δ-阿片受体抑制阿片诱发痛觉过敏的研究进展

背景 阿片类药物是治疗中、重度疼痛的主要药物,长时间应用可出现阿片诱发的痛觉过敏和耐受,而增加药物剂量可造成更严重的痛觉过敏和耐受,从而形成恶性循环,很大程度上限制了阿片类药物在临床工作中的应用.目的 通过对近年δ-阿片受体在痛觉过敏中所起作用的研究进行总结,帮助读者了解国外相关研究的最新趋势和进展.内容 就δ-阿片受体的结构、分布、生理功能和δ-阿片受体的抗痛觉过敏作用的研究进展进行综述.得出如下结论,通过抑制δ-阿片受体磷酸化、敲除δ-阿片受体编码基因和应用δ-阿片受体拮抗剂等方法,可抑制痛觉过敏和耐受的形成.趋向 随着越来越多的学者对δ-阿片受体抑制痛觉过敏的作用达成共识,δ-阿片受体有望成为临床疼痛治疗的新靶点.     

吗啡增强痛觉敏感性机制的研究进展

阿片类物质是传统的镇痛药,用药过程中会出现耐受现象,吗啡耐受现象已经较早被认识并研究。药理学上的吗啡耐受是指吗啡反复使用后其镇痛作用减退或消失,需加大药量才能恢复到耐受前的效果。近30年来研究发现吗啡耐受同时伴有痛觉敏感性的增加,出现痛觉过敏、触诱发痛等现象。由于吗啡耐受及痛觉敏感性的增加都以患者疼痛感觉加剧、吗啡镇痛效果下降为表现,因此医疗工作者只是一味加大吗啡用量,忽视了耐受背后隐藏的痛觉敏感性改变。吗啡导致的痛觉敏感性增强表现为疼痛阈值降低,疼痛强度加大、分布范围变广,     

NMDA受体在痛敏及阿片耐受和依赖中的作用

NMDA受体通过与阿片受体之间的相互作用，介导痛觉过敏以及阿片耐受和依赖的形成和发展，为临床疼痛治疗和阿片类药物依赖的防治提供了新的思路。     

糖皮质激素受体参与阿片耐受机制的研究进展

阿片药物耐受是影响临床应用阿片类药物进行疼痛治疗的主要问题.阿片药物耐受机制复杂,有许多调节因素参与其中.近年的研究提示,糖皮质激素受体在阿片耐受机制的各个环节中均发挥调节作用.如能合理利用糖皮质激素受体的这种调节作用,来找到治疗阿片耐受的突破点,将为难治性疼痛的治疗带来福音.     

NMDA受体在痛敏及阿片耐受和依赖中的作用

NMDA受体通过与阿片受体之间的相互作用,介导痛觉过敏以及阿片耐受和依赖的形成和发展,为临床疼痛治 疗和阿片类药物依赖的防治提供了新的思路。     

氢吗啡酮预防瑞芬太尼复合麻醉患者术后痛觉过敏的临床效果

<正>瑞芬太尼是一种超短效阿片受体激动药,镇痛效应强,起效迅速、剂量易控制,持续输注无蓄积,已广泛应用于临床麻醉。但停药后其镇痛作用迅速消失,可诱发术后急性痛觉过敏[1,2],需要其他药物来抑制痛觉过敏。氢吗啡酮是吗啡的衍生物,其主要作用于μ受体,镇痛效力为吗啡的8~10倍,且不良反应少,能够提供较好的镇痛镇静效果[3,4]。本研究拟对国产氢吗啡酮对瑞芬太尼复合麻醉术后麻醉恢复期痛觉过敏的临床疗效进行评价,为临床应用提供参考。     

吗啡耐受的治疗进展

背景 吗啡作为治疗中到重度疼痛,特别是晚期癌痛的强效药物,长期应用后会出现耐受.吗啡耐受机制研究的不断深入为其治疗提供了大量的思路.目的 文章就近年来的实验研究进展进行综述,以期为吗啡耐受的治疗提供实验室和临床方面的参考.内容 许多学者们发现多种治疗手段均可延缓甚或逆转吗啡耐受,综述主要介绍药物以及针刺治疗.趋向 吗啡与多种药物的联合应用或针刺治疗可能是吗啡耐受治疗的趋势.     

