The effect of intrathecal magnesium sulphate on nociception in rat acute pain models

We examined the antinociceptive effect of intrathecally administered magnesium sulphate (MgSO4) in rats, using acute pain models including mechanical pressure, heat and subcutaneous formalin injection. According to the locomotion test 10 microliters of 6.2% MgSO4 did not produce motor paralysis. At the same dose, responses to pressure and heat were intact, compared with controls given saline. MgSO4 produced depression of pain responses only after the first 10 min in the formalin test. Our studies indicated that MgSO4 did not show remarkable antinociceptive effects in acute pain models.     

Intrathecal adenosine: interactions with spinal clonidine and neostigmine in rat models of acute nociception and postoperative hypersensitivity.

BACKGROUND: Spinal adenosine receptor agonists exert antinociception in animal models of acute and chronic pain, but adenosine itself has not been examined. The authors tested the antinociceptive and antihypersensitivity interactions of intrathecal adenosine and its interactions with intrathecal clonidine and neostigmine in rat models of acute thermal nociception and postoperative hypersensitivity. METHODS: Rats were prepared with lumbar intrathecal catheters. Responses to acute noxious stimulation were evaluated by latency to paw withdrawal from a radiant heat source focused on the hind paw. Postoperative hypersensitivity was measured after an incision in the rat hind paw by application of von Frey filaments to the heel adjacent to the wound. An isobolographic design was used to distinguish between additive and synergistic drug interactions. RESULTS: Spinal administration of clonidine and neostigmine, but not adenosine, produced dose-dependent antinociception to noxious thermal stimulation. Addition of adenosine enhanced the antinociceptive effect of clonidine but not neostigmine. In contrast, each of these three agents alone reversed postoperative hypersensitivity. Pretreatment with the alpha-adrenergic antagonist phentolamine completely reversed adenosine's antihypersensitivity action. Adenosine interacted synergistically with neostigmine and additively with clonidine in reducing postoperative hypersensitivity. CONCLUSIONS: These data indicate that intrathecal adenosine by itself has no antinociceptive properties to acute noxious thermal stimulation in rats, but enhances clonidine's antinociception. In contrast, intrathecal adenosine is active against postoperative hypersensitivity by an adrenergic mechanism. Different interactions between adenosine, clonidine, and neostigmine in acute nociception and postoperative hypersensitivity models are consistent with altered central processing of sensory information after peripheral injury.     

Pharmacology of methadone and its isomers

Methadone is a synthetic opioid analgesic that is used as an alternate to morphine and hydromorphone for patients with severe pain. It is increasingly being used in opioid rotation schedules. Methadone has an asymmetric carbon atom resulting in 2 enantiomeric forms, the d and l isomers. The racemic mixture (dl-methadone) is the form commonly used clinically. Recent studies have revealed the pharmacological activity of the d-methadone isomer. We found that the d isomer of methadone has N-methyl-D-aspartate (NMDA) receptor antagonist activity both in vitro and in vivo. Studies were designed to examine the ability of d-methadone to attenuate the development of morphine tolerance and to modify NMDA-induced hyperalgesia in rats. Repeated dosing with intrathecal morphine produced a 38-fold increase in the morphine ED50 value. This decrease in the potency of morphine was completely prevented by the coadministration of intrathecal d-methadone at 160 microg/rat. In addition, the decrease in thermal paw withdrawal latency induced by the intrathecal administration of 1.64 microg/rat NMDA was completely blocked by pretreatment with 160 microg/rat d-methadone. Thus, the same dose of intrathecal d-methadone that attenuates the development of spinal morphine tolerance blocks NMDA-induced hyperalgesia in rats. These results support the CONCLUSIONS: that d-metha-done affects the development of morphine tolerance and NMDA-induced hyperalgesia by virtue of its NMDA receptor antagonist activity.     

