Toshikatsu Yokota

Inhibitory effect of oxcarbazepine on high-frequency firing in peripheral nerve fibers.

We assessed the effects of oxcarbazepine, an antiepileptic derivative of carbamazepine, on discharges in single cutaneous afferent fibers produced by repetitive high-frequency stimulation (mimicking the abnormal excitation of peripheral nerves in neuropathic pain and paresthesia). After intravenous administration of oxcarbazepine, the later responses in the train dropped out without the earlier ones being affected and, thus, the total number of spikes decreased. The latency of the responses to an individual pulse was unchanged. These results, which indicate that oxcarbazepine inhibits the generation of high-frequency firing without affecting impulse conduction, suggest that this drug may be useful against neuropathic pain and paresthesia.

Computer-assisted infrared thermographic study of axon reflex induced by intradermal melittin

Abstract The aim of the present study was to investigate whether melittin, the principal toxin of the honeybee (Apis mellifera) venom, can be used as an algogenic agent in the study of pain in humans. Five micrograms of melittin in 0.5 ml of saline was intradermally injected into the volar aspect of the forearm. Resultant pain was scored by a visual analogue scale (VAS), and skin temperature change was analyzed by means of a computer‐assisted infrared thermography. Intradermal melittin temporarily produced severe pain, followed by a sustained increase in skin temperature. The skin temperature increase peaked in about 10 min and outlasted 1 h. Topical application of 10% lidocaine gel did not significantly suppress the melittin‐induced pain, but markedly suppressed both the increase in the peak temperature and the area of temperature increase. In conclusion, 5 &mgr;g of melittin is sufficient to produce pain in humans and 10% lidocaine gel differentially decreases the melittin‐induced axon reflex without any significant analgesic effect.

Biphasic vasomotor reflex responses of the hand skin following intradermal injection of melittin into the forearm skin

Melittin is the main toxin of honeybee venom. Previously, we have reported that intradermal injection of melittin into the volar aspect of forearm in humans produces a temporary pain and a subsequent sustained increase in the skin temperature due to axon reflex. To clarify the interaction between nociceptive inputs and vascular changes, we studied the influence of noxious stimulation by intradermal melittin on the vasomotor control of the distal extremities in human volunteers. Temperature changes of the bilateral palmar surface were recorded by means of a computer‐assisted infrared thermography. Unexpectedly, we found a biphasic response of skin temperature. The skin temperature of both fingers and hands decreased immediately after the melittin injection and then increased well above the control level, prior to the injection. There was a considerable individual variation in the baseline skin temperature, prior to melittin. The skin temperature in a finger/hand with lower preinjection value increased more markedly in the second phase. Consequently, the individual variation in the peak temperature of the second phase was less pronounced. The initial decrease was interpreted as sympathetic vasoconstrictor reflex induced by noxious stimulation and the later increase as release of sympathetic vasomotor tone.

Activation of ascending antinociceptive system by vagal afferent input as revealed in the nucleus ventralis posteromedialis

Thalamic nociceptive neurons receiving afferent input from the tooth pulp (TP) were recorded from the nucleus ventralis posteromedialis proper (VPM) in cats anesthetized with urethane and chloralose. Effects of cervical vagus nerve stimulation on responses of TP neurons in the VPM were investigated. Twenty-one tooth pulp specific (TPS) and eight wide dynamic range (WDR) neurons with TP input were obtained from the periphery (shell region) of the posterior half of the VPM. Of these, many were also excited by electrical stimulation of trigeminothalamic tract (TTT) fibers in the trigeminal medial lemniscus. A conditioning-test paradigm was used to examine effects of vagal stimulation on responses of VPM neurons to electrical stimulation of TP and TTT. Inhibition of the responses was observed in 12 TPS and seven WDR neurons. Local anesthetic block of the mesencephalic periaqueductal gray (PAG) and/or nucleus raphe dorsalis (NRD) eliminated the inhibitory effects of vagal stimulation on the responses of both classes of TP neurons to TTT stimulation. In contrast, the inhibitory effects on responses to TP stimulation were insignificantly affected. These data suggest that vagal afferents can activate the ascending antinociceptive pathway from PAG/NRD onto VPM, in addition to activating the descending antinociceptive system acting upon the lower brain stem.

Does intravenous administration of GABAA receptor antagonists induce both descending antinociception and touch-evoked allodynia?

&NA; Effects of intravenous administration of picrotoxin (PTX), a GABAA receptor antagonist, upon activities of wide dynamic range (WDR) neurons in the lumbar spinal cord were studied in urethane–chloralose anesthetized cats. Intravenous PTX augmented tactile evoked responses of WDR neurons, but reduced nociceptive responses dose‐dependently. Spinal transection reversed the suppression of nociceptive responses. In the spinal cat, intravenous PTX enhanced the tactile evoked response. Intravenous PTX enhanced the spontaneous firing of nucleus raphe dorsalis (NRD) and/or ventral periaqueductal gray (PAG) neurons projecting to nucleus raphe magnus. Lidocaine injected into NRD/PAG reversed the antinociceptive action of intravenous PTX. PTX injected into NRD/PAG reduced heat‐evoked responses of WDR units. These data suggest that antinociceptive effects of intravenous PTX is primarily due to disinhibitory activation of the descending antinociceptive system originating from NRD and PAG, and that PTX reinforces touch‐evoked responses in the spinal cord.

