Chronic Deafferentation Research Articles

Responses to spinal microstimulation in the chronically spinalized rat and their relationship to spinal systems activated by low threshold cutaneous stimulation.

We describe the responses evoked by microstimulation of interneuronal regions of the spinal cord in unanesthetized rats chronically spinalized at T10-T12. One to three weeks after spinalization, sites in the lumbar spinal cord were stimulated using trains of low current microstimulation. The isometric force produced by stimulation of a spinal site was measured at the ankle. Responses were reliably observed from stimulation of a region within the first 1250 microm from the dorsal surface of the spinal cord. These responses were clearly not due to direct motoneuronal activation and were maintained after chronic deafferentation. The force evoked by microstimulation and measured at the ankle varied smoothly across the workspace. Simultaneous stimulation of two sites in the spinal cord produced a response that was a simple linear summation of the responses evoked from each of the sites alone. Microstimulation generally produced a highly non-uniform distribution of response directions, biased toward responses which pulled the limb toward the body. Within these distributions there appeared to be two main types of responses. These different types of responses were preferentially evoked by microstimulation of different rostrocaudal regions of the spinal cord. This anatomical organization paralleled the spinal cutaneous somatotopy, as assessed by recording cutaneous receptive fields of neurons at sites to which the microstimulation was applied. This relationship was maintained after chronic deafferentation. The findings described here in the rat spinal cord in large part replicate those previously described in the frog.

Pharmacologic approaches to neuropathic pain

Injury to peripheral or central primary afferent neurons can produce severe and chronic neuropathic or deafferentation pain. This type of pain responds poorly, if at all, to nonsteroidal anti-inflammatory drugs and often is relatively opioid resistant. Several classes of drugs have been used with varying effectiveness to treat neuropathic pain. None are effective for all patients. Tricyclic antidepressants (TCAs) are often considered the drugs of choice at doses that are only one third to one half of the antidepressant doses. Available TCAs are contrasted by their side-effect profiles and pharmacokinetic characteristics. Amitryptyline is the most commonly used drug, but desipramine may be the TCA of choice for this indication. When the TCA alone is not sufficient an anticonvulsant can be added. Recent experience suggests that gabapentin may be the anticonvulsant of choice for this purpose. The used of systemic local anesthetics and topical capsaicin to deplete substance P is also described. Other classes of medications that have been used with varying results are discussed and include autonomic agents, depleting agents, andN-methyl-D-aspartate receptor antagonists. Methods of obtaining complete medication histories and of stopping ineffective drugs are described. The importance of an interdisciplinary, multimodel approach to the management of neuropathic pain is discussed.

Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons

Neurodegenerative diseases affecting the midbrain dopaminergic system have been reported to produce spontaneous pains like in Parkinson's disease. Using various pain tests for acute (hot plate test, HPT, tail flick, TFT, paw pressure test, PPT and paw immersion test, PIT) and chronic deafferentation (autotomy, AT, following peripheral neurectomy) pains in rats, we have investigated the effects on these tests of selective chemical lesions with 6-hydroxydopamine (6-OHDA) or/and kainic acid (KA) either in the striatum or in the substantia nigra (SN) and ventral tegmental area (VTA). 6-OHDA lesions of dopaminergic terminals in the striatum decreased significantly the latencies of all nociceptive reflexes (HPT from 11.7±1.45 s to 7±1.35 s, TFT from 4.5±0.15 s to 3.2±0.16 s and PPT on the contralateral leg from 2.07±0.45 s to 1.05±0.085 s) and accelerated the time of onset (from 10.82±2.3 days to 3.1±0.52 days) and end (from 29.5±5.6 days to 5.2±1.1 days) of AT. These effects were not modified by simultaneous injection of KA and 6-OHDA in the striatum. 6-OHDA lesions in the SN-VTA produced comparable effects to those of similar injections in the striatum, while KA lesions in the SN-VTA did not produce significant changes in the latencies of nociceptive reflexes or in the AT criteria. These results suggest that the dopaminergic system plays a major role in the processing of nociceptive information in the striatum and the limbic areas.