大鼠甲状旁腺功能低下模型建立方法的比较研究

为开展甲状旁腺细胞、组织移植的研究，我们进行了甲状旁腺低下模型建立的探讨。     

Bone healing models in rat tibia after different injuries

AIMS: Gradual elaboration of an adequate and efficient multistage method for experimental remodelling of specific wound healing process--bone repair. Comparison of clinical characteristics with the results of microanatomy, histology, electronmicroscopy and computer morphometry. MATERIAL AND METHODS: An investigation of posttraumatic bone repair after internal fracture, excision and cortical perforation was carried out on 142 young adult male Wistar rats.The repair was studied in normal and affected animals (exercises, immobilization, isolation of periost) at 1-42 days after operation. RESULTS: The posttraumatic bone callus development and the related soft tissue repair, likewise the continuous remodelling, is an ordinary process of osteohisto- and organogenese. In trained rats the blood supply and bone formation is increased, whereas in immobilized animals it is inhibited and destroyed (osteoporose, pseudoarthrosis). After the injury some characteristics of bone repair histogenese will be became evident (after the perforation the primary endosteal and secondary periosteal ossification, inhibition of endosteal bone repair after the isolation of periost etc.). CONCLUSION: The posttraumatic bone healing, like embryohistogenese, has similar repair stages in all models of the experiments as well as similar tissue and cell responses (callus formation, its replacement, bone remodelling, etc.). However, the repair process in general (order of chondrous and/or bone callus stages, etc.) is variable and dependent on the mode and degree of injury. The use of bone cortex perforation in wound healing study is more recommendable as compared to internal fracture and excision (possibility of in situ study the periost and callus tissue compartments in bone repair machinery separately).     

Pain, nociception and the developing infant

The study of paediatric pain and the provision of safe but reliable analgesia for all age groups has become a central issue in paediatric anaesthesia. For the practising paediatric anaesthetist, this represents a major challenge: the developing infant is not a single discrete entity but one that changes constantly with increasing maturity of individual organs. Recent developments in both basic and clinical sciences has given valuable insights into this process, giving the clinician a firm basis to provide analgesia at all ages. This review looks at some of the most interesting recent developments in this field.     

Actions of tramadol, its enantiomers and principal metabolite, O- desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus

Tramadol is an atypical centrally acting analgesic agent with relatively weak opioid receptor affinity in comparison with its antinociceptive efficacy. Evidence suggests that block of monoamine uptake may contribute to its analgesic actions. Therefore, we have examined the actions of (+/-)-tramadol, (+)-tramadol, (-)-tramadol and O-desmethyltramadol (M1 metabolite) on electrically evoked 5-HT efflux and uptake in the dorsal raphe nucleus (DRN) brain slice, measured by fast cyclic voltammetry. Racemic tramadol and its (+)-enantiomer (both 5 mumol litre-1) significantly blocked DRN 5-HT uptake (both P < 0.05) and increased stimulated 5-HT efflux (P < 0.01 (+/-)-tramadol; P < 0.05 (+)-tramadol). The (-)-enantiomer and metabolite, O-desmethyltramadol, were inactive at the concentration tested (5 mumol litre-1). For both (+/-)-tramadol and the (+)-enantiomer, the action on 5-HT efflux preceded an effect on 5-HT uptake, suggesting that uptake block was not the cause of the increased 5-HT efflux and that tramadol might therefore have a direct 5-HT releasing action. This activity, at clinically relevant concentrations, may help to explain the antinociceptive efficacy of tramadol despite weak mu opioid receptor affinity and adds to evidence that tramadol exerts actions on central monoaminergic systems that may contribute to its analgesic effect.      

