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In the anterior lobe of the pituitary gland (AP), non-endocrine cells regulate hormone secretion by endocrine cells. However, the functions of non-endocrine cells in the AP during chronic pain are largely unclear. Here, we show that macrophages, but not folliculostellate (FS) cells, were selectively increased in the AP in the complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain model in rats. In addition, IL-1β expression was increased in the AP, and the IL-1β-immunopositive cells were identified as macrophages. On the other hand, increased macrophage density and IL-1β expression were not detected in a neuropathic pain model induced by partial sciatic nerve ligation (PSL). Furthermore, we found c-Fos expression specifically in the somatotrophs under the chronic inflammatory pain condition. Because IL-1β promotes growth hormone (GH) synthesis and release, our results suggest that AP macrophage contributes to GH release through IL-1βduring chronic inflammatory pain.

Purpose To evaluate outcomes after pituitary radiosurgery in patients with post-stroke thalamic pain syndrome. Methods and Materials From 2002 to 2006, 24 patients with thalamic pain syndrome underwent pituitary radiosurgery at Tokyo Women's Medical University and were followed at least 12 months thereafter. The radiosurgical target was defined as the pituitary gland and its connection with the pituitary stalk. The maximum dose varied from 140 to 180 Gy. Mean follow-up after treatment was 35 months (range, 12–48 months). Results Initial pain reduction, usually within 48 h after radiosurgery, was marked in 17 patients (71%). However, in the majority of cases the pain recurred within 6 months after treatment, and at the time of the last follow-up examination durable pain control was marked in only 5 patients (21%). Ten patients (42%) had treatment-associated side effects. Anterior pituitary abnormalities were marked in 8 cases and required hormonal replacement therapy in 3; transient diabetes insipidus was observed in 2 cases, transient hyponatremia in 1, and clinical deterioration due to increase of the numbness severity despite significant reduction of pain was seen once. Conclusions Pituitary radiosurgery for thalamic pain results in a high rate of initial efficacy and is accompanied by acceptable morbidity. It can be used as a primary minimally invasive management option for patients with post-stroke thalamic pain resistant to medical therapy. However, in the majority of cases pain recurrence occurs within 1 year after treatment.

In the last decade, it became clear that life-cycle cost analysis of existing civil infrastructure must be used to optimally manage the growing number of aging and deteriorating structures. The uncertainties associated with deteriorating structures require the use of probabilistic methods to properly evaluate their lifetime performance. In this paper, the deterioration and the effect of maintenance actions are analyzed considering the performance of existing structures characterized by lifetime functions. These functions allow, in a simple manner, the consideration of the effect of aging on the decrease of the probability of survival of a structure, as well as the effect of maintenance actions. Models for the effects of proactive and reactive preventive maintenance, and essential maintenance actions are presented. Since the probability of failure is different from zero during the entire service life of a deteriorating structure and depends strongly on the maintenance strategy, the cost of failure is included in this analysis. The failure of one component in a structure does not usually lead to failure of the structure and, as a result, the safety of existing structures must be analyzed using a system reliability framework. The optimization consists of minimizing the sum of the cumulative maintenance and expected failure cost during the prescribed time horizon. Two examples of application of the proposed methodology are presented. In the first example, the sum of the maintenance and failure costs of a bridge in Colorado is minimized considering essential maintenance only and a fixed minimum acceptable probability of failure. In the second example, the expected lifetime cost, including maintenance and expected failure costs, of a multi-girder bridge is minimized considering reactive preventive maintenance actions.

Object. Although reports in the literature indicate that thalamic pain syndrome can be controlled with chemical hypophysectomy, this procedure is associated with transient diabetes insipidus. It was considered reasonable to attempt gamma knife surgery (GKS) to the pituitary gland to control thalamic pain. Methods. Inclusion criteria in this study were poststroke thalamic pain, failure of all other treatments, intolerance to general anesthetic, and the main complaint of pain and not numbness. Seventeen patients met these criteria and were treated with GKS to the pituitary. The target was the pituitary gland together with the border between the pituitary stalk and the gland. The maximum dose was 140 to 180 Gy. All patients were followed for more than 3 months. Conclusions. An initial significant pain reduction was observed in 13 (76.5%) of 17 patients. Some patients experienced pain reduction within 48 hours of treatment. Persistent pain relief for more than 1 year was observed in five (38.5%) of 13 patients. Rapid recurrence of pain in fewer than 3 months was observed in four (30.8%) of 13 patients. The only complication was transient diabetes insipidus in one patient. It would seem that GKS of the pituitary might have a role to play in thalamic pain arising after a stroke.