Vestibular neuritis: Clinical-pathologic correlation

Postmortem examination of the brain and temporal bones of a patient with well-documented vestibular neuritis showed selective neuronal loss in Scarpa's ganglia on the side with absent caloric response. There was loss of hair cells and an “epithelialization” of the utricular macule and semicircular canal cristae on the deafferented side, and synaptic density in the vestibular nuclei on the deafferented side was decreased compared with that on the normal side. All findings were consistent with an isolated viral infection of Scarpa's ganglia. This is the first description of the effects of chronic deafferentation on the vestibular sensory epithelia and the vestibular nuclei in a human being. (Otolaryngol Head Neck Surg 1996;114:586-92.)

Vestibular Neuritis: Clinical‐Pathologic Correlation

Postmortem examination of the brain and temporal bones of a patient with well-documented vestibular neuritis showed selective neuronal loss in Scarpa's ganglia on the side with absent caloric response. There was loss of hair cells and an "epithelialization" of the utricular macule and semicircular canal cristae on the deafferented side, and synaptic density in the vestibular nuclei on the deafferented side was decreased compared with that on the normal side. All findings were consistent with an isolated viral infection of Scarpa's ganglia. This is the first description of the effects of chronic deafferentation on the vestibular sensory epithelia and the vestibular nuclei in a human being.

Chapter 5 Opioid receptors in the superficial layers of the rat spinal cord: functional implications in pain processing

This chapter discusses the role of opioids in nociceptive sensory processing in the spinal cord. The superficial layers (I and II) of the dorsal horn that are the main termination sites of fine diameter primary afferent fibers are rich in endogenous opioid substances, and are the main sites of action of morphine on the transmission of nociceptive messages at the spinal level. The chapter essentially discusses the opioid receptors in this region and their functional implication in pain processing, reporting results of quantitative studies performed in the rat. In the first part of this study, it tries to find the respective proportions of the three main types of opioid receptors in the superficial layers of the dorsal horn are; whether these proportions are similar over the rostrocaudal axis of the spinal cord; what their respective pre- and postsynaptic proportions are; whether the rostrocaudal distribution of the thin primary afferent fibers arising from a single dorsal root can be evaluated using opioid ligands as markers; whether there is a plasticity of opioid receptors in chronic deafferentation states. In the second part, it discusses the modifications of opioid binding sites density in relation to neuropathic pain.

Degeneration of afferent neurons and long-term stability of the ventilatory central pattern generator in chronically deafferented crabs

1. The effects of chronic deafferentation, 3-180 days, are tested on the function and morphology of the crab (Carcinus maenas) ventilatory central pattern generator (CPGv). Almost all afferent axons are carried in the mixed sensory/motor levator nerve. The ability to speed the CPGv cycle rate by stimulating this nerve (Wilkens and DiCaprio 1994) decreases as the afferent neurons degenerate. Stimulation of the levator nerve eliminates motor units from the output even after 60 days of deafferentation, similar to the effects seen in acute preparations. 2. The 3 oval organ afferent axons of the levator nerve have central somata and survive scaphognathectomy. Impulses carried by these axons are known to inhibit the CPGv in acutely deafferented preparations and they are believed to be responsible for the persistent inhibition following small afferent degeneration seen here. 3. After 6 months of deafferentation the motor neuron collateral arborization densities within the thoracic ganglia are reduced, but all motor neurons appear to survive. These long-term deafferented CPGvs generate accurate motor patterns at similar rates to the control CPGv, but at reduced intraburst spike frequency. The crab CPGv is quite stable following chronic deafferentation.

Ultrastructural localization of neurotensin immunoreactivity in the stellate ganglion of the cat.

