A prominent signaling pathway in the development of neuropathic pain involves ATP acting on microglial purinergic receptors. Among the P2Y metabotropic receptors, we reported before that the P2Y12 receptor is upregulated in microglia following nerve injury and involved in the phosphorylation of p38 MAPK, and in the development of pain behavior. In this study, we examined the expression of P2Y6, P2Y13, and P2Y14 receptors in the spinal cord and whether these receptors are involved in the pathogenesis of neuropathic pain following peripheral nerve injury. We found that spared nerve injury induced a dramatic increase of not only P2Y12, but also P2Y6, 13, and 14 receptor mRNA expression in spinal microglia. The increase continued for at least 2 weeks after injury. To determine whether p38 MAPK can induce the expression of P2Y receptors, we administered intrathecally the p38 MAPK inhibitor SB203580 and found that it significantly suppressed P2Y6, P2Y13, and P2Y14 but not P2Y12 mRNAs. Intrathecal injection of the specific P2Y6 antagonist MRS2578, specific P2Y13 antagonist MRS2211 or P2Y14 antisense LNA, attenuated mechanical pain hypersensitivity. The mixture of three antagonists for P2Y6, 12, and 13 showed a longer suppressive effect on pain behavior than the individual treatments. Our data demonstrate that ATP and other nucleotides may stimulate activated microglia with the upregulation of P2Y6, P2Y12, P2Y13, and P2Y14 receptors following nerve injury and these receptors are involved in the development of neuropathic pain.
Cancer pain management is centered on opioid therapy. In Japan, 3 types of strong opioid are available for treatment; therefore it is important to use them according to the characteristics of each drug and dosage form. Particularly, oxycodone is suitable as first‐line choice of opioid, which can also be employed as opioid switching when symptoms of the central nervous system is manifested following the use of oral morphine. Furthermore, opioid responsiveness should be taken into account when opioid therapy is carried out; assessment of the analgesic effect is particularly important. Recently, we tried to select suitable treatment modalities by speculating on the pathologic conditions of pain relative to the responsiveness to morphine and causes of pain. In the case of pain with low response to morphine, it was possible to attain good pain control not only by opioid therapy but also by a combination of opioid therapy and nerve block therapy. In cancer pain treatment, appropriate assessment of pathologic conditions of pain and selection of adequate and accurate treatment modalities are essential for improvement of the effect of pain relief.
Intraoperative coursePrior to surgery, a silicone subarachnoidal drainage tube [Silascon (Kaneka Medix, Osaka, Japan), 5 Fr] was inserted from L3 to L4 (5 cm on the cephalad side) to monitor cerebrospinal pressure and to facilitate the suction of cerebrospinal fluid. The patient was positioned for left posterolateral thoracotomy. The cardiopulmonary bypass was obtained by cannulating the right femoral artery and vein, and the pulmonary artery. The venous cannula was advanced to the right atrium, and then the patient was cooled until a blood temperature of 23.5°C and rectal temperature of 25.4°C were reached. Methylprednisolone (1 g) and pentobarbital (250 mg) were given during cooling. Upon circulatory arrest, the patient was placed in the Trendelenburg position and his head was wrapped in a cold ice bag. The circulation was arrested for 28 min. Simultaneously, retrograde cerebral perfusion was performed through the right atrium, and the flow rate was controlled at around 600 ml·min Ϫ1
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