Lack of whole-body pharmacokinetic differences of halothane enantiomers in the rat

BACKGROUND: Halothane is made and used as a racemate (an equimolar mixture of R- and S- enantiomers). This study was initiated to determine whether there were demonstrable enantiomeric differences in the whole-body pharmacokinetics of halothane that might have significance for studies in which racemate is used. METHODS: Adult male Wistar rats were exposed to halothane vaporized in the atmosphere of a closed constant volume chamber supplied with O2 commensurate with CO2 production. Concentrations of halothane enantiomers were measured by a specific gas chromatography-mass spectrometry method. Experiments were performed at four initial concentrations of halothane (0.1%, 0.5%, 1.0%, and 1.5% vol/vol). Enantiomeric differences in whole-body pharmacokinetics were assessed indirectly from the relative chamber atmosphere concentrations of halothane enantiomers. RESULTS: Concentrations of halothane decreased biphasically. The initial more rapid decrease was interpreted as incorporating absorption, distribution, and clearance; the slower decrease was interpreted as principally incorporating metabolic clearance. The ratio of concentrations of the two halothane enantiomers and of the ratios of the respective areas under the concentration-time curves remained constant without differing from unity at any time at any concentration of halothane. The dose-normalized areas under the concentration-time curves for the concentrations 0.1%, 0.5%, and 1.0% did not differ; that for 1.5% was significantly greater, suggesting nonlinear clearance, but the values did not differ significantly between enantiomers at any concentration. CONCLUSIONS: As there were no significant differences in concentrations of the two enantiomers in the chamber atmosphere, enantioselectivity was not demonstrated in the whole-body pharmacokinetics of halothane.     

全麻期间不同强度伤害性刺激下镇痛/伤害性刺激指数的变化及其相关性分析

目的评价镇痛/伤害性刺激指数(ANI)作为一种全新的反映伤害性刺激的监测指标在全麻期间在不同强度伤害性刺激下的变化及其相关性。方法拟行择期全麻腰椎后路椎板切除减压植骨内固定术的成年患者37例,ASAⅠ或Ⅱ级。采用丙泊酚及瑞芬太尼双靶控输注行麻醉诱导和维持,调整丙泊酚血浆靶浓度维持BIS在40~60,依据循环变化调整瑞芬太尼靶浓度。记录特定时点(麻醉诱导后无刺激点、切皮、神经根牵拉)的SBP、HR和ANI等相关数据。ANI、SBP及HR组内比较采用单因素方差分析,Spearman等级相关分析比较ANI、SBP和HR与伤害性刺激强度的相关性,采用偏相关分析评价ANI与SBP及HR的相关性。结果 30例患者完成研究。切皮及神经根牵拉时ANI下降,SBP明显升高(P0.05),而HR无显著变化。ANI与伤害性刺激水平的相关性较SBP和HR高(r=-0.866vs r=0.717、0.056);ANI与HR之间无明显相关性,ANI与SBP之间有一定的负相关性(r=-0.563,P0.01)。结论在全麻腰椎后路手术中,ANI能够较为准确可靠地反映伤害性刺激强度的变化,且与伤害性刺激强度具备很好的相关性。     

Transgastric versus laparoendoscopic single-site peritoneoscopy in a rat model: effects on motility,inflammation, and nociception

Background  

Natural orifice translumenal endoscopic surgery (NOTES) and laparoendoscopic single-port surgery (LESS) are emerging approaches to abdominal surgery that have been advocated as potentially causing fewer physiologic derangements and less pain. This study aimed to compare these procedures in a novel rat model by assessing peritoneal inflammation, gastric motility, and nociception in response to peritoneoscopy performed via NOTES and LESS.     

Morphine postconditioning protects against reperfusion injury in the isolated rat hearts

