Bradykinin is a major inflammatory mediator that produces peripheral pain hypersensitivity by acting on nociceptor peripheral terminals. We show that central sensitization, an activity-dependent increase in synaptic efficacy in the spinal cord, also requires bradykinin B₂ receptor activation. B₂ receptors are expressed in dorsal horn neurons and B₂ agonists substantially augment AMPA and NMDA receptor mediated currents in lamina II neurons, acting pre- and postsynaptically. Augmentation of these currents by bradykinin requires co-activation of protein kinase C (PKC) and A (PKA), the latter via cyclooxygenase-1 (COX1). Administration of an intrathecal B₂-selective antagonist to the spinal cord suppresses behavioral manifestations of central sensitization. Bradykinin is a central synaptic neuromodulator that potentiates glutamatergic synaptic transmission in the spinal cord by activating ampersand kinases, producing pain hypersensitivity.

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   Dopamine (DA) is the most abundant catecholamine in the brain. The important contribution of DA as a neurotransmitter in the brain is well understood. Compared with the enormous literature devoted to DA actions in the brain, little is known about the roles of DA in the spinal cord. Dopaminergic innervation of the spinal cord is largely derived from cerebral structures. The periventricular, posterior (A11) region of the hypothalamus is the principle source of descending dopaminergic pathways. To understand the mechanisms of antinociception mediated by the descending dopaminergic pathway, we examined the actions of DA on nociceptive transmission using whole-cell patch-clamp recordings from substantia gelatinosa (SG) neurons in spinal cord slices. Bath application of DA produced an outward current in almost all SG neurons examined. The DA-induced outward current was blocked by the addition of K⁺-channel blockers (Cs⁺ and TEA) or GDP-β-S into pipette solution, and was reduced in the presence of Ba²⁺. The DA-induced outward current was mimicked by a D2-like receptor agonist, quinpirole, but not by a D1-like receptor agonist, SKF 38393. In addition, the DA-induced outward current was suppressed by a D2-like receptor antagonist, sulpiride, but not by a D1-like receptor antagonist, SCH 23390. These results indicate that DA acts on postsynaptic SG neurons to induce an outward current by G-proteinmediated activation of K⁺ channels through D2-like receptors. This may be a possible mechanism for antinociception by the descending dopaminergic pathway.

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   We employed the functional MRI (fMRI) to investigate the changes of brain activation after reducing of capsaicin-induced heat hyperalgesia. Eight healthy volunteers who have no history of brain vascular disease were enrolled in this study. Capsaicin-induced heat hyperalgesia was developed by topical application of 2% capsaicin cream to anterior surface of left forearm. First fMRI time series were taken an hour after the application of capsaicin and second fMRI time series were taken an hour after medication (Loxoprofen Na: 120 mg). As for the pain task, 45°C wet cotton was put on the region where the heat hyperalgesia was evoked by capsaicin cream. Results of first fMRI time series showed distinct activation in the thalamus, anterior cingulate cortex, supplementary motor area, and prefrontal cortex. An hour after medication, though heat hyperalgesia still remained, all participants reported improvement of pain discomfort (VAS 4.7 to 2.5). Second series fMRI showed activation only in the thalamus. These results suggest that deactivated areas (anterior cingulate, etc.) observed after medication might be involved mainly in the pain related discomfort.

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   The effects of spinal cord stimulation (SCS) on the neuronal activity of the brain were examined by single photon emission computed tomography (SPECT) in patients with chronic neuropathic pain. Regional cerebral blood flow (CBF) in each cortical area and the thalamus decreased in several patients without SCS. Patients with central pain due to thalamic hemorrhage showed a decrease in rCBF in the thalamus contralateral to the painful side. During the stimulation period in SCS, parietal rCBF decreased on the side contralateral to the pain. In contrast, rCBF increased in the bilateral frontal and anterior cingulate cortex and in the contralateral temporal lobe in half of the patients in whom SCS was effective in relieving pain. The decrease in thalamic rCBF in two patients with central pain was improved by the SCS therapy; however, pain was relieved in only one of them. In the majority of patients in whom SCS was not effective, there was no change in rCBF in various cortical areas, even after SCS. These results suggest that, in patients with chronic neuropathic pain, SCS modulates the neuronal activities of several brain areas that are believed to be associated with pain processing.

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   The suppressive effects of low-power laser on excitations evoked by bradykinin in cultured murine dorsal root ganglion neurons associated with C-fibers were studied by measuring cytosolic calcium ion concentrations with confocal laser scanning microscopy. Elevation of the cytosolic calcium ion concentration and calcium oscillations were observed by the stimulation of neurons with bradykinin in a calcium-rich external solution. Any typical calcium oscillation was not observed in a calcium-free solution. The elevation of the calcium ion concentration elicited by bradykinin was suppressed by the irradiation with a Ga-Al-As diode laser (wave length: 830 nm, output power: 16.2 mW, irradiation energy: 49 J/cm²). The suppression was reversible. The laser irradiation does not block the binding of bradykinin to B2 receptor but may interfere with cell membrane components by which action potentials and calcium ion flux might be brought out.

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