The morphological features and cellular relationships of neurotensin-containing axon terminals were studied at light and electron microscopic levels in the cat stellate ganglion using peroxidase and immunogold immunocytochemistry. By light microscopy, neurotensin immunoreactivity was detected within thin varicose fibres distributed throughout the ganglion. Immunoreactive fibres were no longer apparent following chronic deafferentation of the ganglion indicating that they were of extrinsic origin. Ultrastructural analysis of peroxidase immunostained material confirmed the presence of neurotensin immunoreactivity within a subpopulation of axonal varicosities which made synaptic contacts with the dendrites of ganglion cells. Within labelled varicosities neurotensin immunoreactivity was found by both immunoperoxidase and immunogold methods to be concentrated within large dense core vesicles 80-120 nm in diameter. These large dense core vesicles were characteristically distant from the active zone, in keeping with a possible extrasynaptic release of the peptide.

The expression of deafferentation dysesthesias reduced by dorsal root entry zone lesions in the rat.

Extensive longitudinal lesions of the dorsal root entry zone (DREZ) are effective in relieving some chronic deafferentation pain in humans. A deafferentation syndrome follows C5-T2 dorsal root ganglionectomies in rats. The syndrome consists of biting and scratching the completely and partially denervated limb areas, respectively. This study examines the effect of DREZ lesions on the deafferentation syndrome in the rat. Of 37 rats, 24 underwent C5-T2 ganglionectomies only, five received C4-T3 micromechanical DREZ lesions only, and eight underwent ganglionectomies plus simultaneous DREZ lesions. The animals were observed for 45 days post-operatively. Histological analysis of the spinal cord lesions was performed. All rats with ganglionectomies alone exhibited the deafferentation syndrome; however, no rats with DREZ lesions alone showed this feature. Only 25% of rats with combined ganglionectomies and DREZ lesions exhibited the deafferentation syndrome in the first 30 days, whereas 80% of the animals with ganglionectomies only did so. Although 75% of the animals with combined lesions eventually bit the insensitive forepaw, this behavior was significantly attenuated: the day of onset was delayed and the extent of self-mutilation was reduced. Postmortem histological examination of the DREZ lesions indicated a close association between the completeness of the dorsal horn destruction and the reduction or prevention of self-mutilation. These data support the validity of the animal model and also the hypothesis stating that the deafferentation syndrome results from abnormal spontaneous neural activity in the dorsal horn. Moreover, the variability of the histological findings in these experiments stresses the importance of making contiguous and complete dorsal horn lesions in human DREZ surgery.

Does the nervous system depend on kinesthetic information to control natural limb movements?

AbstractThis target article draws together two groups of experimental studies on the control of human movement through peripheral feedback and centrally generated signals of motor commands. First, during natural movement, feedback from muscle, joint, and cutaneous afferents changes; in human subjects these changes have reflex and kinesthetic consequences. Recent psychophysical and microneurographic evidence suggests that joint and even cutaneous afferents may have a proprioceptive role. Second, the role of centrally generated motor commands in the control of normal movements and movements following acute and chronic deafferentation is reviewed. There is increasing evidence that subjects can perceive their motor commands under various conditions, but that this is inadequate for normal movement; deficits in motor performance arise when the reliance on proprioceptive feedback is abolished either experimentally or because of pathology. During natural movement, the CNS appears to have access to functionally useful input from a range of peripheral receptors as well as from internally generated command signals. The unanswered questions that remain suggest a number of avenues for further research.

Event-related brain potentials during orienting to auditory and visual stimulation in spinal cord injured humans.

