Reactive oxygen species (ROS) are a molecular species which come from O₂ generated in intravital energy metabolism and the phylaxis process, and are highly-reactive. Two common examples of ROS are super-oxide (O₂^-) and hydrogen peroxide (H₂O₂). ROS are absolutely necessary to maintain life, but it is thought that surplus ROS which cannot be fully degraded by intracellular enzymes cause various disorders such as cancer or arteriosclerosis. Recent studies have suggested that ROS are involved in chronic pain such as neuropathic pain or inflammatory pain in the spinal cord. For instance, it has been reported that ROS participate in long-term potentiation in the dorsal horn of the spinal cord and is a contributing factor of secondary hyperalgesia. However, the cellular mechanism of ROS is still unclear in the dorsal horn of the spinal cord. To address this issue, we investigated the effect of ROS on glutamatergic excitatory synaptic transmission in substantia gelatinosa (SG) neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. A ROS donor, tert-butyl hydroperoxde (t-BOOH), superfused for 5 min markedly increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). The t-BOOH-induced increases in sEPSC frequency were resistant to tetrodotoxin. However, in the presence of a non-NMDA receptor antagonist, CNQX, t-BOOH did not generate any sEPSC. Furthermore, the tBOOH-induced increases in sEPSC frequency were inhibited by the scavenger N-tert-butyl-α-phenyl nitrone. In the presence of a TRPA1 channel antagonist, HC-030031, t-BOOH-induced increases in sEPSC frequency were inhibited. On the other hand, in the presence of a TRPV1 channel antagonist, capsazepine, t-BOOH-induced increases in sEPSC frequency and amplitude were not affected. These results indicate that ROS enhances the spontaneous release of L-glutamate from presynaptic terminals onto the SG neurons through TRPA1 channel activation.

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　Background and Purpose: In a previous study, we demonstrated that portions of intractable chronic pain must involve conditioned pain. Briefly, formalin injection (UCS) produced licking behavior at the locus (UCR), and repeated injection of formalin in the same context (CS) developed a conditioned nociceptive response (CR). The CR appeared when the animals were injected with saline in the CS, and the CR was completely maintained at the same level even twenty-four days later in the home cage. Since then, we have noted that congenital insensitivity to pain is accompanied by anosmia in mice and humans. There have been several studies on the effect of olfactory stimuli on acute pain (UCS) in animals and humans, but studies regarding the effect of olfactory stimuli on sustained pain are limited. Hence, we attempted to examine the effect of analgesic drugs or olfactory stimulants on the CR, as well as the UCR, using a neuro-psycho-behavioral procedure in mice.
　Methods: The animals were experimentally naïve, adult male, specific-pathogen-free Job:ddY mice. Conditioning was carried out according to the Pavlovian conditioning method. In the fixed experimental context, tone stimuli and injections of 0.25% formalin were repeated in the animals according to a modified formalin test method in the training phase. In the test phase, saline was given in place of formalin in the CS. In the first experiment, the narcotic drug fentanyl or a selective serotonin reuptake inhibitor, fluvoxamine, was intravenously (i.v.) injected in the animals 15 min before introduction to the experimental context. In the second experiment, a sweet odor was given in the experimental space in the experimental context. The odor was a mixture of bee honey and mango, which were preferred odors for the animals. Scopolamine was injected i.v. in the animals in the home cage 15 min before introduction to the experimental context.
　Results: Fentanyl decreased UCR but was ineffective to CR. Fluvoxamine decreased UCR dose dependently but slightly attenuated CR at a higher dose. The sweet odor given in the training phase decreased both the UCR and CR. The sweet odor given at the test phase also decreased the CR. Scopolamine given in the training phase did not influence UCR but significantly reduced CR. Scopolamine and odor given in the training phase reduced both the UCR and CR.
　Discussion: The CR was resistant to analgesic drugs, suggesting that the CR at least partly has similar characteristics with chronic pain. The result may be related to the difference in a speculative neural circuitry of the CR and in the active site of the drugs at the supraspinal level. The sweet odor given in the training phase was effective for both the UCR and CR irrespective of the pretreatment with amnestic drug. The effect of the sweet odor may come from the depressive action of the neural circuitry of both CR and nociceptive pain. Alternatively, the effect may be caused by a deflection from attention to the nociceptive stimuli with the sweet odor.

