正能量英文
1. 长期给予吗啡后突然停药，会引起痛觉过敏。在大鼠切口痛模型中，术前六天持续皮下给予纳洛酮20mg/kg/天会显著降低大鼠后爪的痛觉过敏。（Li X, Angst MS, Clark JD. Opioid-induced hyperalgesia and incisional pain. Anesth Analg. 2001 Jul;93(1):204-9.）
2. 术中应用大剂量雷米芬太尼（0.40μg ·kg-1 ·min-1）比应用小剂量雷米芬太尼（0.05μg ·kg-1 ·min-1）更容易引起痛觉过敏，而应用小剂量氯胺酮（术前0.5mg/kg，随后5 μg ·kg-1 ·min-1，术后2 μg ·kg-1 ·min-1持续48小时）会防止痛觉过敏。（Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative hyperalgesia and its prevention with small-do ketamine. Anesthesiology. 2005 Jul;103(1):147-55.）
3. 通过对大鼠腰段脊髓切片进行电生理研究发现，不含甘氨酸辅料的盐酸雷米芬太尼不能诱发NMDA受体通道的电流，而甘氨酸（雷米芬太尼制剂中的常用辅料）可以诱发NMDA受体通道电流，而且这种通道电流可以被NMDA谷氨酸位点的特异性拮抗剂２－氨基－５－磷酸基戊酸（APV）阻断，而含有甘氨酸辅料的盐酸雷米芬太尼能够诱发与甘氨酸基本一样的NMDA受体通道电流，而且这种电流同样也可以被２－氨基－５－磷酸基戊酸（APV）阻断。盐酸雷米芬太尼能够强化NMDA受体诱发的内向电流，而且这种强化作用可以被μ受体拮
抗剂纳洛酮消除。提示盐酸雷米芬太尼不能直接激活NMDA受体，但是可以通过阿片μ受体强化NMDA通道的作用瑞芬太尼不能直接激活NMDA受体，瑞芬太尼使用后诱导的NMDA受体激活主要通过一条含μ-阿片受体的调节通路来实现的，也就是说μ-阿片受体起着一个桥梁作用。（Guntz E, Dumont H, Rousl C, et al. Effects of remifentanil on N-methyl-D-aspartate receptor: an electrophysiologic study in rat spinal cord. Anesthesiology. 2005 Jun;102(6):1235-41.）；也有研究表明，雷米芬太尼对NMDA受体的这种作用仅是通过激活阿片δ受体实现的。（Zhao M, Joo DT. Enhancement of spinal N-methyl-D-aspartate receptor function by remifentanil action at delta-opioid receptors as a mechanism for acute opioid-induced hyperalgesia or tolerance. Anesthesiology. 2008 Aug;109 (2): 308-17.）
4. NMDA受体是异源多聚体聚合物，在神经病理性疼痛和癌性疼痛中起着重要的作用。（Saito O, Aoe T, Kozikowski A, et al. Ketamine and N-acetylaspartylglutamate peptida inhibitor exert analgesia in bone cancer pain. Can J Anaesth. 2006 Sep;53(9):891-8.）；（Metz AE, Yau HJ, Centeno MV, et al. Morphological and functional reorganization of rat medial prefrontal cortex in neuropathic pain. Proc Natl Acad Sci U S A. 2009 Feb 17;106(
7):2423-8）。其中调节亚单位中的NR2B起着关键性作用（Zhang W, Shi CX, Gu XP, et al. Ifenprodil induced antinociception and decread the expression of NR2B subunits in the dorsal horn after chronic dorsal root ganglia compression in rats. Anesth Analg. 2009 Mar;108(3):1015-20.）
5. Celerier观察到一氧化氮合酶基因敲除小鼠，瑞芬太尼使用后所诱导的痛觉高敏较野生型小鼠明显减弱。此结果提示一氧化氮合酶系统对术后急性疼痛和阿片诱导性痛觉高敏的发生过程中有促进作用，并将一氧化氮合酶系统和NMDA系统联系了起来。术中应用雷米芬太尼会加重术后疼痛的程度，而一氧化氮合酶系统起着重要作用。（Célérier E, González JR, Maldonado R, et al. Opioid-induced hyperalgesia in a murine model of postoperative pain: role of nitric oxide generated from the inducible nitric oxide syntha. Anesthesiology. 2006 Mar;104(3):546-55.）
6. 激动剂激活的受体与G蛋白偶联，引起细胞反应，随后被一系列G蛋白偶联受体激酶磷酸化，这些被磷酸化的G蛋白偶联受体作为底物用于结合调节蛋白β-arrestin，后者作为G蛋白偶联受体信号的负调节因子，能够使激动剂引起的反应脱敏。其它激酶，主要是第二
信使依赖性激酶也在G蛋白偶联受体反应的脱敏中起着重要作用。（G蛋白偶联受体减敏的主要机制是G蛋白偶联受体激酶或第二第二信使依赖性激酶或两者联合引起的G蛋白偶联受体磷酸化，）（Kelly E, Bailey CP, Henderson G. Agonist-lective mechanisms of GPCR densitization. Br J Pharmacol. 2008 Mar;153 Suppl 1:S379-88）
范斯沃斯7. 有证据表明阿片类药物诱导的促炎性胶质细胞激活，可以对抗阿片类药物的镇痛作用，引起阿片药物耐受和痛觉过敏，有可能是通过Toll样受体(TLR)4与髓样细胞分化蛋白2(MD-2)产生作用。（Hutchinson MR, Zhang Y, Shridhar M, et al. Evidence that opioids may have toll-like receptor 4 and MD-2 effects. Brain Behav Immun. 2010 Jan;24(1):83-95. Epub 2009 Aug 11.）
8. 虽然推测阿片类药物所导致的痛觉过敏是由具有神经兴奋性的葡萄糖醛苷代谢产物所引起，但是研究中发现，对经过盐酸纳曲酮预处理的小鼠和敲除μ、δ和k受体的小鼠应用芬太尼，没有产生镇痛作用，但是伤害性缩腿反应潜伏期显著降低，这种痛觉过敏能够被NMDA受体阻断剂MK-801阻断。由于芬太尼在体内进行生物转化时不产生任何葡萄糖醛苷代谢产物，因此，提示阿片类药物诱发产生的痛觉过敏可能与具有神经兴奋性的葡萄糖醛
净月潭国家森林公园
黄渤是哪里人苷代谢产物无关。（Waxman AR, Arout C, Caldwell M, et al. Acute and chronic fentanyl administration caus hyperalgesia independently of opioid receptor activity in mice. Neurosci Lett. 2009 Oct 2;462(1):68-72）
