Effects of μ-, δ-, and κ-opioid agonists and enkephalinase inhibitor RB101 in two inbred rat strains

Analgesic and suppressive effects of selective μ- (DAGO), δ- (DME), and κ- (DAKLI) opioid agonists are compared with those of aminopeptidase N and neutral endopeptidase RB101 in rats of WAG/G and Fischer-344 rats. Fischer-344 rats were more susceptible to suppressive effects of DAGO and analgesic effect of DME. It is concluded that in these rats peculiarities of the μ- and δ-opioid systems determine susceptibility to locomotor depression and analgesia, respectively. There is no correlation between effects of DAGO and RB101 in these strains. This implies that depressive effect of RB101 is not mediated though μ-opioid systems. In contrast, the effects of DMA on pain sensitivity in WAG/G and F-344 rats are opposite to those of RB101. This suggests that specific features in the activity of cerebral δ-OS can determine the sensitivity of RB101-induced analgesia. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 125, No. 5, pp. 551–554, May, 1998     

Changes in thermonociceptive thresholds and the role of enkephalinase A in homeostasis in morphine-tolerant rat offspring

The dynamics of thermonociceptive thresholds as a marker of the state of the endogenous opioid system was studied in the offspring of morphine-tolerant rats. Significant, age-dependent increase in thermonociceptive thresholds and higher levels of enkephalinase A in structures of the endogenous antinociceptive system were observed in the offspring compared with the control. These findings attest to disturbances of the opioid system in the progeny of morphine-tolerant rats and confirm the key role of enkephalinase A in the maintenance of homeostasis disturbed by chronic prenatal morphine treatment. Translated fromByulleten' Eksperimental'noi Biologii I Meditsiny, Vol. 129, No. 5, pp. 560–562, May, 2000     

选择性环氧合酶2抑制剂尼美舒利抑制皮肤瘢痕形成的研究

背景：尼美舒利是一种选择性环氧合酶2抑制剂,可通过抑制环氧合酶2的合成、抑制前列腺素的合成、白细胞的介质释放等环节影响炎症的发生过程,具有解热、镇痛和抗炎作用。 目的：探讨尼美舒利抑制小鼠皮肤瘢痕形成的作用及机制。 方法：昆明种小鼠背部脊柱两侧建立皮肤损伤模型,随机分为模型组、25,50,100 μmol/L尼美舒利组,切口分别涂抹0.5 mL玻璃酸钠凝胶、25,50,100 μmol/L尼美舒利玻璃酸钠分散制剂。 结果与结论：应用25,50 μmol/L尼美舒利可以明显减小瘢痕组织的面积(P < 0.01),但100 μmol/L尼美舒利却造成损伤面积增大(P < 0.05),与模型组相比,不同剂量的尼美舒利治疗的小鼠在创伤形成第3,7,14天环氧合酶2的表达明显降低,且其中50和100 μmol/L尼美舒利治疗的小鼠创口微血管的生成速度明显降低(P < 0.05),提示尼美舒利可以通过适度下调皮肤修复过程中环氧合酶2的表达,控制微血管的形成,达到抑制病理性瘢痕形成的治疗目的,但剂量过大(100 μmol/L)则可抑制创伤的愈合。     

Selective inhibitory effects of pregabalin on peripheral C but not A-delta fibers mediated nociception in intact and spinalized rats

Effects of pregabalin (PGB, 20–80 mg/kg i.v. injection) on spinally-organized nociception were investigated in isoflurane-anesthetized intact and spinalized rats. Responses of single deep spinal dorsal horn (DH) (laminae IV–V) nociceptive-specific (NS) neurons receiving peripheral inputs from A-δ and C fibers to repetitive electrical stimulation (intensity: 3–5 mA; frequency: 1 Hz; pulse duration: 1 ms), mechanical/heat stimulation were recorded extracellularly during physiological condition and s.c. bee venom (BV) induced inflammation. PGB significantly inhibited C-fiber mediated spinal NS neurons' late responses including phenomena of wind-up (temporal summation) and after-discharge. However, the antinociceptive effects of PGB on nociception were not observed until 30 min after its administration. In contrast, no significant inhibitory effect of PGB on A-δ fiber mediated early responses was observed during the experiments. Compared with intact rats, the inhibitory effects of PGB upon nociception vanished in the spinalized animals. This suggests that PGB-induced selective antinociceptive effect on C-fiber mediated nociception is mainly central effects involving supraspinal centers via descending inhibitory controls. Furthermore, pre-treatment, but not post-treatment, with PGB (80 mg/kg) markedly inhibited s.c. BV elicited spontaneous neuronal responses, and noxious mechanical/heat stimuli evoked hyperactivities of spinal NS neurons, indicating that PGB has efficacy of pre-emptive analgesia on pathological pain associated with central sensitization.     

