Responses Of Spinothalamic Tract Cells Research Articles

Memantine attenuates responses of spinothalamic tract cells to cutaneous stimulation in neuropathic monkeys

Several lines of evidence indicate that N-methyl-D-aspartate (NMDA) receptors play an important role in nociception in general and in pathological pain in particular. It has been previously demonstrated in behavioral studies that NMDA receptor antagonists attenuate pathological pain in humans and nociceptive behaviors in animals. In the present study, we investigated the effect of the NMDA receptor antagonist memantine (MEM) on the responses of spinothalamic tract (STT) cells in normal and neuropathic monkeys. Memantine was delivered into the spinal cord through a microdialysis fiber acutely implanted into the dorsal horn. Responses of STT cells to peripheral stimulation within their receptive fields were recorded before and after MEM infusion. In normal animals ( n = 7), 10 mm MEM did not affect STT cell ( n = 7) baseline activity or responses to mechanical stimuli (brush, press or pinch). In neuropathic animals ( n = 6), 1.0, 3.0, 10.0 and 100 mm MEM did not affect baseline activity of STT cells ( n = 7); however, in a dose-dependent fashion, it significantly reduced responses of these cells to all cutaneous stimuli. The data suggest that MEM can have a direct effect on STT cells, blocking NMDA receptors known to be present on this cell population and, furthermore, may be a therapeutic agent for chronic pain.

Dextrorphan attenuates responses of spinothalamic tract cells in normal and nerve-injured monkeys

Spinal cord N-methyl- d-aspartate (NMDA) receptors play an important role in the transmission of acute and chronic pain. The present study investigated the ability of dextrorphan (DEX), a metabolite of dextromethorphan and a clinically safe NMDA antagonist, to attenuate the responses of nociceptive spinothalamic tract (STT) neurons in anesthetized monkeys. The STT cells were recorded extracellularly in the lumbosacral enlargement and were identified by antidromic activation from the ventral posterior lateral thalamic nucleus. DEX administered through a microdialysis fiber inserted into the dorsal horn inhibited the responses of STT cells in normal animals to noxious pinch and heat stimuli. In monkeys made neuropathic by tight ligation of the L7 or S1 spinal nerve, DEX significantly attenuated the responses of STT cells to noxious pinch and heat, as well as to innocuous brushing, pressure and von Frey filament stimuli. These findings strongly suggest that DEX should be considered a potentially useful therapeutic agent for the treatment of neuropathic pain in humans.

Behavioral manifestations of an experimental model for peripheral neuropathy produced by spinal nerve ligation in the primate

A goal of the present study was to document the behavioral changes observed in a model of painful neuropathy in the primate ( Macaca fascicularis). A neuropathic state was induced by tight ligation of the L7 spinal nerve, just distal to the L7 dorsal root ganglion. Sensory testing was done on the ventral surface of the foot, a region that includes the L7 dermatome. Within 1 week following surgery, all monkeys ( n = 3) developed a marked sensitivity to mechanical stimulation (with a camel hair brush and von Frey hairs), indicating the presence of mechanical allodynia. In 2 animals, the increased sensitivity to mechanical stimulation was also observed on the contralateral side. The threshold for withdrawal to a heat stimulus decreased, indicating the presence of heat hyperalgesia. Presentation of various cooling stimuli, such as acetone and cold water baths, suggested that cold allodynia had also developed. These behavioral phenomena are similar to those seen in humans diagnosed with peripheral neuropathic pain. The behavioral abnormalities are discussed in relation to the responses of spinothalamic tract cells recorded from primates with the same peripheral nerve injury (Palecek et al. 1992).

Responses of spinothalamic tract cells to mechanical and thermal stimulation of skin in rats with experimental peripheral neuropathy.

1. Responses of spinothalamic tract (STT) neurons to mechanical and thermal stimulation of skin were recorded under urethane and pentobarbital anesthesia in 12 control rats and in 20 rats with experimental neuropathy. Activity of the STT cells in neuropathic rats was recorded 7, 14, and 28 days after inducing the neuropathy by placing four loose ligatures on the sciatic nerve. 2. All neuropathic animals showed guarding of the injured hindpaw and a shorter withdrawal latency from a radiant heat source of the neuropathic hindpaw than that of the sham-operated paw. 3. STT neurons in neuropathic animals showed the most profound changes 7 and 14 days after the nerve ligation. When compared with STT cells in unoperated animals, approximately half of the neurons had high background activity, responses to innocuous stimuli represented a larger percentage of the total evoked activity in wide dynamic range neurons, and the occurrence and magnitude of afterdischarges to mechanical and thermal stimuli were increased. 4. The mean threshold temperatures of heat-evoked responses of the STT cells in neuropathic animals were not different than those of cells from control animals. However, in neuropathic rats, cells reacting to small heat stimuli usually already had afterdischarges. 5. The increase in the background activity of STT cells is consistent with behavioral observations of spontaneous pain in this model of experimental neuropathy. Furthermore, the afterdischarges of STT cells may parallel the prolonged paw withdrawal in response to noxious stimuli that is seen in these animals and that is evidence for hyperalgesia. However, there was no indication of a lowered threshold for thermal stimuli as might be expected if the animals have thermal allodynia. Mechanical allodynia may have resulted from a relative increase in responsiveness to innocuous mechanical stimuli. However, responses to noxious mechanical stimuli were reduced compared with control, at least at 28 days after the ligation. Peripheral and central mechanisms responsible for the changes in responses of STT cells in neuropathic animals are suggested.

