Effect of carbamazepine and gabapentin on excitability in the trigeminal subnucleus caudalis of neonatal rats using a voltage-sensitive dye imaging technique.

BACKGROUND: The antiepileptic drugs carbamazepine and gabapentin are effective in treating neuropathic pain and trigeminal neuralgia. In the present study, to analyze the effects of carbamazepine and gabapentin on neuronal excitation in the spinal trigeminal subnucleus caudalis (Sp5c) in the medulla oblongata, we recorded temporal changes in nociceptive afferent activity in the Sp5c of trigeminal nerve-attached brainstem slices of neonatal rats using a voltage-sensitive dye imaging technique. RESULTS: Electrical stimulation of the trigeminal nerve rootlet evoked changes in the fluorescence intensity of dye in the Sp5c. The optical signals were composed of two phases, a fast component with a sharp peak followed by a long-lasting component with a period of more than 500 ms. This evoked excitation was not influenced by administration of carbamazepine (10, 100 and 1,000 µM) or gabapentin (1 and 10 µM), but was increased by administration of 100 µM gabapentin. This evoked excitation was increased further in low Mg(2+) (0.8 mM) conditions, and this effect of low Mg(2+) concentration was antagonized by 30 µM DL-2-amino-5-phosphonopentanoic acid (AP5), a N-methyl-D-aspartate (NMDA) receptor blocker. The increased excitation in low Mg(2+) conditions was also antagonized by carbamazepine (1,000 µM) and gabapentin (100 µM). CONCLUSION: Carbamazepine and gabapentin did not decrease electrically evoked excitation in the Sp5c in control conditions. Further excitation in low Mg(2+) conditions was antagonized by the NMDA receptor blocker AP5. Carbamazepine and gabapentin had similar effects to AP5 on evoked excitation in the Sp5c in low Mg(2+) conditions. Thus, we concluded that carbamazepine and gabapentin may act by blocking NMDA receptors in the Sp5c, which contributes to its anti-hypersensitivity in neuropathic pain.

Contralateral and Ipsilateral Interactions in the Somatosensory Pathway in Healthy Humans.

Hyper-adaptability, the ability to adapt to changes in the internal environment caused by neurological disorders, is necessary to recover from various disabilities, such as motor paralysis and sensory impairment. In the recovery from motor paralysis, the pre-existing neural pathway of the ipsilateral descending pathway, which is normally suppressed and preserved in the course of development, is activated to contribute to the motor control of the paretic limb. Conversely, in sensory pathways, it remains unclear whether there are compensatory pathways which are beneficial for the recovery of sensory impairment due to damaged unilateral somatosensory pathways, such as thalamic hemorrhage. Here, we investigated the interaction between the left and right somatosensory pathways in healthy humans using paired median nerve somatosensory evoked potentials (SEPs). Paired median nerve SEPs were recorded at CP3 and CP4 with a reference of Fz in the International 10-20 System. The paired median nerve stimulation with different interstimulus intervals (ISIs; 1, 2, 3, 5, 10, 20, 40, 60, and 100 ms) was performed to test the influence of the first stimulus (to the right median nerve) on the P14, P14/N20, and N20/P25 components induced by the second stimulus (left side). Results showed that the first stimulation had no effect on SEP amplitudes (P14, P14/N20, and N20/P25) evoked by the second stimulation in all ISI conditions, suggesting that there might not be a neural connectivity formed by a small number of synapses in the left-right interaction of the somatosensory pathway. Additionally, the somatosensory pathway may be less diverse in healthy participants.

Interaction of the Left-Right Somatosensory Pathways in Patients With Thalamic Hemorrhage: A Case Report.