Effect of DA-8159, a selective phosphodiesterase type 5 inhibitor, on electroretinogram and retinal histology in rabbits

DA-8159, a selective inhibitor of phosphodiesterase type 5, was developed as a new drug for erectile dysfunction. The effect of DA-8159 on the electroretinogram (ERG) and the retinal histopathology were evaluated in rabbits. The ERG was performed prior to, and 1 and 5 hr after DA-8159 (5 to 30 mg/kg) administration. The plasma concentration of DA-8159 was determined at each time point, and retinal microscopic examination was also performed. There was no statistically significant ERG change at any dose or at any time. Though the 30 Hz flicker showed a prolongation of the implicit time at 5 hr after the administration of either DA-8159 15 mg or 30 mg/kg (p<0.05), but concurrent amplitude decreases were not statistically significant. At a dose of 5 mg/kg, no test drug was detected in the blood after either 1 or 5 hr. At either 15 mg/kg or 30 mg/kg, there was a dose-dependent increase in the blood concentration after 1 hr of drug administration, which decreased with time. In light and electron microscopic examinations of the retina, there was no remarkable change at any dose. These results suggest DA-8159 has a low risk potential to the retina, but further evaluation on the visual functions in human is needed.     

Amelioration of cisplatin-induced rat renal lesions by a cyclooxygenase (COX)-2 selective inhibitor

Cyclooxygenase (COX)-2, an inducible form of COX, plays important roles in inflammatory lesions. We investigated effects of a COX-2 selective inhibitor, NS-398, on cisplatin (CDDP)-induced rat renal lesions. As compared with rats injected with a single dose of CDDP (6 mg/kg; CDDP group), rats who were treated everyday with NS-398 (3 mg/kg) after the CDDP injection (inhibitor group), showed the declines of blood urea nitrogen and creatinine values, and the delay of the peak of regenerating renal epithelial cell number (demonstrable with 5′-bromo-2′-deoxyuridine immunohistochemistry); these findings suggested cytoprotective effects of the inhibitor. Furthermore, the numbers of ED1-immunopositive macrophages and α-smooth muscle actin (α-SMA)-immunopositive myofibroblasts were lower in the inhibitor group than in the CDDP group; mRNA expression of transforming growth factor-β1 (TGF-β1) was also decreased in the inhibitor group. Because the fibrotic area seen after CDDP injection were tended to decrease in the inhibitor group compared with the CDDP group, it was considered that the decreased number of infiltrating macrophages by the inhibitor might lead to the decreased production of TGF-β1, thereby resulting in the reduced number of α-SMA-positive myofibroblasts responsible for fibrosis. Collectively, although these differences between the CDDP and inhibitor groups were not always marked, the COX-2 inhibitor used in this study could ameliorate the CDDP-induced rat renal lesions.     

Effect of stimulation of subthalamic nucleus on grooming movements and their rhythmicity in pups and mature rats

The effect of rhythmic stimulation of subthalamic nucleus on grooming movements and their rhythmicity was studied on mature rats and on 13- and 14-day rat pups. Unilateral monopolar stimulation of subthalamic nucleus was performed on unrestrained animals via implanted electrodes. This stimulation activated virtually all grooming movements (scratching, hair-plucking, licking, and body-shaking); the effect was most pronounced in pups. Acceleration of the rhythm of grooming movements was observed only in rat pups for hair-plucking and scratching on the contralateral side relatively to the stimulated nucleus. In mature rats stimulation of the subthalamic nucleus prolonged grooming movements in most cases, but did not increase their number and rhythm.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 9, pp. 244–246, September, 2004     

Effect of stimulation of subthalamic nucleus on grooming movements and their rhythmicity in pups and mature rats