阿片类药物诱发痛觉过敏的药物干预

摘要应用阿片类药物进行镇痛时可能诱发痛觉过敏,此时增加阿片类药物的剂量不仅不能加强其镇痛效果,反而可能导致疼痛加剧,在这种情况下需应用其他的镇痛药物进行干预。该文总结可用于阿片类药物诱发痛觉过敏的药物及其作用机制,为临床医生选择镇痛药物提供参考。     

兴奋性氨基酸及其受体与阿片耐受

运用阿片类药物治疗疼痛时常产生耐受,而致阿片类药效降低。大量研究表明兴奋性氨基酸及其受体参与影响了阿片类药物的抗伤害性作用及其耐受机制。近年来众多学者通过对兴奋性氨基酸受体进行干预,在增强阿片类药物抗伤害作用的同时抑制其耐受的发展,证明其在阿片耐受的机制中产生了重要影响,并为临床阿片治疗急慢性疼痛提供了新的治疗方案。     

加巴喷丁用于雷米芬太尼复合丙泊酚全麻术后的镇痛效果

雷米芬太尼凭借其起效快、清除快和长时间输注无蓄积等特点在临床上得到了广泛应用.但因其快速代谢的特点,停药后,镇痛作用消失快,导致明显的术后疼痛.甚至会引起痛阈降低和痛觉过敏.加巴喷丁是一种新型的抗癫痫药物,动物实验及临床研究均表明具有抗痛觉过敏作用,可增强吗啡的抗伤害感受作用,不良反应轻微.本研究拟观察加巴喷丁用于雷米芬太尼复合麻醉腹腔镜胆囊切除手术后的镇痛效果及不良反应.从而评价其疗效及安全性.     

Ketamine improves the management of exaggerated postoperative pain observed in perioperative fentanyl-treated rats

BACKGROUND: Although opioids are unsurpassed analgesics, experimental and clinical studies suggest that opioids activate N-methyl-d-aspartate pronociceptive systems leading to pain hypersensitivity and short-term tolerance. Because it is difficult in humans to differentiate pain from hyperalgesia during the postoperative period, the authors performed experimental studies with fentanyl using the rat incisional pain model for evaluating relations between hyperalgesia and short-term tolerance. Because N-methyl-d-aspartate receptor antagonists oppose both pain hypersensitivity and tolerance induced by opioids, the authors examined the capability of ketamine for improving exaggerated postoperative pain management. METHODS: During halothane anesthesia, a hind paw plantar incision was performed in rats receiving four fentanyl subcutaneous injections (100 microg/kg per injection, every 15 min). In some groups, three subcutaneous ketamine injections (10 mg/kg per injection, every 5 h) were performed in saline- or fentanyl-treated rats. One day after surgery, the analgesic effect of morphine (2 mg/kg subcutaneous) was tested. Analgesia, mechanical hyperalgesia, tactile allodynia, and pain score were assessed for several days using the paw pressure vocalization test, the von Frey application test, and the postural disequilibrium test. RESULTS: Fentanyl induced analgesia but also produced exaggerated postoperative pain as indicated by the enhancement of hyperalgesia, allodynia, and weight-bearing decrease after hind paw plantar incision. Ketamine pretreatment prevented such a fentanyl-induced enhancement of postoperative pain and improved its management by morphine. CONCLUSIONS: By opposing postoperative pain hypersensitivity and subsequent short-term tolerance induced by perioperative opioid use, ketamine not only improves exaggerated postoperative pain management but also provides better postoperative rehabilitation.     