Phospholipase C (PLC) beta4, one of the four isoforms of PLCbetas, is the sole isoform expressed in the mouse ventral posterolateral thalamic nucleus (VPL), a key station in pain processing. The mouse thalamus also has been shown to express a high level of metabotropic glutamate receptor type 1 (mGluR1), which stimulates PLCbetas through activation of Galphaq/11 protein. It is therefore expected that the thalamic mGluR1-PLCbeta4 cascade may play a functional role in nociceptive transmission. To test this hypothesis, we first studied behavioral responses to various nociceptive stimuli in PLCbeta4 knock-out mice. We performed the formalin test and found no difference in the pain behavior in the first phase of the formalin test, which is attributed to acute nociception, between PLCbeta4 knock-out and wild-type mice. Consistent with this result, acute pain responses in the hot plate and tail flick tests were also unaffected in the PLCbeta4 knock-out mice. However, the nociceptive behavior in the second phase of the formalin test, resulting from the tissue inflammation, was attenuated in PLCbeta4 knock-out mice. In the dorsal horn of the spinal cord where PLCbeta1 and PLCbeta4 mRNAs are expressed, no difference was found between the wild-type and knock-out mice in the number of Fos-like immunoreactive neurons, which represent neuronal activity in the second phase in the formalin test. Thus, it is unlikely that spinal PLCbeta4 is involved in the formalin-induced inflammatory pain. Next, we found that pretreatment with PLC inhibitors, mGluR1 antagonists, or both, by either intracerebroventricular or intrathalamic injection, attenuated the formalin-induced pain behavior in the second phase in wild-type mice. Furthermore, activation of mGluR1 at the VPL enhanced pain behavior in the second phase in the wild-type mice. In contrast, PLCbeta4 knock-out mice did not show such enhancement, indicating that mGluR1 is connected to PLCbeta4 in the VPL. Finally, in parallel with the behavioral results, we showed in an electrophysiological study that the time course of firing discharges in VPL corresponds well to that of pain behavior in the formalin test in both wild-type and PLCbeta4 knock-out mice. These findings indicate that the thalamic mGluR1-PLCbeta4 cascade is indispensable for the formalin-induced inflammatory pain by regulating the response of VPL neurons.

Brain cyclooxygenase-2 (COX-2), the rate-limiting enzyme in prostaglandin synthesis, is rapidly and transiently induced by convulsions in hippocampal and cortical neurons. Therefore, we examined the effects of COX-2 on the 'rapid kindling' development in COX-2 knockout mice and in mice treated with nimesulide, a COX-2-selective inhibitor. Rapid kindling development was examined based on the incidence of hippocampal EEG seizures and behavioral seizures following repetitive electrical stimulation of the perforant path at an interval of 40 s, and on the total afterdischarge (AD) duration induced by 50 stimulations. In addition, we measured COX-2 mRNA expression by in situ hybridization and PGE2 concentration using enzyme immunoassay following rapid kindling stimulation. The results suggested that brain COX-2 mRNA levels were markedly increased in the hippocampal neurons and the concentration of PGE2 was elevated significantly, and that the incidence of AD and seizure behavior induction and the total AD duration were significantly decreased under conditions of COX-2 deficiency. Therefore, we concluded that inducible COX-2 facilitates the recurrence of hippocampal seizures.

Object. The authors have treated intractable pain, particularly cancer pain related to bone metastasis, with various protocols. Cancer pain has been treated by gamma knife radiosurgery (GKS), targeted to the pituitary gland—stalk, as an alternative new pain control method. The purpose of this study was to investigate a prospective multicenter protocol to prove the efficacy and the safety of this treatment. Methods. Indications for patient inclusion in this treatment protocol were: 1) pain related to bone metastasis; 2) no other effective pain treatment options; 3) general condition rated as greater than 40 on the Karnofsky Performance Scale; 4) morphine effective for pain control; and 5) no previous treatment with radiation (GKS or conventional radiotherapy) for brain metastasis. The authors at one institution have treated two patients, who suffered from severe cancer pain related to bone metastasis, by using GKS. The target was the pituitary gland. The maximum dose was 160 Gy with one isocenter of an 8-mm collimator, keeping the radiation dose to the optic nerve less than 8 Gy. At another institution two patients were treated in the same way; an additional five patients were treated similarly with targeting of the pituitary gland with two isocenters of 4-mm collimator. In all nine cases, pain resolved without significant complication. Pain relief was observed within several days, and this effect was prolonged until the day that they died. At a follow up of 1 to 24 months, no recurrences and no hormonal dysfunction were observed. Conclusions. Despite insufficient experience, the efficacy and the safety of GKS for intractable pain were demonstrated in nine patients. This treatment has the potential to ameliorate cancer-related pain, and GKS will play a more important role in the treatment of intractable pain. More experience and additional refined study protocols are needed to evaluate which parameters are important, to determine what treatment strategy is the best, and to clarify the safest option for patients with intractable cancer pain.