The effect of rhythmic stimulation of subthalamic nucleus on grooming movements and their rhythmicity was studied on mature rats and on 13- and 14-day rat pups. Unilateral monopolar stimulation of subthalamic nucleus was performed on unrestrained animals via implanted electrodes. This stimulation activated virtually all grooming movements (scratching, hair-plucking, licking, and body-shaking); the effect was most pronounced in pups. Acceleration of the rhythm of grooming movements was observed only in rat pups for hair-plucking and scratching on the contralateral side relatively to the stimulated nucleus. In mature rats stimulation of the subthalamic nucleus prolonged grooming movements in most cases, but did not increase their number and rhythm. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 138, No. 9, pp. 244–246, September, 2004     

两种镇痛方式对妇科术后病人镇痛效果的比较

目的观察硬膜外吗啡术后镇痛与静脉曲马多复合芬太尼术后镇痛这两种镇痛方式对妇科术后病人镇痛效果比较。方法将80例心功能（ASA）Ⅰ-Ⅱ级的妇科手术病人随机分成A、B组，每组各40例。A组病人采用硬膜外持续微量注射镇痛泵（PCEA）泵入吗啡术后镇痛，B组病人采用静脉自控微量注射镇痛泵（PCIA）泵入曲马多复合芬太尼术后镇痛。观察并记录病人术后的疼痛情况、头痛头晕、恶心呕吐、术后排气、拔除尿管后的第一次排尿时间以及意外脱管等。结果两组间视觉模拟评分（VAS）评分比较、头痛头晕、恶心呕吐总发生率、术后排气均无统计学意义（P〉0．05）。A组拔除尿管后的第一次排尿时间较B组短（P〈0．05）。结论静脉联合应用曲马多和芬太尼镇痛安全有效，有利于术后病人充分配合治疗和早期活动，促进早期康复，值得临床推广应用。     

Sex-specific modulation of spinal nociception by alpha2-adrenoceptors: differential regulation by estrogen and testosterone

Sex-related differences in antinociception produced by the activation of alpha(2)-adrenoceptors (alpha(2)-ARs) have been reported, however, the precise role of gonadal steroids is still unknown. Hence, we hypothesized that estrogen and testosterone modulate antinociceptive effects of clonidine (an alpha(2)-AR agonist) on N-methyl-D-aspartate- (NMDA) and heat-induced spinal nociception. We also investigated whether estrogen or testosterone alters the expression of alpha(2A)-adrenoceptors in the spinal cord. Sprague-Dawley (SD) rats were implanted with PE10 cannulae in the intrathecal space of the lumbosacral spinal cord and divided into male, proestrous and diestrous female, ovariectomized (OVX), estradiol-treated OVX (OVX+E), castrated male (GDX), testosterone (GDX+T) and estradiol-treated castrated male (GDX+E) groups. Clonidine dose-dependently inhibited NMDA-induced scratching behavior in the male and OVX groups but to a significantly lesser extent in the OVX+E group. It also increased the tail withdrawal latency in the male, OVX, diestrous and GDX+T groups but not in the OVX+E, proestrous, GDX and GDX+E groups. Levels of alpha(2A)-AR mRNA were significantly higher in the OVX, estradiol-treated OVX, GDX and GDX+E animals. In contrast, alpha(2A)-AR protein levels were higher in estradiol-treated OVX, GDX, GDX+T and GDX+E animals as compared with the male. Indeed, no correlations were observed between changes in the mRNA or protein levels of alpha(2A)-AR and behavioral observations. These results support our hypothesis that sex-related differences in alpha(2)-AR-mediated modulation of spinal nociception are gonadal hormone-dependent: estrogen attenuates antinociceptive effects in females whereas testosterone is required for the expression of antinociception in males. In addition, results also revealed that the mechanism of action of gonadal hormones may not involve a global alternation in expression of alpha(2A)-AR in the spinal cord. Estrogen-induced attenuation of alpha(2)-AR-mediated inhibition of nociception could contribute to the higher prevalence of pain syndromes in women.     