Ketamine Improves the Management of Exaggerated Postoperative Pain Observed in Perioperative Fentanyl-treated Rats

Background: Although opioids are unsurpassed analgesics, experimental and clinical studies suggest that opioids activate N-methyl-d-aspartate pronociceptive systems leading to pain hypersensitivity and short-term tolerance. Because it is difficult in humans to differentiate pain from hyperalgesia during the postoperative period, the authors performed experimental studies with fentanyl using the rat incisional pain model for evaluating relations between hyperalgesia and short-term tolerance. Because N-methyl-d-aspartate receptor antagonists oppose both pain hypersensitivity and tolerance induced by opioids, the authors examined the capability of ketamine for improving exaggerated postoperative pain management.

Methods: During halothane anesthesia, a hind paw plantar incision was performed in rats receiving four fentanyl subcutaneous injections (100 [mu]g/kg per injection, every 15 min). In some groups, three subcutaneous ketamine injections (10 mg/kg per injection, every 5 h) were performed in saline- or fentanyl-treated rats. One day after surgery, the analgesic effect of morphine (2 mg/kg subcutaneous) was tested. Analgesia, mechanical hyperalgesia, tactile allodynia, and pain score were assessed for several days using the paw pressure vocalization test, the von Frey application test, and the postural disequilibrium test.

Results: Fentanyl induced analgesia but also produced exaggerated postoperative pain as indicated by the enhancement of hyperalgesia, allodynia, and weight-bearing decrease after hind paw plantar incision. Ketamine pretreatment prevented such a fentanyl-induced enhancement of postoperative pain and improved its management by morphine.     

Nitrous oxide revisited: evidence for potent antihyperalgesic properties

BACKGROUND: Although opioids are unsurpassed analgesics for surgery, they also induce an N-methyl-D-aspartate-dependent enhancement of postoperative hyperalgesia. Because nitrous oxide (N2O) has anti-N-methyl-D-aspartate properties, the purpose of this study was to evaluate nitrous oxide ability to prevent such an opioid-induced hyperalgesia in rats. METHODS: First, preventive effects of 50/50% N2O-O2 on the development of delayed hyperalgesia observed after inflammatory pain (hind paw carrageenan injection on D0) were examined for several days. Second, the ability of nitrous oxide (10-40%) to limit opioid-induced hyperalgesia induced by fentanyl was evaluated in nonsuffering rats. Third, antihyperalgesic effects of various nitrous oxide concentrations (20-50%) were assessed in both inflammatory and incisional pain models in fentanyl-treated rats (4 x 100 microg/kg subcutaneously). Finally, the analgesic effect of a single dose of morphine was evaluated 24 h after fentanyl administration and nitrous oxide (D0) to assess its preventive effect on acute morphine tolerance in both nonsuffering and hind paw-incised rats. RESULTS: When applied on D0, nitrous oxide reduced delayed hyperalgesia induced by inflammation. Exposure to nitrous oxide on D0 also reduced opioid-induced hyperalgesia in nonsuffering rats in a dose-dependent manner. In fentanyl-treated rats with inflammatory or incisional pain, nitrous oxide strongly limited both magnitude and duration of hyperalgesia. Moreover, nitrous oxide exposure on D0 opposed development of acute tolerance to analgesic effects of morphine administered on D1 in both nonsuffering and incised fentanyl-treated rats. CONCLUSIONS: Nitrous oxide, an N-methyl-D-aspartate receptor antagonist, prevented the enhancement of pain sensitivity induced by both nociceptive inputs and fentanyl and opposed acute morphine tolerance. Results suggest that perioperative nitrous oxide use reduces exaggerated postoperative pain and morphine consumption.     

The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance

Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-D-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): -15.8%, -46.6%, -85.1% (4 x 20, 4 x 60, 4 x 100 microg/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 x 60 microg/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness. IMPLICATIONS: Fentanyl-induced analgesia is followed by early hyperalgesia (hours), acute tolerance to the analgesic effects of morphine, and long-lasting hyperalgesia (days). All these phenomena are totally prevented by repeated administrations of the NMDA-receptor antagonist, ketamine, simultaneously with fentanyl and morphine administration.     

