吗啡耐受及内脏痛敏的相关机理

目的　吗啡耐受是一种潜在的痛觉过敏 ,慢性内脏炎痛刺激后也产生内脏痛敏。因此探讨慢性内脏炎痛刺激及吗啡耐受间共同的细胞机理及N 甲基 D 天冬氨酸 (NMDA)受体相关的调节机理 ,为合理用药及药物开发提供实验依据。方法　利用急慢性内脏痛炎痛模型 ,直肠扩张痛阈测定及生物化学检测的方法进行机理研究。结果　结肠炎症和慢性吗啡耐受的大鼠均出现直肠扩张痛阈降低 ,即内脏痛敏现象 ,而慢性地佐环平 (MK 80 1)和L NG 硝基精氨酸甲酯 (L NAME)处理吗啡组的平均痛阈末见明显改变。内脏炎痛和耐受组大鼠脊髓及海马部位一氧化氮合酶 (NOS)上调 ,而MK 80 1和L NAME预处理组含量无明显变化。慢性内脏炎痛及吗啡耐受组背角神经元 [Ca2 + ]i 显著增高 ,而MK 80 1预处理的炎痛及耐受组则无明显改变。结论　吗啡耐受和痛觉敏感化在机理上存在某些共同之处 ,均在NMDA受体的激活、一氧化氮生成及细胞内钙上发生可塑性变化。     

外周神经损伤诱发异常传入性活动的动力学变化

外周神经受到损伤的初期,损伤区传递冲动能力减弱和速度减慢,随后发生传导阻滞和神经髓鞘膜脱落的形态学病变。此时可记录到不同类型的传入神经纤维的异常传入放电活动,粗纤维产生规则的高频的异位放电,细纤维有不规则的阵发性放电。对脱髓鞘膜区进行逆行性刺激可引起放电频率增加,单次脉冲的逆行性刺激可使部分C类纤维产生多次的异位放电。脱髓鞘膜区对K~ 通道阻断剂以及外源性的去甲肾上腺素异常敏感,提示异常电活动是受伤神经区轴突膜上离子通道和介质受体发生变化的结果。     

Sumatriptan (5-HT1B/1D-agonist) causes a transient allodynia

Unpleasant sensory symptoms are commonly reported in association with the use of 5-HT1B/1D-agonists, i.e. triptans. In particular, pain/pressure symptoms from the chest and neck have restricted the use of triptans in the acute treatment of migraine. The cause of these triptan induced side-effects is still unidentified. We have now tested the hypothesis that sumatriptan influences the perception of tactile and thermal stimuli in humans in a randomized, double-blind, placebo-controlled cross-over study. Two groups were tested; one consisted of 12 (mean age 41.2 years, 10 women) subjects with migraine and a history of cutaneous allodynia in association with sumatriptan treatment. Twelve healthy subjects (mean age 38.7 years, 10 women) without migraine served as control group. During pain- and medication-free intervals tactile directional sensibility, perception of dynamic touch (brush) and thermal sensory and pain thresholds were studied on the dorsal side of the left hand. Measurements were performed before, 20, and 40 min after injection of 6 mg sumatriptan or saline. Twenty minutes after injection, sumatriptan caused a significant placebo-subtracted increase in brush-evoked feeling of unpleasantness in both groups (P < 0.01), an increase in brush-evoked pain in migraineurs only (P = 0.021), a reduction of heat pain threshold in all participants pooled (P = 0.031), and a reduction of cold pain threshold in controls only (P = 0.013). At 40 min after injection, no differences remained significant. There were no changes in ratings of brush intensity, tactile directional sensibility or cold or warm sensation thresholds. Thus, sumatriptan may cause a short-lasting allodynia in response to light dynamic touch and a reduction of heat and cold pain thresholds. This could explain at least some of the temporary sensory side-effects of triptans and warrants consideration in the interpretation of studies on migraine-induced allodynia.     

Secondary heat hyperalgesia induced by melittin in humans.