Neural plasticity compensates for the loss of motor function after stroke. However, whether neural plasticity occurs in the somatosensory pathways after stroke is unknown. We investigated the left-right somatosensory interaction in two hemorrhagic patients using a paired somatosensory evoked potentials (p-SEPs) recorded at CP3 and CP4, which was defined as an amplitude difference between the SEPs of paired median nerve stimulations to both sides and that of single stimulation to the affected side. Patient 1 (61-year-old, left thalamic hemorrhage) has a moderate motor impairment, severe sensory deficit, and complained of pain in the affected right upper limb. Patient 2 (72-year-old, right thalamic hemorrhage) had slight motor and sensory impairments with no complaints of pain. Single SEPs (s-SEPs) were obtained by stimulation of the right and left median nerves, respectively. For paired stimulations, 1 ms after the first stimulation to the non-affected side, followed by a second stimulation to the affected side. In patient 1, a s-SEP with stimulation to the non-affected side and a p-SEP were observed in CP4. However, a s-SEP was not observed in either hemisphere with stimulation to the affected side. On the other hand, in patient 2, a s-SEP in CP3 with stimulation to the non-affected side and in CP4 with stimulation to the affected side were observed; however, a p-SEP was not observed. In addition, to investigate the mechanism by which ipsilateral median nerve stimulation enhances contralateral p-SEP in patient 1, we compared the SEP averaged over the first 250 epochs with the SEP averaged over the second 250 epochs (total number of epochs recorded: 500). The results showed that in the patient 1, when the bilateral median nerve was stimulated continuously, the habituation did not occur and the response was larger than that of the s-SEP with unilateral median nerve stimulation. In the current case report, the damage to the thalamus may cause neuroplasticity in terms of the left-right interaction (e.g., left and right S1). The somatosensory input from the affected side may interfere with the habituation of the contralateral somatosensory system and conversely increase the response.

Learning signals from the superior colliculus for adaptation of saccadic eye movements in the monkey.

Vital to motor learning is information about movement error. Using this information, the brain creates neural learning signals that instruct a plasticity mechanism to produce appropriate behavioral learning. Little is known, however, about brain structures that generate learning signals for voluntary movements. Here we show that signals from the superior colliculus (SC) can drive learning in saccadic eye movements in the monkey. Electrical stimulation of the SC deeper layers, subthreshold for evoking saccades, was applied immediately (approximately 60 ms) after the end of horizontal saccades in one or both directions. The target disappeared during saccades and remained invisible for 1 s to eliminate effects of postsaccadic visual information. Repetitive pairing of saccades with SC stimulation produced a marked, two-dimensional shift in movement endpoint relative to the target location. The elicited endpoint shift took a gradual, approximately exponential course over several hundred saccades as in visually induced saccade adaptation. The shift in movement endpoint remained nearly unchanged after stimulation was discontinued, indicating involvement of neuronal plasticity. When both rightward and leftward saccades were paired with stimulation, their endpoints shifted in similar directions. The endpoint shift was directed contralaterally to the stimulated SC. The direction and size of the endpoint shift depended on the stimulation site in the SC. We propose that the SC, a brainstem structure long known to be crucial for saccade execution, is involved in motor learning and sends signals that dictate the direction of adaptive shift in saccade endpoint.

Saccade adaptation as a model of learning in voluntary movements.

Motor learning ensures the accuracy of our daily movements. However, we know relatively little about its mechanisms, particularly for voluntary movements. Saccadic eye movements serve to bring the image of a visual target precisely onto the fovea. Their accuracy is maintained not by on-line sensory feedback but by a learning mechanism, called saccade adaptation. Recent studies on saccade adaptation have provided valuable additions to our knowledge of motor learning. This review summarizes what we know about the characteristics and neural mechanisms of saccade adaptation, emphasizing recent findings and new ideas. Long-term adaptation, distinct from its short-term counterpart, seems to be present in the saccadic system. Accumulating evidence indicates the involvement of the oculomotor cerebellar vermis as a learning site. The superior colliculus is now suggested not only to generate saccade commands but also to issue driving signals for motor learning. These and other significant contributions have advanced our understanding of saccade adaptation and motor learning in general.

Laudanosine has no effects on respiratory activity but induces non-respiratory excitement activity in isolated brainstem-spinal cord preparation of neonatal rats.

Laudanosine, a degradation of neuomuscular blocking agent atracurium, crosses the blood-brain barrier and is indicted to trigger seizures at high concentration. In Xenopus Oocytes expressing nicotinic acetylcholine receptors (nAChRs), laudanosine has activating and inhibiting effects on nAChRs depending on its concentration. nAChRs is related to respiratory activities and thus, in the present study, we analyzed effects of laudanosine on central respiratory activities using isolated brainstem-spinal cord preparation of neonatal rats. The rhythmic inspiratory burst activity of the C4 spinal ventral root was recorded using a glass suction electrode as an index of respiratory rate. After superfusion with mock cerebrospinal fluid (CSF), the preparation was superfused with mock CSF containing laudanosine 1, 10 or 100 microM for 60 minutes. Laudanosine 1, 10 and 100 microM (n = 10 in each) did not induce any effects on C4 respiratory rate. In all 10 preparations, laudnosine 100 microM induced non-respiratory excitement activities that are possibly same as seizure observed in vivo study.