Background Psychological conditions affect pain responses in the human anterior cingulate cortex (ACC) according to brain imaging analysis. The rodent prefrontal cortex (PFC) including cingulate areas is also related to the affective dimension of pain. We previously reported PFC nociceptive responses inhibited by inputs from the amygdala, such as with dopamine (DA) D2 receptor (D2R) blockers, to show decreased effect on amygdala projections. In this study, we examined whether direct projections from the ventral tegmental area (VTA) to the PFC affect nociceptive responses in the PFC. Results High frequency stimulation (HFS, 50 Hz, 30 s) delivered to the VTA produced long-lasting suppression (LLS) of nociceptive responses in the rat PFC including cingulate and prelimbic areas. Nociceptive responses evoked by mechanical pressure stimulation (2 s duration at 500 g constant force) applied to the tails of urethane-anesthetized rats were recorded using extracellular unit recording methods in the PFC. HFS delivered to the VTA, which has been reported to increase DA concentrations in the PFC, significantly suppressed nociceptive responses. The LLS of nociceptive responses persisted for about 30 minutes and recovered to the control level within 60 min after HFS. We also demonstrated local microinjection of a selective D2 agonist of DA receptors to induce LLS of mechanical nociceptive responses, while a D2 but not a D1 antagonist impaired the LLS evoked by HFS. In contrast, DA depletion by a 6-hydroxydopamine injection or a low concentration of DA induced by a κ-opiate receptor agonist injected into the VTA had minimal effect on nociceptive responses in the PFC. Conclusion HFS delivered to VTA inhibited nociceptive responses for a long period in PFC. DA D2R activation mediated by local D2 agonist injection also induced LLS of mechanical nociceptive responses. The mesocortical DA system may modify PFC nociceptive responses via D2 activity.

Effects of tetanic bursts (200 Hz, 10 pulses) on field potentials elicited by ventral posterolateral thalamic nucleus (VPL) stimulation were investigated in the feline somatosensory cortex. In the first experiments, field potentials elicited by VPL stimulation (test pulse) were simultaneously recorded in the primary (SI) and the secondary (SII) somatosensory cortex in six animals. Potentiation of field potentials recorded in SII was induced by tetanic stimulation of VPL in all six animals, whereas the same tetanic bursts failed to produce significant changes in SI in four of the six animals. The results suggest that plastic changes in somatosensory processing take place in SII rather than SI. In subsequent experiments, features of the potentiation observed in SII were examined in 20 animals. The field potentials were simultaneously recorded at 16 points placed vertically at 150-μm intervals from the cortical surface. The potentiation of field potentials (to 110–170% of control values) observed at depths between 600 and 1350 μm lasted more than 90 min after tetanic stimulation. Poststimulus histograms of multiple-unit activities revealed a long-lasting increase in the number of unit discharges evoked by VPL stimulation. This change in the number of activated cellsis regarded as a cause of potentiation of SII field potentials. In the last session, the effects of N-methyl- d -aspartate (NMDA) receptor antagonists on the potentiation of SII field potentials were investigated. Cortical intraventricular injection of d -2-amino-5-phosphonovalerate (APV) and dl -2-amino-7-phosphonoheptanoic acid (APH) prevented induction of the potentiation in SII. NMDA receptor activation participates in forming this SII potentiation.

Background Projections from hippocampal CA1-subiculum (CA1/SB) areas to the prefrontal cortex (PFC), which are involved in memory and learning processes, produce long term synaptic plasticity in PFC neurons. We examined modifying effects of these projections on nociceptive responses recorded in the prelimbic and cingulate areas of the PFC. Results Extracellular unit discharges evoked by mechanical noxious stimulation delivered to the rat-tail and field potentials evoked by a single stimulus pulse delivered to CA1/SB were recorded in the PFC. High frequency stimulation (HFS, 100 Hz) delivered to CA1/SB, which produced long-term potentiation (LTP) of field potentials, induced long-term enhancement (LTE) of nociceptive responses in 78% of cases, while, conversely, in 22% responses decreased (long-term depression, LTD). These neurons were scattered throughout the cingulate and prelimbic areas. The results obtained for field potentials and nociceptive discharges suggest that CA1/SB-PFC pathways can produce heterosynaptic potentiation in PFC neurons. HFS had no effects on Fos expression in the cingulated cortex. Low frequency stimulation (LFS, 1 Hz, 600 bursts) delivered to the CA1/SB induced LTD of nociceptive discharges in all cases. After recovery from LTD, HFS delivered to CA1/SB had the opposite effect, inducing LTE of nociceptive responses in the same neuron. The bidirectional type of plasticity was evident in these nociceptive responses, as in the homosynaptic plasticity reported previously. Neurons inducing LTD are found mainly in the prelimbic area, in which Fos expression was also shown to be inhibited by LFS. The electrophysiological results closely paralleled those of immunostaining. Our results indicate that CA1/SB-PFC pathways inhibit excitatory pyramidal cell activities in prelimbic areas. Conclusion Pressure stimulation (300 g) applied to the rat-tail induced nociceptive responses in the cingulate and prelimbic areas of the PFC, which receives direct pathways from CA1/SB. HFS and LFS delivered to the CA1/SB induced long-term plasticity of nociceptive responses. Thus, CA1/SB-PFC projections modulate the nociceptive responses of PFC neurons.