In intact humans, deprivation of somatosensory and kinesthetic sensations result in significant alterations in perception and information processing. There have been very few studies to discover if the loss of sensation with spinal cord injury (SCI) in humans affects perceptual operations. We hypothesized that the SCI participant would either exhibit arousal, perceptual, and information processing alterations similar to experimentally sensory deprived subjects (who provide the closest human analogue), or that the somatosensory cortex would show reorganization for the processing of other modalities of stimulation. The subjects consisted of 16 paraplegic, 13 quadriplegic, and 22 non SCI controls. Subjects received an auditory orienting task consisting of a 500 Hz tone presented 20 times each at 66, 75, 88, and 101 db and a visual orienting task incorporating light flashes of 115, 123, 131, and 140 lux presented 20 times each. EEG information processing data were recorded from C3 and C4 for 100 msec prior to and 500 msec post stimulation. Information processing variables, analyzed as event-related potentials, indicated that the somatosensory cortex of SCI groups had a flattened response to auditory stimulation. The control group had a significantly larger P2 component. We concluded that these data signified that the somatosensory cortex did not reorganize function in response to chronic deafferentation nor was the SCI subject hyperresponsive to stimulation.

Chronic deafferentation in monkeys differentially affects nociceptive and nonnociceptive pathways distinguished by specific calcium-binding proteins and down-regulates gamma-aminobutyric acid type A receptors at thalamic levels.

Chronic deafferentation of skin and peripheral tissues is associated with plasticity of representational maps in cerebral cortex and with perturbations of sensory experience that include severe "central" pain. This study shows that in normal monkeys the nonnociceptive, lemniscal component of the somatosensory pathways at spinal, brainstem, and thalamic levels is distinguished by cells and fibers immunoreactive for the calcium-binding protein parvalbumin, whereas cells of the nociceptive component at these levels are distinguished by immunoreactivity for 28-kDa calbindin. Long-term dorsal rhizotomies in monkeys lead to transneuronal degeneration of parvalbumin cells at brainstem and thalamic sites accompanied in the thalamus by a down-regulation of gamma-aminobutyric acid type A receptors and an apparent increase in activity of calbindin cells preferentially innervated by central pain pathways. Release from inhibition and imbalance in patterns of somatosensory inputs from thalamus to cerebral cortex may constitute subcortical mechanisms for inducing changes in representational maps and perturbations of sensory perception, including central pain.

Self-injurious behavior: a review of the behavior and biology of self- mutilation

The authors describe the clinical characteristics of self-injurious behavior, giving special emphasis to self-injurious behavior occurring among individuals with character disorders. They review data suggesting the involvement of serotonergic, dopaminergic, and opiate neurotransmitter systems in the expression of self-injurious behavior. Self-injurious behavior occurs among mentally retarded individuals, psychotic patients, prison populations, and individuals with severe character disorders. Although theoretical psychological models of self-injurious behavior are helpful in understanding the patient's experience of self-injury, no generally useful therapeutic approach has yet evolved from these models. Data derived from animal models and treatment studies suggest the involvement of opiatergic and dopaminergic mechanisms in self-injury among the mentally retarded. Serotonergic influences on self-injurious behavior may be present in varying forms of this behavior. The scientific literature on the benefits of pharmacological agents for mentally retarded individuals is beset with a number of problems. Support is emerging, however, for the use of lithium and carbamazepine with self-injuring mentally retarded patients, and some behavioral interventions appear to be successful for mentally retarded individuals. Self-injuring patients with borderline personality disorder may benefit from milieu treatment. Although no form of treatment has yet been demonstrated to be of general benefit, the literature suggests that therapeutic trials with dopamine antagonists, serotonin reuptake inhibitors, and opiate antagonists may be of value.