Melittin, which is a principal protein of honeybee venom, can induce mechanical hyperalgesia in humans. The characteristics of the melittin induced mechanical hyperalgesia are quantitatively and qualitatively different from those evoked by capsaicin. The aim of the present study was to investigate in detail secondary heat hyperalgesia induced by melittin in humans. In six healthy volunteers, 10 microg of melittin was injected intradermally on the volar forearm, and VAS score to radiant heat stimuli (focused light from a xenon lamp) was assessed around the injection site 5, 30, and 60 min after injection. For normalization purposes, a pain rating index was calculated as the individual heat evoked VAS scores obtained after melittin divided by the individual baseline VAS scores. A two-way ANOVA revealed a significant increase of the pain rating index over time (F=3.6; P=0.03). The pain rating index at 60 min was significantly larger than at 5 min (P=0.04) and at 30 min (P=0.03). These results demonstrated slowly developing secondary heat hyperalgesia after injection of melittin. A possible contribution of peripheral inflammatory responses to the manifestation of secondary heat hyperalgesia is suggested, which in reality render the distinction between the primary and secondary area of heat hyperalgesia unnecessary.     

Pain response in heroin users: personality, abstinence, and modulation by benzodiazepines

We compared cold-pain responses among male current opioid users with and without concurrent benzodiazepine use, long-term ex-users, and healthy controls. Forty-eight current opioid users (14 concurrently using benzodiazepines), 34 ex-users (abstinent for ≥1 y) and 63 controls received cold-pressor tests. Pain threshold (first reporting pain) and pain tolerance (total immersion time) were recorded. Pain thresholds were similar in ex-users and current users; pain tolerance was similar in ex-users and controls. Net pain tolerance (endurance) in ex-users was intermediate between the other two groups. Current users showed higher pain threshold and shorter pain tolerance than controls (p<0.05). Current users not co-using benzodiazepines showed the lowest pain tolerance and net pain tolerance, and differed significantly from controls, ex-users, and current users co-using benzodiazepines (p<0.05). Neuroticism was higher in current users than in the other two groups (p<0.001), extraversion marginally lower (p<0.05); net pain tolerance differences remained significant after controlling for these. Benzodiazepine use modulates pain tolerance in opioid users. Pain responses altered by opioid use may partially recover with abstinence.     

布托啡诺、芬太尼用于抑制瑞芬太尼致术后痛觉过敏临床研究

目的比较布托啡诺与芬太尼干预瑞芬太尼（remifentanil）复合丙泊酚（propofol）静脉全麻患者苏醒后痛觉过敏的效果,评价布托啡诺镇痛的有效性和安全性。方法选择丙泊酚复合瑞芬太尼静脉全麻下择期行腹腔镜下胆囊切除术患者50例,ASAⅠ~Ⅱ级,随机分为2组：芬太尼组（F组）关腹前冲洗腹腔时静脉注射芬太尼2μg/kg,布托啡诺组（B组）关腹前冲洗腹腔时静脉注射布托啡诺30μg/kg。观察：①诱导前（T1）、苏醒后即刻（T2）、苏醒后1 h（T3）、苏醒后6 h（T4）时点的VAS评分、Ramsay评分、收缩压（SBP）、舒张压（DBP）、心率（HR）、血氧饱和度（SpO2）、呼吸抑制的发生率;②手术时间、意识恢复时间（呼之睁眼时间）、拔管时间。结果①2组患者的手术时间、意识恢复时间和拔管时间的差异无统计学意义（P〉0.05）;②与F组相比,B组在T2、T3、T4的Ramsay评分明显占优（P〈0.05或P〈0.01）,苏醒后6 h（T4）的VAS评分优于F组（P〈0.05）;③B组呼吸抑制的发生率明显低于F组（P〈0.05）。结论布托啡诺较芬太尼可更安全、有效地预防丙泊酚复合瑞芬太尼静脉全麻后痛觉过敏的发生。     