Electroencephalographic (EEG) changes in relation to hemodynamic changes at the onset of cardio-pulmonary (C-P) bypass circulation in 31 cases undergoing open heart surgeries were studied. Rapid and extensive changes in systemic circulation, which were followed by abnormal EEGs, appeared within the first five minutes of C-P bypass. Abnormal EEG patterns including disappearance of fast waves, slowing under 6 Hz in frequency with high voltage and flattening were observed in 64% of the cases. The relations between the appearance of these abnormal EEGs and hemodynamic factors such as mean arterial pressure (mAP), central venous pressure (CVP), rate of decrease in mAP and rate of change in CVP, were analyzed in order to elucidate causes of development of the abnormal EEGs. Only the rate of decrease in mAP at the onset of C-P bypass had a high correlation (p less than 0.01) with the appearance of abnormal EEGs. The findings suggest that rapid circulatory changes in the first five minutes of C-P bypass may induce disruption of cerebral autoregulation.

Diagnostic modalities that can distinguish brain tumors from eloquent cortices or nerve fiber bundles are important for neurosurgery. For identifying nerve fiber bundles, various techniques such as diffusion tensor imaging and subcortical stimulation mapping have been used. In this article, we propose localization of nerve fiber bundles by polarization-sensitive optical coherence tomography (PS-OCT) for the first time. PS-OCT performs tomographic imaging by measuring the travel distance and the change in polarization of the backscattered light from the tissue at different traverse positions, enabling selective visualization of birefringent tissues such as nerve fiber bundles. We examined the imaging of nerve fiber bundles in blocks of fixed rat brains. Nerve fiber bundles in internal and external capsules of the rat brains appearing on the surfaces of the coronal, horizontal, and sagittal planes were identified as to their locations and orientations. The nerve fiber bundles were clearly visualized by PS-OCT. The image penetration depth of the PS-OCT images was about 1.0 mm in gray matter and about 0.5 mm in white matter, so the refractive indices of gray and white matters were assumed to be 1.4.

The surface and depth distributions of mandibular canine, tooth pulp-evoked potentials (TPEPs) in the trigeminal brainstem nuclear complex were studied in anesthetized cats. Three pairs of positive-negative waves or components were elicited from each trigeminal brainstem nucleus (main sensory, MSN; oralis, NO; interpolaris, NI; caudalis or medullary dorsal horn, NC). The location and dipole orientation of the current generator source for each pair of components in each nucleus were determined by using the topographic amplitude distribution of TPEPs in both their normal-reference and inverted polarities and the isoelectric contour line. The current sources for all components were the following: MSN--dorsomedial subnucleus; NO--dorsolateral portion; NI--dorsomedial portion; NC--medial part of superficial and intermediate laminae. These loci are consistent with the central terminal zones of mandibular tooth pulp afferents reported in previous neuroanatomical studies. Measurements of mean peak latencies suggest that tooth pulp A beta afferents contribute to the putatively presynaptic (P1-N1) and monosynaptic (P2-N2) components found in all trigeminal brainstem nuclei and that A delta afferents contribute to the later and possibly polysynaptic components (P3-N3) in the same nuclei. The pertinence of these findings to the theory that both non-nociceptive and nociceptive intradental inputs project to rostral and caudal nuclei are discussed.

Anti-nociceptive effects of fluvoxamine, administered by intracerebroventricular (i.c.v.) injection, include inhibited pain behavior in both formalin-induced acute pain (p

Introduction: In this study, we compared the choice of medical specialty and subspecialty interest among problem-based-learning (PBL) graduates and non-PBL graduates. Materials and Methods: Questionnaires were mailed to a total of 1398 female doctors who graduated from Tokyo Women’s Medical University (TWMU) between 1989 and 2003. The response rate was over 30%, giving 248 respondents who had undergone a PBL curriculum (PBL+) and 220 subjects who had not (PBL-). Current specialty of the graduates were compared between the PBL+ and PBL-, and also compared with the general Japanese female doctors (Control 1 and 2) of similar age groups. Respondents were analysed in terms of their interests in subspecialty medical care or general medical practise, which includes comprehensive medical care, primary care and basic medicine. Internal medicine doctors working in the university hospitals were compared with those working outside the university hospitals. Internal medicine doctors were also compared with specialists in ophthalmology, otolaryngology, dermatology and psychiatry. Subjects were compared by odds ratio (OR) to examine group difference in the field of interest. OR >2.0 was considered statistically significant. Results: Most doctors in all groups chose internal medicine. More PBL+ internal medicine doctors showed interests in comprehensive medical care and primary care; more PBL+ internal medicine doctors working outside university hospitals showed interest in comprehensive medical care and primary care when compared with those who were working in the university hospitals. The PBL- graduates did not show such a characteristic. Conclusions: More PBL+ graduates who chose internal medicine showed interest in holistic medical practices such as primary care and community medicine and more PBL+ specialists showed sustained interest in their respective fields. Key words: Educational outcome, Medical education, Professional carrier, Specialty interest

