensory axons arises from the site of spontaneous electrogenesis.
Injured sensory axons trapped in a neuroma or freely regenerating in the distal nerve stump, frequently display ectopic mechanosensitivity, spontaneous impulse discharge or both. This abnormal neural activity is thought to contribute to spontaneous and movement-evoked neuropathic paraesthesias, dysaesthesias and pain, as well as to allodynia and hyperalgesia. The present paper examines the relationship between mechanosensitivity and spontaneous discharge in three distinct sciatic nerve injury models in the rat: nerve transection (neuroma), nerve crush and chronic nerve constriction injury (CCI). Impulse pattern analysis was used to determine that the sites of mechanosensitivity and of spontaneous electrogenesis are either identical or very close to one another. This suggests that mechanosensitivity and spontaneous firing are aspects of a single underlying pathophysiological process. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.
Journal Article↗
Spike-evoked suppression and burst patterning in dorsal root ganglion neurons of the rat.
1. A low level of spontaneous impulse discharge is generated within dorsal root ganglia (DRGs) in intact animals, and this activity is enhanced following nerve injury. Many physiological stimuli present in vivo are capable of augmenting this ectopic discharge. Whatever their cause, episodes of sharply accelerated DRG firing tend to be followed by 'after-suppression' during which discharge falls below baseline rate. In this study we examined the process of postexcitation suppression of firing rate, and how it shapes spike patterning in primary sensory neurons. 2. We recorded intracellularly from sensory neurons in excised rat DRGs in vitro. Trains of spikes triggered by intracellular current pulses evoked a prolonged hyperpolarizing shift. This shift appeared to be due to activation of a Ca(2+)-dependent K+ conductance (9K(Ca)). Spikes evoked by just-suprathreshold pulses triggered a hyperpolarizing shift and spike cessation. As the shift decayed, spiking was restored. The net result was bursty (on-off) discharge, a previously unexplained peculiarity of ectopic discharge in some DRG neurons in vivo. 3. Conditioning nerve tetani delivered to axons of neurons which share the DRG with the impaled neuron evoked transient depolarization ('cross-depolarization'). However, when stimulus strength was increased so as to include the axon of the impaled neuron, the net result was a hyperpolarizing shift. Nerve stimulation that straddled the threshold of the axon of the impaled neuron drove it intermittently, but it always drove axons of at least some neighbouring neurons. The result was dynamic modulation of the membrane potential of the impaled neuron as cross-depolarization and spike-evoked hyperpolarizing shifts played off against one another. Membrane potential shifted in the hyperpolarizing direction whenever the axon was activated, and shifted in the depolarizing direction whenever it was silent. Dynamic modulation of this sort probably also occurs in vivo when stimuli are drawn over the surface of the skin.
Animals↗
Adrenosensitivity of injured afferent neurons does not require the presence of postganglionic sympathetic terminals.
Nerve injury sometimes triggers neuropathic pain states that are exacerbated by sympathetic efferent activity. A classic example is causalgia. The mechanism of coupling between sympathetic efferent activity and the afferent discharge responsible for pain sensation is a subject of controversy. Some authors hold to the 'direct coupling hypothesis' which proposes that noradrenaline (NA), released from sympathetic varicosities, acts directly on alpha-adrenoreceptors located in the membrane of injured primary afferents. Others believe that coupling is indirect; that the effects of NA are mediated by additional, non-adrenergic, chemical substances and their receptors (the 'indirect coupling hypothesis'). For example, it has been proposed that in inflamed skin NA acts back on the sympathetic endings which, secondarily, release a prostanoid mediator which sensitizes afferent endings. We report that the responsiveness of injured afferent axons to systemically applied NA persists, and in fact increases in prevalence, in rats that underwent prior chemical or surgical sympathectomy. The observation of adrenosensitivity in injured afferents in the absence of sympathetic postganglionic endings is consistent with the direct coupling hypothesis, which associates adrenosensitivity with the injured afferent axon. It is not consistent with the indirect coupling hypothesis which requires the presence of sympathetic endings as a source for NA-evoked prostanoid release.
Adrenergic alpha-Agonists↗