Postischemic Cerebral Blood Flow and Neuroeffector Mechanisms

The influence of neuroeffector mechanisms in the regulation of postischemic cerebral blood flow was investigated by microsphere determination in 8 cats after chronic unilateral vascular deafferentation by trigeminal ganglionectomy. The animals were subjected to 90 min of reperfusion following 10 min of global ischemia induced by 4-vessel occlusion and systemic hypotension. Cortical hyperemia 30 min after reperfusion was attenuated by up to 48% in cortical gray matter ipsilateral to the side of trigeminal ganglionectomy (p less than 0.01). Axon reflex mechanisms involving the release of neuropeptides from peripheral sensory nerve fibers, such as substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin A (NKA), mediate this response. SP and NKA cause vasodilation by endothelium-dependent mechanisms (endothelium-dependent relaxing factor), whereas CGRP relaxes vascular smooth muscle by direct receptor interactions. Studies were therefore undertaken to determine the extent to which endothelium-dependent mechanisms mediate the hyperemia following global cerebral ischemia. In 7 intact cats, the postischemic response of pial arterioles to the topical application of acetylcholine (ACh; 10(-7) M), an endothelial-dependent vasodilator, was measured using a closed cranial window technique. Although ACh increased pial arteriolar caliber by 17% under resting conditions, the same dose elicited a vasoconstrictor response (87% of pre-ACh diameter 30 min after reperfusion) for the first 60 min of reperfusion after 10 min of ischemia. ACh-induced vasodilation was restored by 75 min (105%), but was less than control even at 120 min (109 vs. 117%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of lesions in the anterolateral columns and dorsolateral funiculi on self-mutilation behavior in rats

The possible role of the anterolateral columns (ALCs) and dorsolateral funiculi (DLF) in pain mechanisms was examined from the effects of lesions in these tracts (alone or combined) on tests for chronic deafferentation pain (autotomy) in rats. Spinal lesions alone (i.e., without denervation) in either ALC or DLF or combined DLF-ALC did not lead to any form of self-mutilation behavior. Cervical surgery, without spinal lesion, followed by limb denervation (sham) resulted in similar autotomy characteristics to those observed following limb denervation alone (control). Both results were considered as one set of controls. ALC lesions simultaneous with, or 1–2 weeks prior to limb denervation (ipsilaterally or contralaterally) produced significant delay in onset of autotomy and decrease in percentage of rats showing this behavior. DLF lesions followed by limb denervation produced significant acceleration of onset of autotomy and increase in percentage of rats showing this behavior. Combined DLF-ALC lesions with limb denervation produced intermediate effects between those observed following either ALC or DLF lesions alone. These results give further support to the concept that autotomy is related to rostral transmission of nociceptive information and that a spino-bulbo-spinal inhibitory loop involving the DLF and ALC is triggered by chronic deafferentation pain.

Evoked-Potential Monitoring during Dorsal Root Entry Zone Surgery

Somatosensory evoked potentials (SEP) were monitored intraoperatively in 15 patients who underwent spinal cord radiofrequency thermal dorsal root entry zone (DREZ) lesion procedures to treat chronic deafferentation pain. We found a significant correlation between transient latency shifts (recovery to prelesion values in the postlesioning period) of the first positive peak of the SEP (P1) during lesion production and the patients' subsequent postoperative neurological status (p less than 0.01). Transient increases in P1 latency above 2 ms were associated with detectable but transient postoperative sensorimotor deficits that resolved weeks to months after surgery. In 1 patient, the intraoperative P1 latency failed to return to baseline values; this patient had irreversible postoperative sensorimotor dysfunction. In 9 patients, we confirmed the value of recording bilateral SEP, using the contralateral side of the spinal cord (with no lesions) as a control. This experience has resulted in an improved SEP monitoring strategy: we now reconsider the risk-benefit ratio of additional DREZ lesions if early lesion production results in increased P1 latency. Rapid normalization of the P1 latency indicates that any postoperative deficits likely will resolve. Failure of P1 latency to return to control levels during the surgical wound closure period (approximately 1 h) indicates the high probability of permanent neurological deficits.