Background/Aims: Manipulation of brain functions via Gamma Knife (GK) irradiation would have numerous applications in clinical and experimental neurology. Methods: Alteration of brain functions in the unilaterally irradiated striatum was indexed through monitoring freely moving rat behaviors. Spontaneous activity and rotations on the apomorphine test, which can detect dopaminergic function imbalance, were indexed employing our behavior tracking system. The spatial distribution of necrotic lesions was explored using serial sections, and was assumed to represent the real foci of the GK target. Results: Distinct behavioral alterations corresponded to the precise locations of the lesions in various areas of the basal ganglia. Displacement of the irradiation sites in the anteromedial direction increased spontaneous activity, and posterolateral shift provoked circling behavior on the apomorphine test. Conclusion: Accurate positioning of the target is crucial for experimental GK irradiation locally focused on domains of a small brain such as that of the rat. Here, we propose a protocol for converting the ‘intended’ focus, based on brain map coordinates, to a ‘planned’ focus on the MR imaging coordinate system with the Régis-Valliccioni stereotactic frame.

Object. An animal model has been developed to study the effect of gamma knife surgery(GKS) on cerebral function. Methods. A rat was fixed in a newly developed Régis—Valliccioni frame that enables the target region to be planned directly on the magnetic resonance images. The left striatum was irradiated with 150 Gy via a 4-mm collimator of the Leksell gamma knife. Apomorphine (dopamine agonist) was administered to elicit a circling behavior (apomorphine test) after the GKS so as to examine the time course of the changes in dopaminergic functions of irradiated striatum. After a series of behavioral analyses, irradiated brains were subjected to histological examination. Necrosis was observed in the irradiated area surrounded by hemorrhage and gliosis. The distance between the histologically estimated and planned centers of the irradiation areas was 1.0 ± 0.5 mm. The extent of the distance was due to errors along dorsoventral axis. The distribution of the irradiation areas influenced the activity and the circling behaviors in apomorphine test, which was suggestive of involvement of the nigrostriatal pathway. Conclusions. Targeting by using the Régis—Valliccioni frame was very accurate compared with targeting with coordinates based on brain maps used hitherto. Although targeting improved the accuracy, further effort will still be necessary to reduce errors along dorsoventral axis. The apomorphine test indicated a reduced dopaminergic function of the irradiated area including striatum, which accompanied histological changes after a high dose of irradiation (150 Gy).

Tokyo Women's University has career support systems for a female physician. Basic career support is provided for a young female physician who has children. Our University runs the nursery school which takes care of children in day and night. It also helps mothers (female physician) when children are sick. The university also provides short time office hours system for doctors who take care of their children. Both men and women can take advantage of the system. These systems can assist for female physicians to keep their position in hospitals and universities. Then, the next step of a career support is a project for higher-ranking position. Publishing scientific papers and developing good reputation as excellent physicians are essential for promotion. How can we support female physicians for promotion? Our university establishes a scientific research grant and a one-year scholarship for female physicians. We just start the support, therefore, we expect out come in future. We have been developing support systems for female physicians, however effects have not been sufficient yet. We should take more active action to promote female physicians in our society.

Rationale: Two or three decades ago, cancer pain was treated by surgical/chemical hypophysectomy. In one report, the control of central pain (thalamic pain syndrome) was also approached with chemical hypophysectomy. Although in most of the patients these treatments resulted in a decrease in severe pain, concomitantly severe adverse effects (panhypopituitarism, diabetes insipidus and visual dysfunction) occurred in most patients. This historical evidence prompted us to perform Gamma Knife surgery (GKS) for this kind of intractable severe pain using a high irradiation dose to the pituitary stalk/gland. In the majority of patients, marked pain relief was achieved, surprisingly without any of the complications mentioned above. Materials and Methods: A prospective multicenter study was conducted to evaluate the efficacy and safety in patients treated in Prague, Hong Kong and Tokyo. Indications of this treatment were: (1) failure of other effective treatment approaches prior to GKS, (2) good general patient condition (Karnofsky performance status >40%), (3) response to morphine for pain control (cancer pain), and (4) no previous radiotherapy of brain metastases (GKS/conventional radiotherapy). Eight patients with severe cancer pain due to bone metastasis and 12 patients with post-stroke thalamic pain syndrome were treated with GKS. The target was the border between the pituitary stalk and gland. Maximum dose was 160 Gy for cancer pain and 140 Gy for central pain. Follow-up included 6 patients (>1 month) with cancer pain and 8 patients (> 6 months) with thalamic pain syndrome. Results: All patients (6/6) with cancer pain experienced significant pain reduction, and 87.5% (7/8) of the patients with thalamic pain had initially significant pain reduction. In some patients, pain reduction was delayed for several hours. Pain relief was noted within 7 days (median 2 days). No recurrence was observed in the patients with cancer pain. However, in 71.4% (5/7) of the patients with thalamic pain syndrome, disease recurred during the 6-month follow-up. Up to now, other complications have not been observed. Conclusion: Our clinical study protocol is only preliminary. Further clinical results on the management of thalamic pain are required to develop this treatment protocol. However, efficacy and safety have been shown in all our cases. In our opinion, this treatment has a potential to control severe pain, and GKS will play an important role in the management of intractable pain.