Variation in opioid use during PCA in adolescents

The objective of this investigation was to determine if the variability in the use of opioids for pain following surgery is related to variability in blood concentration of opioids used for pain relief. We measured morphine use and morphine blood concentration in a group of otherwise healthy adolescent girls following spinal surgery. There was considerable variability in morphine use and morphine blood levels as indicated by a large range of values and a moderately large standard deviation. Morphine blood concentration correlated with morphine use. Neither morphine use nor morphine concentration correlated with pain scores. The data indicate that there is considerable variability among patients in the amount of opioid needed to achieve comfort and in the blood concentration associated with comfort. The cause of this variability does not appear to be related to metabolism of opioid, but may be related to psychological differences, differences in pain tolerance and threshold, or differences in the way patients use PCA.     

The role of opioid receptor internalization and beta-arrestins in the development of opioid tolerance

Opioid tolerance, a phenomenon characterized by decreased analgesic effects obtained by the same dose of opioids after repeated use of the opioids, is a significant clinical problem. Traditional theory attributes receptor desensitization and internalization and post-receptor adaptation to the development of opioid tolerance. However, morphine, a commonly used opioid, induces tolerance but is not an effective drug to induce opioid receptor desensitization and internalization. Recent studies found that internalized opioid receptors can become competent receptors and recycle back to the cell surface membrane after dephosphorylation. Thus, receptor internalization may be a way to reduce opioid tolerance. Multiple studies have suggested a key role of beta-arrestins in opioid receptor desensitization and internalization and opioid tolerance. Although beta-arrestin 1 and beta-arrestin 2 are important for these effects induced by opioids with high intrinsic efficacy such as etorphine and fentanyl, morphine tolerance may be mediated mainly via beta-arrestin 2. Modification of opioid receptor internalization by affecting the interaction between opioid receptors and beta-arrestins may be a therapeutic target for reducing opioid tolerance.     

Nitrous Oxide Revisited: Evidence for Potent Antihyperalgesic Properties

Background: Although opioids are unsurpassed analgesics for surgery, they also induce an N-methyl-d-aspartate-dependent enhancement of postoperative hyperalgesia. Because nitrous oxide (N2O) has anti-N-methyl-d-aspartate properties, the purpose of this study was to evaluate nitrous oxide ability to prevent such an opioid-induced hyperalgesia in rats.

Methods: First, preventive effects of 50/50% N2O-O2 on the development of delayed hyperalgesia observed after inflammatory pain (hind paw carrageenan injection on D0) were examined for several days. Second, the ability of nitrous oxide (10-40%) to limit opioid-induced hyperalgesia induced by fentanyl was evaluated in nonsuffering rats. Third, antihyperalgesic effects of various nitrous oxide concentrations (20-50%) were assessed in both inflammatory and incisional pain models in fentanyl-treated rats (4 x 100 [mu]g/kg subcutaneously). Finally, the analgesic effect of a single dose of morphine was evaluated 24 h after fentanyl administration and nitrous oxide (D0) to assess its preventive effect on acute morphine tolerance in both nonsuffering and hind paw-incised rats.

Results: When applied on D0, nitrous oxide reduced delayed hyperalgesia induced by inflammation. Exposure to nitrous oxide on D0 also reduced opioid-induced hyperalgesia in nonsuffering rats in a dose-dependent manner. In fentanyl-treated rats with inflammatory or incisional pain, nitrous oxide strongly limited both magnitude and duration of hyperalgesia. Moreover, nitrous oxide exposure on D0 opposed development of acute tolerance to analgesic effects of morphine administered on D1 in both nonsuffering and incised fentanyl-treated rats.     