Distribution of nociceptive neurons in the ventrobasal complex of macaque thalamus

In urethane-chloralose anesthetized Japanese macaques, the distribution of nociceptive neurons within the thalamic ventrobasal (VB) complex was studied. Nociceptive specific (NS) and wide dynamic range (WDR) neurons were found in the periphery of the contralateral integument compartment of the VB complex. Thus, they formed a shell at the perimeter of this compartment with a somatotopic organization. The compartment consisted of large parts of nucleus ventralis posteromedialis (VPM) and nucleus ventralis posterolateralis, pars caudalis (VPLc). NS neurons were located more caudally than WDR neurons. In the NS zone of VPM, the forehead was represented caudally, and oral structures rostrally. In the ventral NS zone of VPM, there was a sequential representation of the tongue, gum and mandibular skin from the medial to the lateral edge. The hand was represented medially in the NS zone of VPLc, and its representation dominated in the rostral NS zone. There was a sequential representation of the cervical, thoracic, lumbar, sacral and caudal segments mediolaterally along the dorsal VPLc. In the medial half of ventral NS zone of VPLc, the upper body half was represented, and in the lateral half, the lower body half. The foot was represented at or near the medial edge of lateral half. In the rostral WDR zone, the trunk and peripheral face were represented.

Electrophysiological study of dorsal column function in streptozocin-induced diabetic rats: comparison with 2,5-hexanedione intoxication.

Dorsal column function and peripheral motor and sensory conduction velocities (MCV, SCV) were evaluated in experimental diabetic rats and compared with those in 2,5-hexanedione (2,5-HD) intoxicated rats. Hyperglycemia was induced by a single injection of streptozocin, and electrophysiological studies were performed 4 and 12 weeks after the injection. For 8 weeks 2,5-HD was administered daily by drinking water to make the 2,5-HD neuropathy rats. Age-matched rats were used as control. In diabetic rats, gracile surface potentials evoked by electrical stimulation of the lumbosacral trunk remained normal during the experimental period, whereas the N and P waves of the evoked potentials were suppressed and the duration of the N wave was prolonged in the 2,5-HD rats. In 4-week diabetic rats, the antidromic compound action potentials of the gracile tract recorded at the most proximal site of lumbosacral trunk were normal. In 12-week diabetic rats, the gracile tract conduction velocity (GTCV) was decreased, although the duration of these potentials was normal. By contrast, the GTCV was decreased and the duration was markedly prolonged in 2,5-HD rats. These findings might indicate that temporal dispersion of incoming volleys in the gracile tract is increased in 2,5-HD rats, but not in diabetic rats. These results suggest that diabetic myelopathy exists that but the magnitude and progression of this condition are quite different from those of 2,5-HD intoxication, typical dying-back-type neuropathy and that the dorsal column is less vulnerable than the peripheral nerve in diabetes mellitus.

Non-serotonergic midbrain neurons are involved in picrotoxin-induced analgesia. An immunohistochemical study in the rat

Intravenous picrotoxin inhibits spinal nociceptive neurons through disinhibitory activation of neurons in the periaqueductal gray (PAG) and nucleus raphe dorsalis (NRD), where the descending antinociceptive system arises. We found Fos-like immunoreactivity in PAG/NRD neurons after intravenous injection of picrotoxin. This distribution of c-Fos expression is consistent with a role of PAG/NRD for antinociception; neurons with intense Fos-like immunoreactivity was also clustered in the Edinger-Westphal nucleus (EW). Double fluorescence immunohistochemistry for c-Fos and serotonin revealed that PAG/NRD/EW neurons expressing c-Fos were non-serotonergic. These data suggest that non-serotonergic PAG/NRD/EW neurons are involved in the picrotoxin-induced analgesia.

Trigeminal nociceptive neurons in the intalaminar nuclei of the cat thalamus

. r. r AIM OF INVESTIGATION: In order to understand functional signirlcance or trigeminal nociceptive neurons in the intralaminar nuclei, their response characteristics were studied in the cat. Furthermore, it was attempted to identify neurons relaying trigeminal nociceptive input to the intralaminar nuclei and inhibition of synaptic transmission in nociceptive neurons of the intralaminar nuclei were examined following electrical stimulation of the nucleus raphe magnus (NRM) or of the periagueducal grey (PAG). METHODS: Experiments were carried out on cats anesthetized with urethane and chloralose. Single unit activities were recorded from the thalamus using glass capillary microelectrodes filled. with 2% pontamine sky blue in 1 M sodium acetate. RESULTS: Trigeminal nociceptive neurons were found in the nuclei centralis lateralis, paracentralis, centralis medialis, parafascicularis and subparafascicularis. They had a bilateral receptive field on the head. In addition, most of them were activated by noxious stimulation of the spinal nerve territory and by visceral sympathetic afferents. Following electrical stimulation of contralateral nucleus centralis lateralis , a majority of trigeminal nociceptive neurons in the dorsolateral part of the subnucleus reticularis ventralis of the caudal medulla oblongata were antidromically activated, suggesting that these nociceptive neurons relay trigeminal nociceptive input to the nucleus centralis lateralis. Responses of trigeminal nociceptive neurons in the intralaminar nuclei were inhibited following electrical stimulation of either the NRM or the PAG. CONCLUSION: Trigeminal nociceptive neurons were found in the intralaminar nuclei and their characteristics were clarified.