Serotonin (5-HT) mediated anti-nociceptive effects induced by an anti-depressant, trazodone, are related to 5-HT(1A) receptor activities at the supraspinal level. 5-HT(3) receptor activation via the descending anti-nociceptive pathways may contribute to the trazodone mediated anti-nociception at the spinal level. Intracerebroventricular (i.c.v.) injection of trazodone dose-dependently impaired nociceptive responses in the formalin test in mice. Six and 15 microg of trazodone inhibited the early (P

The authors have treated intractable pain, particularly cancer pain related to bone metastasis, with various protocols. Cancer pain has been treated by gamma knife radiosurgery (GKS), targeted to the pituitary gland-stalk, as an alternative new pain control method. The purpose of this study was to investigate a prospective multicenter protocol to prove the efficacy and the safety of this treatment.Indications for patient inclusion in this treatment protocol were: 1) pain related to bone metastasis; 2) no other effective pain treatment options; 3) general condition rated as greater than 40 on the Kamofsky Performance Scale; 4) morphine effective for pain control; and 5) no previous treatment with radiation (GKS or conventional radiotherapy) for brain metastasis. The authors at one institution have treated two patients, who suffered from severe cancer pain related to bone metastasis, by using GKS. The target was the pituitary gland. The maximum dose was 160 Gy with one isocenter of an 8-mm collimator, keeping the radiation dose to the optic nerve less than 8 Gy. At another institution two patients were treated in the same way; an additional five patients were treated similarly with targeting of the pituitary gland with two isocenters of 4-mm collimator. In all nine cases, pain resolved without significant complication. Pain relief was observed within several days, and this effect was prolonged until the day that they died. At a follow up of 1 to 24 months, no recurrences and no hormonal dysfunction were observed.Despite insufficient experience, the efficacy and the safety of GKS for intractable pain were demonstrated in nine patients. This treatment has the potential to ameliorate cancer-related pain, and GKS will play a more important role in the treatment of intractable pain. More experience and additional refined study protocols are needed to evaluate which parameters are important, to determine what treatment strategy is the best, and to clarify the safest option for patients with intractable cancer pain.

We characterized nociceptive discharges induced by mechanical stimulation and the modulating effects of orphanin FQ on noxious responses in the rat brain stem gigantocellular reticular nucleus (Gi). A pressure pulse of constant force and rising rate was delivered by a mechanical stimulator with feedback control, allowing responses to be analyzed statistically. A pressure pulse of 300 g, which evoked C-fiber mediated nerve responses, was delivered to the tail. Two excitatory (45/58) and one inhibitory (13/58) types of extracellular unit discharges were recorded in Gi. One of the excitatory types was a phasic discharge (13/45) elicited at the onset and/or the end of stimulation. Latencies of the phasic discharges (0.104+/-0.1 s) were shorter than those of other type (tonic) discharges (0.43+/-0.2 s). The tonic discharges (32/45), which frequently persisted past the end of stimulation without adaptation, were classified into two groups. The first group of tonic type units (23/45) was high threshold, like nociceptive specific neurons in the primary sensory cortex, while the second group of neurons (9/45) responded to a wide range of stimulus intensities. The mean frequency, response duration and spike numbers gradually increased with stimulus intensity change in all nine neurons. The neurons encode mechanical stimulus intensity with discharge frequency, response duration and evoked spike numbers. Local injection of orphanin FQ (200 ng/2 microl) changed high threshold tonic type spike numbers in a biphasic manner, i.e., there was an early phase suppression (5-30 min, p=0.016) and a late phase enhancement (30-60 min, p=0.027). In contrast, phasic type discharges did not show an altered discharge pattern in response to orphanin FQ. Thus, orphanin FQ affects small fiber-mediated nociceptive responses and may behave as a complex modulator of pain systems in the brain stem.