Orexin-B antagonized respiratory depression induced by sevoflurane, propofol, and remifentanil in isolated brainstem-spinal cords of neonatal rats.

Orexins (hypocretins) play a crucial role in arousal, feeding, and endocrine function. We previously reported that orexin-B activated respiratory neurons in the isolated brainstem-spinal cords of neonatal rats. We herein determined whether orexin-B antagonized respiratory depression induced by sevoflurane, propofol, or remifentanil. We recorded C4 nerve bursts as an index of inspiratory activity in a brainstem-spinal cord preparation. The preparation was superfused with a solution equilibrated with 3% sevoflurane alone for 10 min and the superfusate was then switched to a solution containing sevoflurane plus orexin-B. Sevoflurane decreased the C4 burst rate and the integrated C4 amplitude. The C4 burst rate and amplitude were reversed by 0.5 µM orexin-B, but not by 0.1 µM orexin-B. The decrease induced in the C4 burst rate by 10 µM propofol or 0.01 µM remifentanil was significantly antagonized by 0.1 µM orexin-B. Respiratory depression induced by a higher concentration (0.1 µM) of remifentanil was not restored by 0.1 µM orexin-B. These results demonstrated that orexin-B antagonized respiratory depression induced by sevoflurane, propofol, or remifentanil.

Orexin induces excitation of respiratory neuronal network in isolated brainstem spinal cord of neonatal rat.

Endogenous neuropeptides known as orexins (hypocretins) play important roles in the regulation of feeding, drinking, endocrine function, and sleep/wakefulness. Orexin neuron projection sites include the rostral ventrolateral medulla of brainstem, which is related to the control of breathing. Previous studies suggest that orexins modulate the central CO2 ventilatory response during wakefulness in rodent. In the present study, we examined the effects of the orexinergic system on central respiratory control by adding orexin into a superfusion medium in the isolated brainstem-spinal cord of neonatal rat. Exposure to orexin B resulted in dose-dependent increases in C4 burst rate via brainstem, but not spinal cord. These increases in C4 burst rate induced concomitant increases in the depolarizing cycle rate of pre-inspiratory (Pre-I) and inspiratory (Insp) neurons. Tonic discharge was induced on C4 recording, although the rhythmic bursts of Pre-I and Insp neurons were maintained. Expiratory (Exp) neurons were also depolarized on administration of orexin B. Our findings indicate that orexin B activates central respiratory activity, mainly through depolarization and decreases in membrane resistance in Pre-I and Insp neurons, and possibly through early initiation of the expiratory phase induced by depolarization of Exp neurons.

Effect of carbamazepine and gabapentin on excitability in the trigeminal subnucleus caudalis of neonatal rats using a voltage-sensitive dye imaging technique

BACKGROUND: The antiepileptic drugs carbamazepine and gabapentin are effective in treating neuropathic pain and trigeminal neuralgia. In the present study, to analyze the effects of carbamazepine and gabapentin on neuronal excitation in the spinal trigeminal subnucleus caudalis (Sp5c) in the medulla oblongata, we recorded temporal changes in nociceptive afferent activity in the Sp5c of trigeminal nerve-attached brainstem slices of neonatal rats using a voltage-sensitive dye imaging technique. RESULTS: Electrical stimulation of the trigeminal nerve rootlet evoked changes in the fluorescence intensity of dye in the Sp5c. The optical signals were composed of two phases, a fast component with a sharp peak followed by a long-lasting component with a period of more than 500 ms. This evoked excitation was not influenced by administration of carbamazepine (10, 100 and 1,000 µM) or gabapentin (1 and 10 µM), but was increased by administration of 100 µM gabapentin. This evoked excitation was increased further in low Mg²+ (0.8 mM) conditions, and this effect of low Mg²+ concentration was antagonized by 30 µM DL-2-amino-5-phosphonopentanoic acid (AP5), a N-methyl-D-as-partate (NMDA) receptor blocker. The increased excitation in low Mg²+ conditions was also antagonized by carbamazepine (1,000 µM) and gabapentin (100 µM). CONCLUSION: Carbamazepine and gabapentin did not decrease electrically evoked excitation in the Sp5c in control conditions. Further excitation in low Mg²+ conditions was antagonized by the NMDA receptor blocker AP5. Carbamazepine and gabapentin had similar effects to AP5 on evoked excitation in the Sp5c in low Mg²+ conditions. Thus, we concluded that carbamazepine and gabapentin may act by blocking NMDA receptors in the Sp5c, which contributes to its anti-hypersensitivity in neuropathic pain.