P2X7受体拮抗剂A438079对肠易激综合征结肠扩张刺激大鼠DCN核团中P2X7、OX42、IL-1β、P38及骶髓后角中CGRP表达的影响

目的探讨P2X7特异性受体拮抗剂A438079对肠易激综合征(irritable bowel syndrome,IBS)致内脏高敏感化大鼠在结肠扩张刺激状态时,骶髓后联合核(dorsal commissural nucleus,DCN)中P2X7、OX42、IL-1β、P38及脊髓背角中CGRP表达的变化,为探讨IBS内脏敏化的神经机制提供理论依据。方法以15只旋毛虫感染大鼠建立肠易激综合征模型,随机分为三组,总共分为:B.IBS大鼠结肠扩张刺激组(n=5)、C.IBS大鼠鞘内注射0.9%生理盐水后结肠扩张刺激组(n=5)、D.IBS大鼠鞘内注射A438079后结肠扩张刺组(n=5)。另外以5只正常大鼠作正常大鼠结肠扩张刺激组(n=5)、。采用免疫荧光组织化学方法观察大鼠DCN中P2X7、OX42、IL-1β、P38及脊髓后角中CGRP表达变化。结果与B组IBS扩张刺激组相比较,D组鞘内注射拮抗剂A438079后在结肠扩张刺激时IBS大鼠DCN核团中P2X7、OX42、IL-1β、P38及骶髓后角中CGRP的表达量均明显下降(P<0.01)。结论 P2X7受体在IBS致内脏敏化过程中广泛参与,并可能起重要作用。     

Synthesis and anticonvulsant activity of 1-(2-(8-(benzyloxy)quinolin-2-yl)-1-butyrylcyclopropyl)-3-substituted urea derivatives

H‐Dmt‐D‐Arg‐Phe‐Lys‐NH₂ ([Dmt¹]DALDA) is a synthetic tetrapeptide with extraordinary selectivity for the mu‐opioid receptor and is an extremely potent analgesic. [Dmt¹]DALDA is unusual in the way that the greater part of its analgesic potency appears to be produced by its actions in the spinal cord. Furthermore, [Dmt¹]DALDA inhibits norepinephrine re‐uptake and is a mitochondria‐targeted antioxidant. Such characteristics may make [Dmt¹]DALDA particularly effective against neuropathic pain. The present study was designed to compare the effects of [Dmt¹]DALDA and morphine on thermal hyperalgesia in an experimental neuropathic pain model. Neuropathic pain was induced in rats by surgical ligation of the L5 spinal nerve, and thermal pain thresholds were assessed by latencies of paw withdrawal to radiant heat. The increase in paw withdrawal latency was greater after the administration of [Dmt¹]DALDA than that of morphine in neuropathic rats at doses that were equianalgesic in naïve animals. We conclude that [Dmt¹]DALDA is more effective than morphine against thermal hyperalgesia in this experimental model of neuropathic pain.     

Involvement of glutamate NMDA and AMPA receptors, glial cells and IL-1β in the spinal hyperalgesia evoked by the chemokine CCL2 in mice

We study here the involvement of excitatory amino acid receptors, glial cell activation and IL-1β release in the spinal hyperalgesia evoked by the chemokine CCL2 (MCP-1). Three hours after the intrathecal administration of CCL2 (1-100 ng), mice exhibit dose-dependent thermal hyperalgesia, that was inhibited by the coadministration of the antagonist of chemokine receptor type 2 (CCR2) RS504393 (0.3-3 μg). To assess the involvement of excitatory amino acid receptor sensitisation, CCL2 was coadministered with CPP (0.3-3 ng) and NBQX (25-250 ng), antagonists of NMDA and AMPA receptors, respectively. Both drugs blocked CCL2-evoked hyperalgesia, strongly suggesting that CCL2 evokes in vivo NMDA and AMPA receptor sensitisation, as previously described in electrophysiological studies. Furthermore, this rapid induction of CCL2-mediated hyperalgesia was blocked by the previous acute administration of the microglial inhibitor minocyclin (4.9 μg) or the astroglial inhibitor l-aminoadipate (1.6 μg). Since IL-1β can be released by activated glial cells we tested whether this cytokine could be underlying the spinal sensitisation induced by CCL2. The administration of the type I IL-1 receptor antagonist, IL-1ra (3-30 μg), partially prevented CCL2-evoked hyperalgesia. Finally, to elucidate if IL-1β could produce NMDA and AMPA receptor sensitisation by itself, we performed experiments in which this cytokine was i.t. administered. Thermal hyperalgesia induced by IL-1β (30 pg) was completely prevented by the coadministration of CPP (3 ng) but unaffected by NBQX (250 ng). Globally, our results suggest that spinal CCL2 induces thermal hyperalgesia by sensitising NMDA and AMPA receptors in a process that involves glial activation and IL-1β release.