Language：English   Publishing type：Research paper (scientific journal)  

Opioid usage for pain therapy is limited by its undesirable clinical effects, including paradoxical hyperalgesia, also known as opioid-induced hyperalgesia (OIH). However, the mechanisms associated with the development and maintenance of OIH remain unclear. Here, we investigated the effect of serotonin inhibition by the 5-HT3 receptor antagonist, ondansetron (OND), as well as serotonin deprivation via its synthesis inhibitor para-chlorophenylalanine, on mouse OIH models, with particular focus on astrocyte activation. Co-administering of OND and morphine, in combination with serotonin depletion, inhibited mechanical hyperalgesia and astrocyte activation in the spinal dorsal horn of mouse OIH models. Although previous studies have suggested that activation of astrocytes in the spinal dorsal horn is essential for the development and maintenance of OIH, herein, treatment with carbenoxolone (CBX), a gap junction inhibitor that suppresses astrocyte activation, did not ameliorate mechanical hyperalgesia in mouse OIH models. These results indicate that serotonin in the spinal dorsal horn, and activation of the 5-HT3 receptor play essential roles in OIH induced by chronic morphine, while astrocyte activation in the spinal dorsal horn serves as a secondary effect of OIH. Our findings further suggest that serotonergic regulation in the spinal dorsal horn may be a therapeutic target of OIH. PERSPECTIVE: The current study revealed that the descending serotonergic pain-facilitatory system in the spinal dorsal horn is crucial in OIH, and that activation of astrocytes is a secondary phenotype of OIH. Our study offers new therapeutic targets for OIH and may help reduce inappropriate opioid use.

DOI： 10.1016/j.jpain.2020.12.008

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

KEY POINTS: Neuropathic pain spreads spatially beyond the injured sites, and the mechanism underlying the spread has been attributed to inflammation occurring in the spinal cord. However, the spatial spread of spinal/cortical potentiation induced by conduction block of the peripheral nerves can be observed prior to inflammation. In the present study, we found that spreading potentiation and hypersensitivity acutely induced by unilateral hindpaw ischaemia are nitric oxide (NO)-dependent and that NO is produced by ischaemia and quickly diffuses within the spinal cord. We also found that NO production induced by ischaemia is not observed in the presence of an antagonist for group II metabotropic glutamate receptors (mGluRs) and that neuronal NO synthase-positive dorsal horn neurons express group II mGluRs. These results suggest strongly that NO-mediated spreading potentiation in the spinal cord is one of the trigger mechanisms for neuropathic pain. ABSTRACT: Cortical/spinal responses to hindpaw stimulation are bilaterally potentiated by unilateral hindpaw ischaemia in mice. We tested the hypothesis that hindpaw ischaemia produces nitric oxide (NO), which diffuses in the spinal cord to induce spatially spreading potentiation. Using flavoprotein fluorescence imaging, we confirmed that the spreading potentiation in hindpaw responses was induced during ischaemia in the non-stimulated hindpaw. This spreading potentiation was blocked by spinal application of l-NAME, an inhibitor of NO synthase (NOS). Furthermore, no spreading potentiation was observed in neural NOS (nNOS) knockout mice. Spinal application of an NO donor was enough to induce cortical potentiation and mechanical hypersensitivity. The spatial distribution of NO during unilateral hindpaw ischaemia was visualized using 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM). An increase in fluorescence derived from the complex of DAF-FM with NO was observed on the ischaemic side of the spinal cord. A similar but smaller increase was also observed on the contralateral side. Somatosensory potentiation after hindpaw ischaemia is known to be inhibited by spinal application of LY354740, an agonist of group II metabotropic glutamate receptors (mGluRs). We confirmed that the spinal DAF-FM fluorescence increases during hindpaw ischaemia were not observed in the presence of LY354740. We also confirmed that approximately half of the nNOS-positive neurons in the superficial laminae of the dorsal horn expressed mGluR2 mRNA. These results suggest that disinhibition of mGluR2 produces NO which in turn induces a spreading potentiation in a wide area of the spinal cord. Such spreading, along with the consequent non-specific potentiation in the spinal cord, may trigger neuropathic pain.

DOI： 10.1113/JP277615

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

We evaluated an alternative technique for ultrasound-guided proximal level obturator nerve block that might facilitate needle visualisation using in-plane ultrasound guidance. Twenty patients undergoing transurethral bladder tumour resection requiring an obturator nerve block were enrolled into a prospective observational study. With the patient in the lithotomy position, the transducer was placed on the medial thigh along the extended line of the inguinal crease, and aimed cephalad to view a thick fascia between the pectineus and obturator externus muscles that contains the obturator nerve. A stimulating nerve block needle was inserted at the pubic region and advanced in-plane with the transducer in an anterior-to-posterior direction. Eight ml levobupivacaine 0.75% was injected within the fascia. The median (IQR [range]) duration for ultrasound identification of the target and injection were 8.5 (7-12 [5-24]) s and 62 (44.5-78.25 [39-383]) s, respectively. All blocks were successful. A cadaver evaluation demonstrated that the dye injected into the target fascia using our technique travelled retrogradely through the obturator canal, and surrounded the anterior and posterior branches of the obturator nerve both proximally and distally to the obturator canal. We believe that this is a promising new technique for ultrasound-guided proximal level obturator nerve block.

DOI： 10.1111/anae.13336

Web of Science

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Language：Japanese   Publisher：日本臨床麻酔学会  

声門近傍を占拠する喉頭乳頭腫を発症した5歳男児の麻酔を経験した.喉頭乳頭腫は嗄声や呼吸困難などの症状出現時,声門を閉塞するほど巨大化していることが多く,しばしば呼吸管理や気道確保法に難渋する.本症例では手術5日前のファイバー所見から右側臥位,喉頭展開による気管挿管が可能と判断されたが,短期間での腫瘍の急速な増大によって手技変更を余儀なくされ,結果的に気管支ファイバー挿管によって気道確保し得た.本疾患は,進行や再発による繰り返しの手術が必要となる.毎回の手術前の入念な気道評価とそれに基づいた麻酔計画の立案が重要である.また,気道確保の際には耳鼻咽喉科医と密な連携を取り,周到な準備が求められる.(著者抄録)

DOI： 10.2199/jjsca.32.791

CiNii Article

CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2013034782

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