The organization of ascending pain-related projections to the anterior cingulate cortex was examined in the rat by means of retrograde transneuronal labeling with rabies virus. Three days after the virus injection into the anterior cingulate cortex, a large number of labeled neurons were observed in the thalamus (i.e., the parafascicular and centrolateral nuclei) and the limbic-related structures (i.e., the orbital cortex and the basolateral amygdaloid nucleus). The neuronal labeling in these regions became much more intense four days after the virus injection. At the four-day post injection period, the submedius nucleus of the thalamus also contained many labeled neurons. In addition, retrograde labeling simultaneously occurred in the brainstem regions, such as the parabrachial nuclei and the caudal division of the spinal trigeminal nucleus. At the same timing or a little later stage, labeled neurons were seen in the trigeminal ganglion. The present results suggest that the ascending pathways linking the trigeminal ganglion and the anterior cingulate cortex may play important roles in the processing of noxious information in association with the emotional aspect of pain.

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   Glutamate and its receptors play a critical role in the process of nociceptive transmission at the spinal cord. Recent studies have shown that multiple glutamate receptors are also expressed on peripheral primary afferent terminals, and they may contribute to peripheral nociceptive signaling. In the present study, evoked pain sensation and axon reflex were evaluated in order to investigate whether the subcutaneous injection of glutamate excites nociceptors. In human study, 1.0M glutamate was subcutaneously injected into the forearms of 8 healthy human volunteers. Glutamate caused severe pain immediately after injection and a peak pain was observed within 5 minutes. Although the intensity of pain gradually decreased, slight pain was still observed 15 min after injection. The area which exceeds the average skin temperature prior to injection, monitored by thermography, started to increase about 3 min after injection, reached a peak in 20-25 min and then decayed gradually. In rats, 1.0M, 0.5M or 0.1M glutamate was subcutaneously injected into the sole of hindpaws. 1.0M and 0.5M glutamate, but not 0.1M glutamate produced a significant skin temperature increase on the side ipsilateral to the injection site compared to the contralateral side. The skin temperature of the ipsilateral paw increased immediately after injection, reached a peak in 5-10 min and then decayed to the same degree as contralateral paw 60 min after injection. Increase of skin temperature induced by 1.0M or 0.5M glutamate was significantly larger than increase induced by 0.1M glutamate for 60 minutes after injection. Conversely, co-injection of 0.25% lidocaine with 1.0M glutamate did not produce a significant increase of skin temperature. These data demonstrate that subcutaneous injection of glutamate evokes pain sensation and axon reflex. It is suggested that peripheral glutamate would create a vicious circle where pain is maintained if glutamate is released from peripheral terminals via axon reflex following nociceptive stimulus.

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   Although intrathecal administration of adenosine analogues is known to result in antinociception, cellular mechanisms for this action have not been fully addressed yet. We examined a detail of the actions of adenosine on holding currents, excitatory (glutamatergic) and inhibitory (GABAergic and glycinergic) transmission in substantia gelatinosa (SG) neurons of an adult rat spinal cord slice, and compared their actions in efficacy with each other. Superfusing adenosine (1 mM) induced a current (peak amplitude: 17.6 ± 1.8 pA at -70 mV, n=30) which reversed at a potential being close to the equilibrium potential for K⁺. K⁺-channel inhibitors, Ba²⁺ (100 µM) and 4-aminopyridine (5 mM), reduced the peak amplitude of this current by 65 ± 8% (n=3) and 46 ± 3% (n=3), respectively. An A₁ adenosine-receptor agonist, N⁶-cyclopentyladenosine (CPA, 1 µM), produced a similar outward current having a peak amplitude of 17.6 ± 2.9 pA (n=3) at -70 mV. Adenosine (100 µM) and CPA (1 µM) reduced the peak amplitude of dorsal root-evoked monosynaptic Aδ -fiber EPSCs by 39 ± 5% (n=15) and 50 ± 4% (n=3), respectively. Focally-evoked GABAergic and glycinergic IPSCs in the presence of a non-NMDA receptor antagonist (CNQX) were also reduced in peak amplitude by adenosine [100 µM; by 39 ± 6% (n=6) and 50 ± 7% (n=4), respectively] or CPA [1 µM; by 55 ± 6% (n=3) and 51 ± 17% (n=3), respectively]. All of the adenosine actions were inhibited by an A₁ antagonist, 8-cyclopentyl 1,3-dipropylxanthine (1 µM). With respect to efficacies of adenosine, EC₅₀ values for adenosine in inducing outward currents (hyperpolarizations) and reducing monosynaptic Aδ -fiber EPSC, GABAergic and glycinergic IPSC amplitudes were 130, 130, 24 and 21 µM, respectively. It is concluded in SG neurons that adenosine at low doses depresses inhibitory transmission while adenosine at high doses induces hyperpolarization and inhibits excitatory transmission, all of which are due to the activation of A₁ receptors. Considering that the SG plays a pivotal role in modulating nociceptive transmission from the periphery, it is suggested that adenosine at low and high concentrations may elicit nociception and antinociception, respectively.

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   It is widely known that sensation of the pain is derived from sensory-discriminative factor and emotional factor. Especially in chronic pain, emotional factors and psychosocial backgrounds are more likely to contribute for the patients' discomfort. The aim of this study is to investigate how emotional factor of pain participates in intractable pain. We employed fMRI to compare the brain activations occurring in the orthopaedic neuropathic pain patients with allodynia and normal individuals in response to the visual virtual painful experience. During fMRI scanning, a video demonstrating an actual tactile stimulation of the palm and its imitation were shown to participants. In contrast to normal individuals,allodynia patients also displayed activation of the areas reflecting emotions: frontal lobe and anterior cingulate. These findings suggest that brain have important role in the development and maintaining of peripheral originated chronic painful condition.

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