BACKGROUND: Postconditioning is a novel strategy of attaining cardioprotection. Previous studies have suggested morphine mimics the effects of ischemic preconditioning. Whether it is also capable of producing postconditioning or not is still unclear. The purpose of this study was to determine (1) whether morphine postconditioning (MPostcond) would protect the heart against reperfusion injury and the subtype(s) of opioid receptors (OR) involved, (2) whether combining MPostcond with morphine preconditioning (MPC) would afford additive cardioprotection, and (3) to evaluate the role mitochondrial adenosine triphosphate-sensitive potassium (mito-K atp) channel played in MPostcond. MATERIALS AND METHODS: Isolated perfused rat hearts were subjected to 45 min of ischemia followed by 1 h of reperfusion. First, three morphine concentrations (0.3, 3.0 and 30 microM) were used to study the protective effect of MPostcond. Second, the effect of blockade of OR subtypes by three antagonists (nonselective OR antagonist naloxone, kappa-OR antagonist nor-binaltorphimine, and delta-OR antagonist naltrindole) on MPostcond was investigated. Third, the protective effects of MPC, MPostcond and the combining MPC with MPostcond on reperfusion injury were compared. Last, the effect of blockade of mito-K atp by 5-hydroxydecanoate on MPostcond was studied. MPostcond was induced by a 10-min perfusion of morphine in Krebs-Ringer's solution performed at the onset of reperfusion, and MPC was produced by a 20-min perfusion of morphine 10 min before ischemia. Infarct size (IS/AAR, as a percentage of the area at risk) was determined by 2,3,5-triphenyltetrazolium staining. RESULTS: IS/AAR was significantly reduced after MPostcond from 58% +/- 8% (control) to 37% +/- 6% (morphine 3.0 microM, P < 0.01). This effect was abolished by coadministering naloxone (58% +/- 7%), nor-binaltorphimine (52% +/- 5%), but not naltrindole (34% +/- 5%). MPC and MPostcond had similar extent of protective effect on IS/AAR, and combining MPC with MPostcond did not afford further cardiprotection. 5-Hydroxydecanoate also abolished the cardioprotection of MPostcond. Unexpectedly, all three OR antagonists and 5-hydroxydecanoate themselves also afforded some extent of cardioprotection. CONCLUSIONS: MPost confers cardioprotection via activating kappa-OR but not delta-OR and opening mito-K atp channels. MPost and MPC have no additive protection. kappa-OR and mito-K atp channel may play a dual role in protecting ischemia-reperfusion injury.     

Predicting the different progressions of early pressure injury by ultraviolet photography in rat models

Early pressure injury (PI) can result in either spontaneous healing (SH) or deterioration into ulcer (DU). However, determining whether PI will progress into SH or DU on the basis of non‐blanchable erythema only is difficult. In this study, we constructed two animal PI models to mimic SH and DU injuries and observed haemorrhage by using ultraviolet (UV) photography to develop potential clinical indicators for predicting the progression of early PI. Macroscopy, UV photography, and skin temperature observations were obtained. In the SH group, macroscopic observation showed the erythema was obvious at 0.5 hours after decompression and faded gradually had almost disappeared at 72 hours. In the DU group, the erythema persisted, and an erosion appeared at 24 hours after decompression and expanded at 36 hours. The erythema developed into an obvious ulcer at 48 hours and enlarged at 72 hours. The obvious ulcer found at 48 hours through macroscopic observation was clearly visible at 36 hours with UV photography, and a significant difference in grey values between the two groups was found at as early as 18 hours (P < .05). This study provided evidence showing that UV photography can predict the different progression stages of early PI. Additionally, when combined with the transparent disc method, UV photography also can be used to identify the circulatory disorders of early PI, such as haemorrhage or hyperaemia and even congestion.     