We investigated the long-lasting effects of mechanical vibratory stimulation of the skin on the excitability of feline cortical neurons in the forelimb areas of the primary (SI) and secondary (SII) somatosensory cortices. Conditioning mechanical stimuli were 300 bursts of 10 pulses at 200 Hz delivered with a 10-s interburst interval from a mechanical stimulator. Test field potentials and unit discharges were evoked by electrical stimulation to the ventral posterolateral thalamic nucleus (VPL) or by single mechanical stimuli applied to the skin. In SII, the mechanical burst stimulation to the skin increased the amplitudes of field potentials and the frequency of unit discharges elicited by single mechanical stimuli applied to the skin. The vibratory conditioning stimulus also produced a similar potentiation of the VPL-evoked field potentials (126-139% increase in amplitude, P0.05) with an associated increase in firing rates of extracellularly recorded neuronal activity (117%, P0.001). These potentiations persisted through the entire experimental period of 120 min. The translaminar current source density analysis calculated from the VPL-evoked field potentials increased to 127% of the control value (P0.01). In contrast, in SI we observed no significant changes in the field potential amplitudes or in the currents generated in superficial layers (91-117%). Taken together with the previous finding that tetanic electrical stimulation of VPL induces long-lasting potentiation of the VPL-evoked cortical responses in SII but not of those in SI, the present results suggest that SII has a large capacity for the rapid functional plasticity involved in the learning that occurs during repeated tactile experiences.

The effects of protein kinase C (PKC) inhibitors on the induction of long lasting potentiation (LLP) of field potentials in the feline somatosensory cortex were studied. LLP was induced by high frequency stimulation (HFS, 200 Hz) of the ventral posterolateral thalamic nucleus. First, the effects of a protein kinase inhibitor, H-7, and a specific PKC catalytic domain inhibitor, chelerythrine, on the LLP in the secondary somatosensory cortex (SII) were investigated. Intracortical microinjections of H-7 and chelerythrine at 30 min before HFS inhibited induction of LLP in SII, while an injection of chelerythrine at 60 min after LLP induction had no effect on the potentiation. Second, changes in PKC activity in the presence of calcium and phosphatidylserine were investigated in SII after induction of LLP. Triton-soluble membrane fractional PKC activity had increased to 350% of the control value with low frequency test stimulation (0.1 Hz) by five min after HFS. In contrast, PKC activities of cytosolic fractions decreased to 25.6% of the control value. At 60 min after HFS, the PKC activity level returned to the control value, despite persistent potentiation in all cases. PKC activation is considered to be one of the factors required for induction of LLP but not for maintenance in SII.

Background We previously demonstrated nociceptive discharges to be evoked by mechanical noxious stimulation in the prefrontal cortex (PFC). The nociceptive responses recorded in the PFC are conceivably involved in the affective rather than the sensory-discriminative dimension of pain. The PFC receives dense projection from the limbic system. Monosynaptic projections from the basolateral nucleus of the amygdala (BLA) to the PFC are known to produce long-lasting synaptic plasticity. We examined effects of high frequency stimulation (HFS) delivered to the BLA on nociceptive responses in the rat PFC. Results HFS induced long lasting suppression (LLS) of the specific high threshold responses of nociceptive neurons in the PFC. Microinjection of N-methyl-D-aspartic acid (NMDA) receptor antagonists (2-amino-5-phosphonovaleric acid (APV), dizocilpine (MK-801)) and also metabotropic glutamate receptor (mGluR) group antagonists (α-methyl-4-carboxyphenylglycine (MCPG), and 2-[(1S,2S)-2-carboxycyclopropyl]-3-(9H-xanthen-9-yl)-D-alanine (LY341495)), prevented the induction of LLS of nociceptive responses. We also examined modulatory effects of dopamine (DA) on the LLS of nociceptive responses. With depletion of DA in response to 6-hydroxydopamine (6-OHDA) injection into the ipsilateral forebrain bundle, LLS of nociceptive responses was decreased, while nociceptive responses were normally evoked. Antagonists of DA receptor subtypes D2 (sulpiride) and D4 (3-{[4-(4-chlorophenyl) piperazin-1-yl] methyl}-1H-pyrrolo [2, 3-b] pyridine (L-745,870)), microinjected into the PFC, inhibited LLS of nociceptive responses. Conclusions Our results indicate that BLA-PFC pathways inhibited PFC nociceptive cell activities and that the DA system modifies the BLA-PFC regulatory function.

1. The response properties of 39 periodontal ligament mechanoreceptors (PDLMs) and 12 intradental mechanoreceptors (IMs) related to the intact mandibular canine tooth were isolated by extracellular recording methods from the ipsilateral trigeminal semilunar ganglion. 2. The stimulus threshold and response magnitude of individual PDLMs depended on the direction of steady force applied to the intact canine tooth. Canine PDLMs as a population, however, did not have a preferred stimulus direction. IMs were activated only by a rapid mechanical transient applied to the intact tooth in any direction. The stimulus threshold and response magnitude of each IM were approximately equipotent in all stimulus directions. 3. Application of quantifiable ramp-and-hold stimulation showed that PDLMs can encode the intensity of steady forces as well as the rate of force ramps. Increasing the ramp rates decreased the total ramp discharge but increased the peak discharge frequency. IMs encoded only the rate of force ramps that were applied by percussion. Higher ramp rates increased both the total discharges and peak discharge frequency of IMs. 4. The dynamic response properties of PDLMs and IMs were clearly differentiated by sinusoidal vibratory stimulation. The maximum frequencies for entrainment of IM discharge at the stimulus cycle length (251 +/- 103 Hz, mean +/- SD) and at any periodicity including multiples of the stimulus cycle length (295 +/- 100 Hz) were significantly higher than the maximum frequencies for PDLM discharge entrainment at the stimulus cycle length (103 +/- 53 Hz) and at any periodicity (133 +/- 62 Hz). 5. The functional similarities of PDLMs and IMs, respectively, to slowly adapting type II mechanoreceptors and Pacinian corpuscle receptors in the skin are discussed. Our present findings, which complement earlier anatomic and behavioral evidence, strongly suggest that IMs subserve nonnociceptive and nonpain functions. Both PDLMs and IMs may provide a continuum of dynamic afferent inputs necessary for tactile sensibility of teeth.