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　Habituation to pain has been addressed in many recent studies. It is clear that patients with chronic pain do not become habituated to the pain; however, little is known about habituation to the inner experience of pain. We investigated the brain mechanisms underlying habituation to the inner experience of pain by using event-related potentials (ERPs), which provide superior temporal resolution, and low-resolution brain electromagnetic tomography (LORETA), which enables identification of regions of nervous activity.
　Fifteen healthy subjects participated in this study. The subjects were shown 4 sets of photographic images, with each set shown 30 times. The images included 15 images of a hand subjected to pain (painful condition). The subjects were instructed to imagine themselves in that condition and to imagine the pain they may experience in such a situation (inner experience of pain). Electroencephalography was continuously performed via 128 scalp electrodes mounted on an electrode cap. ERPs were recorded during the inner experience of pain; we also recorded N110 responses for emotional components and P3 responses for cognitive evaluation. To investigate habituation to the inner experience of pain, the mean amplitudes of P3 and N110 recordings were calculated for the first 2 (early sets) and last 2 (late sets) sets of trials for each painful condition; next, early sets were compared with late sets. We also analyzed the change in nervous activity after habituation to the inner experience of pain by LORETA analysis.
　The amplitude of central P3 responses was significantly lower for the late image sets than the early image sets of the painful condition. However, the mean amplitude of N110 responses did not significantly change. LORETA analysis of P3 responses showed reduced activity in the left secondary somatosensory area and left posterior insular cortex, indicating that the sensory component of the inner experience of pain was lower in the late sets than in the early sets.
　During habituation to the inner experience of pain, the P3 response, which is related to cognitive evaluation of this experience, changed, and brain activity, which reveals the sensory component of the inner experience of pain, reduced. Our study suggests that habituation to the inner experience of pain occurs at the point of recognition of the sensory component of pain. We hypothesize that pain recognition necessary for habituation to the inner experience of pain.

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　The effect of hypnotic intervention for the refractory chronic pain patients was examined along with the process of patients' selection and their psychological characteristics.
　The total 596 visit patients in the first year were statistically examined concerning duration of pain, scores of psychological distress (Hospital Anxiety and Depression Scale) and disability (Pain Disability Assessment Scale) at the initial visit and the treatment outcome at the end of the first year. The duration of chronic pain was significantly related to disability but not to psychological distress at the initial visit. At the end of the first year of multidisciplinary pain treatment, 44% of total patients were under treatment, 19% finished treatment (10% evidently improved and 9% accepted their pain), 12% were referred and 25% dropped out. The group of patients who were evidently improved was not different concerning the duration of pain, but significantly less anxious, less depressed and less disabled at the initial visit than the other groups.
　Among the 261 patients under treatment, 33 patients (5.6% of total patients) were introduced into individual psychological interventions in consideration of 1) poor outcome in pharmacological and physical treatments, 2) unstable treatment relationship and marked pain behaviors, 3) obvious psychological distress, 4) event-related fluctuations in pain. They were significantly more anxious and depressed at the initial visit, than those who were not introduced to psychological intervention. Multiple bio-psycho-social factors were identified; tender points in 21 patients (by physiotherapist), stressful life events around the onset of pain in 26, serious daily conflicts at present in 30, catastrophizing thinking in 21, repressive thinking in 12, avoidance in 2 and perseverative coping in 6. Many of them did not or partly perceive their somatic tension / discomfort. Multiple factors were considered to inhibit the effect of treatment in those patients.
　In individual hypnosis, therapeutic conversation, permissive induction and indirect suggestions were employed. Direct suggestions for analgesia were not applied. Among 33 patients, 25 patients experienced hypnotic analgesia during sessions, 14 of whom finished their sessions with the decreased daily pain level or the enhanced effect of medication until the end of the 3^rd year. Among them, 5 patients evidently improved (one phantom limb pain and 4 other chronic pain). Hypnosis successfully helped 42% of the patients who had failed to respond to multi disciplinary treatment. The psychosomatic resources in patients need to be more attended and utilized in chronic pain treatment.

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