Responses of spinothalamic tract cells in the superficial dorsal horn of the primate lumbar spinal cord.

1. The responses of thirty-five spinothalamic tract (s.t.t.) cells in or near lamina I of the dorsal horn were examined in chloralose- and barbiturate-anaesthetized monkeys (Macaca fascicularis). Many of the cells could be classified on the basis of receptive field properties as either wide dynamic range (w.d.r.) cells or as high-threshold (h.t.) cells. 2. Thalamic stimulation sites for antidromic activation of the s.t.t. cells were in or around the ventral posterior lateral nucleus. Axons of the s.t.t. cells had a mean conduction velocity of 17 m/s (33 and 14 m/s for w.d.r. and h.t. cells, respectively). Mean minimum afferent conduction velocity averaged 37 m/s (52 and 23 m/s for w.d.r. and h.t. cells, respectively). Background activity was low (mean of 2.3 impulses/s). 3. An alternative classification of the cells was based on a kappa means cluster analysis of the responses to a series of mechanical stimuli. The response profiles for a given cell were normalized, and those of the s.t.t. cells in or near lamina I were analysed along with the responses of a population of s.t.t. cells, largely in laminae IV-VI, that had been described previously. S.t.t. cells in or near lamina I were distributed amongst three of the four groups of cells determined by the cluster analysis (types 2-4). 4. Vibratory stimuli excited most of the w.d.r. but none of the h.t. cells tested. Best frequencies were 5-10 Hz (at 100 and 500 microns indentations). 5. Most w.d.r. but few h.t. cells responded to cutaneous cooling. All of the cells responded to noxious heating, but w.d.r. cells had steeper stimulus-response curves. 6. After a series of noxious heat stimuli, the thresholds for noxious heat were lowered and responses to lower-intensity noxious heat stimuli were enhanced (sensitization). However, responses to more intense stimuli were reduced (inactivation). Similar changes were seen in the responses to graded mechanical stimuli. 7. It is concluded that s.t.t. cells in or near lamina I can signal noxious cutaneous stimuli but have poor coding abilities for innocuous mechanical stimuli. Some of these cells respond to innocuous thermal stimuli, but their role in thermoreception is unclear. The small receptive fields suggest that these cells could contribute to stimulus localization.

Responses of spinothalamic tract cells in the cat cervical spinal cord to innocuous and graded noxious stimuli.

The response properties of spinothalamic tract (STT) cells in the dorsal horn of the cervical spinal cord were examined in chloralose-anesthetized cats. The activity of 56 STT cells located in laminae IV-VI was studied, with most activity isolated in the lateral part of the dorsal horn. The level of background activity in STT cells was low (mean = 1.2 impulses/sec; n = 26). Conduction velocity estimates for STT axons ranged from 9 to 76 m/sec (mean = 38 m/sec; n = 56) and were not correlated with the recording site in the spinal cord. Most cells were antidromically activated from an electrode in the medial part of the posterior group of nuclei in the thalamus. Excitatory receptive fields were ipsilateral to the recording site, and for 38 of 40 neurons were confined to the forelimb. Although receptive fields were often restricted to part of the paw, they did not include glabrous skin. Among 31 cells classified, four groups were identified: low-threshold (LT) cells (13%) responded to pressure and brushing of the skin; high-threshold (HT) cells (13%) responded only to noxious pinching or squeezing of the skin; wide-dynamic-range (WDR) cells (58%) responded to innocuous mechanical stimuli but had a greater response to noxious stimuli; deep (D) cells (16%) responded to manipulation of subcutaneous tissues such as muscle. Heat stimuli 30 sec in duration, in the range of 43-55 degrees C, were applied to the receptive fields of 14 neurons that included representatives from all three groups with cutaneous input. Nine neurons responded to heat with thresholds that ranged from 47 degrees to 55 degrees C (mean = 51 degrees C). The responses of these nine STT cells increased with increasing stimulus intensity in the noxious range. In the cat cervical dorsal horn, STT cells can signal the occurrence of noxious stimuli on the body surface, and, judging by the sizes of their peripheral receptive fields, are capable of signaling precise information about the location of the damage. Furthermore, some cells are able to signal the intensity of a noxious heating pulse.