不同镇痛方式在开胸术后的镇痛效果及对肺功能影响

目的观察不同镇痛方式在开胸手术后的镇痛效果及其对肺功能的影响。方法39例ASAⅠ~Ⅱ级,在硬膜外复合全身麻醉下行侧开胸手术的病人,术后随机接受罗哌卡因(罗哌组,n=10)、甲磺酸罗哌卡因(甲罗组,n=10)和布比卡因(布比组,n=10)硬膜外镇痛(patient controlled epidural analgesia,PCEA)及吗啡(吗啡组,n=9)静脉镇痛(patient controlled intravenous analgesia,PCIA)。结果术后1、2、5d静息时的疼痛评分罗哌组和甲罗组均明显低于布比组,但与吗啡组相比无明显差异;术后1d静息时疼痛评分吗啡组也明显低于布比组,但术后2、5d两组间无明显差异。术后1、2、5d咳嗽时疼痛评分罗哌组均明显低于布比组和吗啡组;各时间咳嗽时疼痛评分布比组和吗啡组之间无明显差异。术后1、2dPaCO2罗哌组均明显低于布比组,术后1dPaCO2罗哌组也明显低于布比组;术后1、2dPaCO2罗哌组均明显高于吗啡组,但与布比组之间无明显差异。术后1、2、5d用力肺活量和呼吸峰流速四组间无明显差异。结论罗哌卡因和甲磺酸罗哌卡因加舒芬太尼可安全用于开胸手术后硬膜外镇痛,其镇痛效果优于布比卡因加芬太尼硬膜外镇痛和吗啡静脉镇痛,并使术后病人维持更好的呼吸功能,且不增加副作用的发生率。     

Effect of gonadotropin-releasing hormone analogue on thermal nociception in mice

Intraperitoneal treatment with an analogue of gonadotropin-releasing hormone in doses of 0.004–450 μg/kg produced an analgesic effect on male mice in the hot plate test. Castration significantly elevated the nociceptive thresholds. In castrated mice the effects of the test peptide were less pronounced and had an algesic nature. Our results indicate that these effects depend on functional activity of the hypothalamic-pituitary-gonadal axis. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 2, pp. 153–156, February, 2006     

Effects of Selank on behavioral reactions and activities of plasma enkephalin-degrading enzymes in mice with different phenotypes of emotional and stress reactions

Comparative study of plasma activities of enkephalin-degrading enzymes in mice with different phenotypes of emotional and stress reactions revealed significant differences between intact BALB/c and C57Bl/6 mice by the half-life of plasma leu-enkephalin. Selank in a dose of 100 /kg produced an anxiolytic effect in the open-field test and increased the half-life of plasma leu-enkephalin in BALB/c mice, but had no effect on behavioral reactions and enkephalinase activities in C57Bl/6 mice. Our results suggest that anxiolytic activity of Selank is associated with inhibition of enkephalin-degrading enzymes.     

The inhibitory effect of Selank on enkephalin-degrading enzymes as a possible mechanism of its anxiolytic activity

Examination of patients with various forms of anxiety and phobic disorders (according to DSM-4 criteria) demonstrated a considerable shortening of enkephalin half-life and reduced total enkephalinase activity in the blood during generalized anxiety, but not during panic disorders and agoraphobia. This was probably related to low blood concentration of endogenous inhibitors of enkephalin-degrading enzymes in patients with generalized anxiety disorders. Heptapeptide Selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro), which attenuates behavioral anxiety reactions and does not cause side effects typical of most anxiolytics, dose-dependently inhibited enzymatic hydrolysis of plasma enkephalin (IC50 15 M). Selank was more potent than peptidase inhibitors bacitracin and puromycin in inhibiting enkephalinases. These results suggest that high efficiency of Selank in the therapy of anxiety and phobic disorders, including generalized anxiety, is due to its ability to inhibit enkephalin hydrolysis.     

Effect of systemic administration of beta-casomorphine-7 on nociception in rats

M. V. Lomonosov Moscow State University. Institute of Molecular Genetics, Russian Academy of Sciences, Moscow. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 114, No. 9, pp. 284–286, September, 1992.     

Effects of a highly selective plasma kallikrein inhibitor on collagen-induced arthritis in mice

A study was conducted to evaluate the effects of a new, highly selective plasma kallikrein inhibitor, PKSI-527, on collagen-induced arthritis (CIA) in mice. PKSI-527 or indomethacin was administered daily intraperitoneally from day 20 postimmunization. Clinical evaluation was performed, and two of the components of the kallikrein-kinin system, high-molecular-weight (HMW) kininogen and plasma prekallikrein, were assyed. PKSI-527, as well as indomethacin, reduced the severity of arthritis significantly. PKSI-527, but not indomethacin, restored consumed components of the kallikrein-kinin system. These results suggest that PKSI-527 suppresses CIA by modifying the kallikrein-kinin system and PKSI-527 as a synthetic plasma kallikrein inhibitor would be a valuable tool to study the mechanism of inflammation of arthritic diseases.