Selective synaptic actions of thiopental and its enantiomers

BACKGROUND: There is conflicting evidence concerning the extent to which the intravenous general anesthetic thiopental acts by enhancing inhibitory gamma-aminobutyric acid-mediated (GABAergic) synaptic transmission or by inhibiting excitatory glutamatergic transmission. Yet there are remarkably few studies on the effects of thiopental on functional synapses. In addition, the degree of stereoselectivity of thiopental acting at synapses has yet to be tested. METHODS: The actions of thiopental and its enantiomers on GABAergic and glutamatergic synapses were investigated using voltage clamp techniques on microisland cultures of rat hippocampal neurons, a preparation that avoids the confounding effects of complex neuronal networks. RESULTS: Racemic thiopental markedly enhanced the charge transfer at GABAergic synapses without significantly affecting the peak of the postsynaptic current. At a surgically relevant concentration (25 microm), charge transfer was increased by approximately 230%. However, even at twice this concentration there were no significant effects on glutamatergic postsynaptic currents. At GABAergic synapses, thiopental acted stereoselectively, with the S(-) enantiomer being approximately twice as effective as the R(+) enantiomer at enhancing charge transfer. CONCLUSIONS: Thiopental stereoselectively enhances inhibitory GABAergic synaptic transmission in a way that reflects animal potencies, supporting the idea that this is a principal mode of action for this drug. The absence of any effect on glutamatergic synapses at surgically relevant concentrations suggests that the inhibition of these excitatory synapses is not an important factor in producing thiopental general anesthesia.     

Neuronal plasticity in relation to nociception and healing of rat achilles tendon.

Nerve regeneration and the occurrence of three neuropeptides; i.e. substance P (SP), calcitonin gene related peptide (CGRP) and galanin (GAL), were studied during healing of tendon rupture in the rat by semi-quantitative immunohistochemistry. The neuronal findings were related to nociception as assessed by hindpaw withdrawal latencies at thermal and mechanical tests.Experimental rupture of rat Achilles tendon--normally devoid of nerves--elicited extensive nerve ingrowth into the rupture site in the early phase of healing followed by almost complete fiber disappearance (weeks 12-16). The ingrowth of SP and CGRP positive fibers, seen already at weeks 1-2, was associated with increased nociception. Subsequently, the occurrence of GAL positive fibers at weeks 4-6 was associated with decreased nociception. An even stronger relationship to nociception during healing was observed when the rate of change in neuropeptide expression instead of the expression in absolute terms was considered, according to the "cascade" formula of SP(')+CGRP(')-GAL(').It may prove that the observed temporal occurrence of different neuropeptides reflects a role of the peripheral nervous system in regulating synchronously nociception and healing.     

大鼠脑内不同部位海人酸点燃模型的比较

目的 探讨制作简便、效果良好的海人酸(KA)点燃致痫模型方法。方法 立体定向操作下于岛叶、杏仁核和侧脑室局部注射海人酸1.0μl,观察致痫大鼠的行为学和脑电图改变,检测其病理学变化,比较其点燃特征。结果 行为学、脑电图和病理学证实岛叶点燃组与传统致痫(杏仁核、侧脑室)点燃组比较,具有相同的致痫特征;同时,岛叶点燃组初次发作时间为(59.96±4.36)min,静止持续时间为(11.90±0.54)d,明显快于杏仁核组和侧脑室组(P＜0.05)。结论 岛叶本身具备致痫潜能,大鼠岛叶海人酸致痫模型具有缩短实验周期、降低实验成本的优势。     

The effects of diacerhein on mechanical allodynia in inflammatory and neuropathic models of nociception in mice

In this study we analyzed the systemic antiallodynic properties of diacerhein, a drug used to treat osteoarthritis, in inflammatory and neuropathic models of nociception in mice. The effects of diacerhein were compared with those of gabapentin, a drug used clinically for the management of neuropathic pain. Similar to gabapentin, diacerhein was able to significantly reverse the mechanical allodynia induced by carrageenan. A significant inhibition of carrageenan-induced nociception was also observed when diacerhein was administered by the intrathecal but not by the intraplantar route. The treatment with diacerhein or with gabapentin also inhibited the mechanical allodynia induced by complete Freund's adjuvant (CFA) or after the partial ligation of the sciatic nerve (PLSN). In the same range of doses, diacerhein or gabapentin did not affect the locomotor activity, motor coordination, or body temperature of the animals. The present results indicate that diacerhein produces marked antiallodynic effects in carrageenan and CFA nociception models and also inhibits the neuropathic pain after PLSN, with an efficacy similar to that observed for gabapentin. Diacerhein may be a potentially interesting tool for the management of inflammatory and neuropathic pain.