9. μ阿片受体与NMDA受体共同启动了痛觉过敏，但是维持仅是依靠NMDA受体的激活。（Suarez-Roca H, Silva JA, Arcaya JL, Quintero L, et al. Role of mu-opioid and NMDA receptors in the development and maintenance of repeated swim stress-induced thermal hyperalgesia. Behav Brain Res. 2006 Feb 28;167(2):205-11）
写雷锋日记10. 纳洛酮在非常低剂量的时候具有镇痛作用，而在较高剂量的时候不具备这种作用。（Sloan P, Hamann S. Ultra-low-do opioid antagonists to enhance opioid analgesia. J Opioid Manag. 2006 Sep-Oct;2(5):295-304）
11. 羟考酮与极低剂量的纳曲酮联合应用，能够产生很好的镇痛作用。（Webster LR, Butera PG, Moran LV, et al. Oxytrex minimizes physical dependence while providing effective analgesia: a randomized controlled trial in low back pain. J Pain. 2006 Dec;7(12):937-46）
12.环丁甲羟氢吗啡（nalbuphine）与纳洛酮联合应用对患者妇科手术患者的术后疼痛有好处。（Gordon AT, Levine JD, Dubois MY, et al. Open-label exploration of an intravenous nalbuphine and naloxone mixture as an analgesic agent following gynecologic surgery. Pain Med. 2007 Sep;8(6):525-30）百香果柠檬蜂蜜
古代四大丑女13. 小剂量纳洛酮加入到用于臂丛神经阻滞的利多卡因溶液中，无论该溶液中是否含有芬太尼，都会延长臂丛神经阻滞的镇痛时间。（Movafegh A, Nouralishahi B, Sadeghi M, et al. An ultra-low do of naloxone added to lidocaine or lidocaine-fentanyl mixture prolongs axillary brachial plexus blockade. Anesth Analg. 2009 Nov;109(5):1679-83）
14. Anesthesiology. 2008 Mar;108(3):484-94.
Gabapentin prevents delayed and long-lasting hyperalgesia induced by fentanyl in rats.团支书申请书
Van Elstraete AC, Sitbon P, Mazoit JX, Benhamou D.
Université Paris-Sud, Assistance Publique-Hôpitaux de Paris, Département d'Anesthésie-Réanimation, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France.
Comment in:
Anesthesiology. 2008 Mar;108(3):352-4.
BACKGROUND: Opioid-induced hyperalgesia can develop rapidly after opioid exposure. Neuropathic pain and opioid-induced hyperalgesia share common pathophysiologic mechanisms. Gabapentin is effective for the management of neuropathic pain and may therefore prevent opioid-induced hyperalgesia. This study tested the effectiveness of gabapentin for prevention of long-lasting hyperalgesia induced by acute systemic fentanyl in uninjured rats. Involvement of the alpha2delta auxiliary subunits of voltage-gated calcium channels in the prevention of opioid-induced hyperalgesia by gabapentin also was assd. METHODS: Hyperalgesia was induced in male Sprague-Dawley rats with subcutaneous fentanyl (four injections, 20, 60, or 100 microg/kg per injection at 15-min intervals). Intraperitoneal (30, 75, 150, or 300 mg/kg) or intrathecal (300 microg) gabapentin was administered 30 min before or 300 min after (intraperitoneal 150 mg/kg) the first fentanyl injection. Sensitivity to nociceptive stimuli (paw-pressure test) was ass
d on the day of the experiment and for veral days after injections. The effects combining gabapentin with intrathecal ruthenium red (20 ng) also were assd. RESULTS: Fentanyl administration was followed by an early increa (analgesia) and by a later and sustained decrea (hyperalgesia) in nociceptive thresholds. Gabapentin did not significantly modify the early analgesic component but do-dependently prevented the delayed decrea in nociceptive threshold. Ruthenium red partially, but significantly, oppod the prevention of opioid-induced hyperalgesia by gabapentin. CONCLUSIONS: Intraperitoneal and intrathecal gabapentin prevents the development of hyperalgesia induced by acute systemic exposure to opioids. This prevention may result, at least in part, from binding of gabapentin to the alpha2delta auxiliary subunits of voltage-gated calcium channels.