Modulation of remifentanil-induced analgesia,hyperalgesia, and tolerance by small-dose ketamine in humans

Adding a small dose of ketamine to opioids may increase the analgesic effect and prevent opioid-induced hyperalgesia and acute tolerance to opioids. In this randomized, double-blinded, placebo-controlled crossover study, we investigated the effect of remifentanil combined with small concentrations of ketamine on different experimental pain models. Pain detection thresholds to single and repeated IM electrical stimulation and to repeated transcutaneous electrical stimulation, pressure pain tolerance threshold, and sedative, respiratory, and cardiovascular side effects were assessed in 14 healthy volunteers. Saline, remifentanil alone, and remifentanil combined with ketamine at target plasma concentrations of 50 or 100 ng/mL were administered in four study sessions. The ketamine infusion was started after baseline testing at a constant target concentration. Remifentanil was started after testing with ketamine alone at an initial target concentration of 1 ng/mL and then increased to 2 ng/mL and decreased to 1 ng/mL. The last test series were started 10 min after discontinuation of remifentanil. Acute remifentanil-induced hyperalgesia and tolerance were detected only by the pressure pain test and were not suppressed by ketamine. Remifentanil alone induced significant analgesia with all pain tests. Ketamine further increased the remifentanil effect only on IM electrical pain. Remifentanil at a 2 ng/mL target concentration induced a slight respiratory depression that was antagonized by ketamine. We conclude that ketamine effects on opioid analgesia are pain-modality specific. IMPLICATIONS: Coadministration of ketamine and morphine for pain relief is still controversial. Our experimental pain study with volunteers showed that ketamine enhances opioid analgesia without increasing sedation and reduces respiratory depression. Opioid-induced hyperalgesia and tolerance were not affected by ketamine and depended on the type of nociceptive stimulus. This may explain the conflicting results on opioid tolerance in previous studies.     

Characterization of the antinociceptive and pronociceptive effects of methadone in rats

BACKGROUND: Recently, it has been appreciated that in addition to their antinociceptive properties, opioid analgesics also can enhance pain sensitivity (opioid-induced hyperalgesia [OIH]). OIH may enhance preexisting pain and contribute to dose escalation, tolerance, and misuse/abuse of opioids. Better information is needed to determine which opioid or opioid combinations may be least likely to produce OIH and therefore possibly represent better choices for pain management. Herein the authors have examined the hyperalgesic and antinociceptive properties of racemic methadone and its enantiomers alone and in combination with morphine in rats. Methadone is of particular interest because it possesses both micro-receptor agonist and N-methyl-d-aspartate receptor antagonist activities. METHODS: The antinociceptive and hyperalgesic properties of d,l-methadone, l-methadone, and d-methadone were characterized by dose and sex using the thermal tail-flick test (high and low intensity). The responses to l- and d-methadone combinations with morphine were also determined with this model. RESULTS: Antinociceptive and hyperalgesic effects of d,l-methadone were demonstrated. These effects were related to dose but not to sex. The degree of hyperalgesia was greater with l-methadone compared with d,l-methadone. In contrast, d-methadone (N-methyl-d-aspartate antagonist) did not produce hyperalgesia. Furthermore, d-methadone blocked morphine hyperalgesia, enhanced antinociception, and abolished sex-related differences. This seems to be the result of antagonistic activity of d-methadone at the N-methyl-d-aspartate receptor. CONCLUSION: The current findings with methadone are supportive of previous findings implicating mu-opioid and N-methyl-d-aspartate receptor mechanisms in OIH. Better understanding of OIH may help in choosing the most appropriate opioids for use in the treatment of pain.     

Do opioids induce hyperalgesia?

Opioids are the most potent drugs for treatment of acute and chronic pain. However, accumulating evidence suggests that opioids may paradoxically also enhance pain, often referred to as opioid-induced hyperalgesia. Opioid-induced hyperalgesia is defined as an increased sensitivity to pain or a decreased pain threshold in response to opioid therapy. Several mechanisms have been proposed to support opioid-induced hyperalgesia. However, it remains unclear whether opioid-induced hyperalgesia develops during continuous chronic application of opioids or on their withdrawal. This review provides a comprehensive summary of clinical research concerning opioid-induced hyperalgesia and the molecular mechanisms of opioid withdrawal and opioid tolerance and other potential mechanisms which might induce hyperalgesia during opioid therapy will be discussed. The status quo of our knowledge will be summarized and the clinical relevance of opioid-induced hyperalgesia will be discussed.