Summary: Changes in the strength of recurrent inhibition in the feline cortex in cobalt (CoCl2)-induced epilepsy were observed. The strength of inhibition was analyzed in terms of paired-pulse depression of the amplitude of somatosensory evoked potentials (SEPs) elicited by stimulation of the ventral posterolateral (VPL) thalamic nucleus. An enhancement in recurrent inhibition was observed shortly after CoCl2 application. The size of the amplitude of cortical evoked potentials (EPs) elicited by VPL stimulation increased simultaneously. The reduction of inhibition that appeared later was associated with after discharges (ADS) evoked by VPL stimulation. These ADS frequently extended to epileptic discharges. These results suggest that the reduction in recurrent inhibition induced by CoCl2 application plays an important role in the spread of seizure activity.

The distribution of tooth pulp-evoked potentials (TPEPs) was characterized in the primary motor (MI), primary somatosensory (SI) and secondary somatosensory (SII) cortices of the monkey. Bipolar electrical tooth pulp stimulation elicited TPEP components P23 and N44 over SI, P26 and N72 over MI, and P72, N161, P280, N420, P561 and N662 over SII. Muscular artifacts and extradental input did not affect the TPEP as demonstrated by experiments using a neuromuscular blocking agent and removal of the pulp, respectively. The short latency TPEPs recorded over SI and MI were evoked by low stimulus intensities and activation of A beta nerve fibers, whereas the long latency TPEPs recorded over SII required higher stimulus intensities and the additional recruitment of A delta nerve fibers. Intracortical recordings revealed polarity reversals of components P23 and N44 in area 3b, P26 and N72 in area 4, and P72, N161, P280, N420, P561 and N662 in the upper bank of the lateral sulcus (SII). Evidence presented in this study suggests that TPEPs recorded from SI and MI relate to non-nociceptive mechanisms while TPEPs recorded from SII relate to nociceptive mechanisms.

Experiments were performed to characterize cerebral cortical activity and pain behavior elicited by electrical stimulation of the tooth pulp in unanesthetized monkeys. Four monkeys were trained on two different operant paradigms: two on a simple escape task and two on an appetitive tolerance-escape task. All monkeys were implanted with bipolar stimulating electrodes in the right maxillary canine tooth and subdural recording electrodes over the left primary (SI) and/or secondary (SII) somatosensory cortices. Subdural tooth pulp-evoked potentials (TPEPs) recorded over the SII consisted of components P1 (27.5 ms), N1 (40.3 ms), P2 (84.0 ms), N2 (163.5 ms), P3 (295.3 ms), and N3 (468.0 ms). The long latency component (P3-N3) was found exclusively over the SII and was elicited by high intensity stimulation. The appearance of component P3-N3 required the recruitment of Aδ nerve fibers into the maxillary nerve compound action potential and was correlated with high frequencies of escape. Administration of morphine sulfate (4 mg/kg, i.m.) caused a contemporaneous reduction in escape frequency and in the amplitude of P3-N3 recorded over the SII. The relationships between TPEP amplitude, escape behavior and Aδ nerve fiber activity strongly suggest that the SII is involved with nociception and pain behavior.

A cluster of trigeminal nociceptive neurons was located in the lateral sulcus on the upper bank of the frontoparietal operculum in a region bordering between cortical areas SII and 7b. These neurons were isolated in cortical cell layers IV and V-VI. All nociceptive neurons responded exclusively to noxious mechanical stimulation of cutaneous receptive fields on the face/head or intraoral tissue. Sustained noxious mechanical stimulation elicited slowly adapting responses that accurately encoded the duration of the stimulation. Prolonged discharges following removal of noxious stimulation were not observed. These nociceptive specific neurons poorly encoded graded noxious stimuli. Trigeminal somatosensory neurons within and surrounding the SII-7b cluster were not topographically organized according to divisions of the trigeminal nerve, laterality of receptive fields, or division of face/head and intraoral receptive fields. The thalamocortical, corticocortical and indirect corticolimbic connectivities of SII and area 7b and the possible role of SII-7b nociceptive neurons in learning, memory and avoidance behaviors are discussed.