The role of norepinephrine in adult rat somatosensory (SmI) cortical metabolism and plasticity

Stimulation of rat facial vibrissae increases glucose utilization in the corresponding barrels (lamina IV) and associated columns in laminae I–VIa of the contralateral first somatosensory (SmI) cortex as assessed autoradiographically by the uptake of [ 14C]2-deoxyglucose (2-DG). Chronic deafferentation (2 months) by bilateral vibrissectomy with sparing of the C3 vibrissa (SC3) in adult Sprague-Dawley rats produced no change in the rate of LCGU but led to an increased areal extent of the metabolic representation of the SC3 barrel (39%, P < 0.001) and column (31%, P < 0.003) as compared to rats with fully intact vibrissae. In other rats with intact facial vibrissae, 6-hydroxydopamine lesions of the locus coeruleus (LC) depleted ipsilateral cortical norepinephrine (NE) by more than 90% and, 2 months later, led to an 11% and 21% increase in C3 barrel and column metabolic representations, respectively, as compared to the contralateral SmI cortex with intact NE levels ( P < 0.05). When bilateral vibrissectomy was combined with a unilateral LC lesion, the SC3 barrel and column metabolic representation on the LC-intact side enlarged as expected but no enlargement occurred on the NE-depleted side (20% difference; P < 0.05). Therefore, the effect of NE on the SmI cortex depends on the status of its afferent input. NE inhibits the spread of metabolic activity beyond the activated barrel and column in the intact cortex, but independently modulates plastic enlargement in the partially deafterented SmI cortex.

Dorsal root entry zone lesions for conus medullaris root avulsions.

We have found dorsal root entry zone (DREZ) lesions to be an effective treatment of chronic deafferentation pain in patients who have had avulsions of the dorsal rootlets from the spinal cord. Eight patients were operated in whom chronic pain of the lower extremity resulted from dorsal root avulsions from the conus medullaris. In 7 of the 8 patients, the mechanism of injury was a motor vehicle accident; all 7 sustained severe pelvic trauma. Seven of the 8 patients remained pain-free, off all narcotics, with an average follow-up of 33 months. All patients had DREZ lesions of the conus performed by radiofrequency techniques.

Lateral excitation in the cat lateral geniculate nucleus.

Visual responses were elicited by global phase reversal stimuli in cells of the cat dorsal lateral geniculate nucleus (dLGN) after small retinal lesions had been centered on each receptive field. After acute lesions of different sizes exclusively lateral inhibition was found. When GABAergic inhibition was blocked by continuous microiontophoretic application of bicuculline lateral excitation emerged in dLGN cells partially deafferented by small and medium size acute retinal lesions, but not in those affected by large lesions. This indicates the presence of excitatory retinal inputs at the periphery of the dLGN cell dendrites which are normally suppressed by strong, long-ranging lateral inhibitory processes. After chronic deafferentation, the remaining excitatory inputs increase in effectiveness and lateral excitation is seen without blockade of inhibition. The maximal lateral spread of excitation (300 micron) in the dLGN is distinctly smaller than the extent of lateral inhibition (1000 micron).

Electrophysiological effects of paraoxon on the giant interneurons in the American cockroach, Periplaneta americana

Effects of the organophosphate insecticide, paraoxon, on the ventral grant interneurons of the American cockroach ( Periplaneta americana) were studied by using intracellular microelectrodes. Within 5 min after paraoxon treatment, the efficacy of transmission at the cercal-to-giant interneuron synapse was markedly reduced or blocked, and alternating waves of depolarization and repolarization were initiated in the giant interneurons. Superimposed on these waves were high-frequency bursts of overshooting and nonovershooting spikes. Comparisons of paraoxon-induced activity in the cell body and at sites along the axon of the giant interneurons indicated that the cyclical waves, as well as high-frequency spikes, originated in the sixth abdominal ganglion rather than at more anterior sites. The effects of paraoxon were not mimicked by the application of exogenous acetylcholine, the latter causing a sustained depolarization and repetitive spiking of giant interneurons but not cyclical bursting or alternations in membrane potential. Although the precise origin of the paraoxon-induced activity is not known, several lines of evidence (e.g., results from chronic deafferentation experiments) suggest that cholinergic inputs from cercal afferent fibers are not involved in initiating the bursting.