Responses of spinothalamic tract cells in the thoracic spinal cord of the monkey to cutaneous and visceral inputs.

Somatovisceral convergence was demonstrated in recordings from 15 of 16 spinothalamic tract cells in the lower thoracic spinal cords of anesthetized monkeys. Inputs were produced by mechanical (or sometimes electrical) stimulation of the skin over the lower trunk and by electrical stimulation of the greater splanchnic nerve through a buried electrode. The volley in the greater splanchnic nerve was monitored using a buried electrode on the sympathetic chain. Spinothalamic tract cells could be excited by activity in A delta and C fibers, but no effects produced by A beta fibers were noted. In some cases inhibitory effects were observed due to movement of hair on the trunk, and inhibitory interactions could be demonstrated between cutaneous and visceral afferent volleys.

Excitation of primate spinothalamic neurons by cutaneous C-fiber volleys.

1. The responses of spinothalamic tract cells in the lumbosacral spinal cords of anesthetized monkeys were examined following electrical stimulation of the sural nerve or the application of noxious thermal and mechanical stimuli to the skin on the lateral aspect of the foot. 2. The spinothalamic tract neurons were classified as wide dynamic range (WDR), high-threshold (HT), or low-threshold (LT) cells on the basis of their responses to mechanical stimuli. 3. All of the WDR and HT spinothalamic tract cells tested responded to volleys in A- and C-fibers. However, strong C-fiber responses were more common in HT than in WDR cells. 4. The responses atributed to C-fibers were graded with the size of the C-fiber volley. The latencies of the responses attributed to C-fibers indicated that the fastest afferents involved had a mean conduction velocity of 0.9 m/s. The responses remained after anodal blockade of conduction in A-fibers. 5. Temporal summation of the responses of spinothalamic tract cells was demonstrated both to brief trains of stimuli at 33 Hz and to single stimuli repeated at 1- to 2-s intervals. The latter phenomenon is often called "windup." 6. The responses of several spinothalamic tract cells to noxious heat pulses could still be elicited during anodal blockade of conduction in A-fibers. Similarly, it was possible to demonstrate an excitatory action of noxious mechanical stimuli despite interference with conduction in A-fibers by anodal current. 7. The cells investigated were located either in the marginal zone or in the layers of the dorsal horn equivalent to Rexed's laminae IV-VI in the cat. The cells were generally activated antidromically from the caudal part of the ventral posterior lateral nucleus of the thalamus.

Effects of dorsal column stimulation on primate spinothalamic tract neurons.

The effect of dorsal column stimulation on spinothalamic tract cells was investigated in anesthetized monkeys. The dorsal column stimuli were applied at midthoracic or at cervical levels of the cord, while the responses of spinothalamic tract cells of the lumbosacral enlargement were examined. A dorsal column volley depressed the activity of spinothalamic tract cells for about 150 ms. A similar depression was observed whether the spinothalamic tract cell was classified as hair activated, low, or high threshold, based on its response properties to cutaneous stimulation. The hair-activated and low-threshold spinothalamic tract cells were initially excited by the dorsal column volley, but often it was possible to demonstrate that a depression could be produced by stimuli which were too weak to cause excitation of these cells. Depression was produced both of the responses of spinothalamic tract cells to electrical stimulation of peripheral nerves and to mechanical stimulation of cutaneous nociceptors. A similar depression was produced by electrical stimulation of large afferents in peripheral nerves. The pathway mediating the depression of spinothalamic tract cells was shown to involve antidromic invasion of collaterals of dorsal column fibers. The best points for stimulation of the cord to produce a depression were over the ipsilateral dorsal column. A lesion interrupting the dorsal column eliminated the depression of cells below the lesion, whereas a lesion of much of the lateral column had no effect. The mechanism of the depression is likely to be complex. Apart from interactions at an interneuronal level, dorsal column volleys can be presumed to collide with sensory input from afferents which project up the dorsal column; collision would interfere chiefly with the responses of hair-activated and low-threshold spinothalamic tract cells. In addition, dorsal column volleys were shown to evoke inhibitory postsynaptic potentials in some spinothalamic tract neurons, and they also produced primary afferent depolarization, at least of large cutaneous afferemts. The excitation of hair-activated and low-threshold spinothalamic tract cells argues against their participation in signaling pain, since dorsal column stimulation in humans does not produce pain at stimulus intensities and frequencies which should activate such neurons. Alternatively, an ascending volley in the dorsal column or in other pathways may interfere with pain transmission in the brain.