Stability of sufentanil citrate with levobupivacaine HCl in NaCl 0.9% infusion after microwave freeze-thaw treatment

BACKGROUND: Sufentanil is a powerful central anesthetic and analgesic of the opiate family that can be used with levobupivacaine for epidural administration. Advance preparation of intravenous solution could be useful to improve quality, time management, and cost-savings of drug delivery. OBJECTIVE: To investigate how freezing, long-term storage, and microwave thawing can affect the stability of sufentanil citrate and levobupivacaine HCl in NaCl 0.9% (saline) (w/v) polyvinyl chloride (PVC) bags. METHODS: The stability of 5 bags of solution containing sufentanil 500 microg and levobupivacaine 625 mg per 500 mL of saline solution in PVC bags was studied after freezing for 4 months at -30 degrees C, thawing in a microwave oven with a validated cycle, and storage at 4 degrees C. The concentrations of the drugs were measured by HPLC using a reversed-phase column, a mobile phase consisting of 18% acetonitrile (v/v) in tertabutyl ammonium hydrogen sulfate buffer 0.03 M pH 3.00 +/- 0.05, and UV detection at 235 nm for sufentanil and 260 nm for levobupivacaine. Visual inspection and pH measurement were also performed. RESULTS: No color change or precipitation was observed. Sufentanil and levobupivacaine were stable for at least 70 days at 4 degrees C after freezing and thawing. Throughout this period, the 95% lower confidence limit of the concentration-time profile remained >90% of the initial concentration. During this period, the pH value remained stable. CONCLUSIONS: Within the limits defined here, a mixture of sufentanil citrate and levobupivacaine HCl may be prepared in advance and kept frozen.     

罗哌卡因复合舒芬太尼腰-硬联合麻醉用于剖宫产的临床疗效观察

目的观察罗哌卡因复合舒芬太尼腰-硬联合麻醉用于剖宫产的临床疗效。方法将2009年11月至2010年6月130例择期行剖宫产术的产妇随机分为对照组及观察组,对照组65例采用罗哌卡因腰硬联合麻醉,观察组65例采用罗哌卡因复合舒芬太尼腰-硬联合麻醉,比较分析两组的临床效果。结果观察组的麻醉起效时间明显短于对照组,镇痛维持时间与术后疼痛评分均优于对照组,两组间比较差异均有统计学意义(P<0.05);两组手术时间、新生儿Apgar评分、不良反应发生率比较,差异均无统计学意义(P>0.05)。结论罗哌卡因复合舒芬太尼腰-硬联合麻醉用于剖宫产效果满意,镇痛效果更佳。     

Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain.

Patients with reflex sympathetic dystrophy or causalgia characteristically have ongoing pain and pain to light touch (hyperalgesia). Some of these patients obtain relief of their pain following interruption of sympathetic function to the affected area and, therefore, have sympathetically maintained pain (SMP). Evidence suggests that the pain and hyperalgesia in SMP are related to activation of peripheral adrenergic receptors. We wished to determine the contribution of alpha 1- and alpha 2-adrenergic receptors in SMP and thus examined the effects of local application of adrenergic agents in patients with SMP. The alpha 2-adrenergic agonist clonidine, available as a transdermal patch, was delivered topically to the patients' hyperalgesic skin. In four patients with SMP, clonidine eliminated or substantially reduced hyperalgesia to mechanical and cold stimuli. In three of these patients the effects were confined to the skin region beneath the patch, suggesting a peripheral and not central effect. The relief of hyperalgesia was not due to a local anesthetic effect since touch thresholds were unaffected. Topical clonidine did not relieve hyperalgesia of similar severity for two other patients whose hyperalgesia and pain were unaffected by sympathetic ganglion blocks (i.e., diagnosed as having sympathetically independent pain). In two SMP patients, intradermal injection of norepinephrine or phenylephrine (a specific alpha 1-adrenergic agonist) at a site treated with clonidine evoked intense pain and rekindled the pre-clonidine hyperalgesia at that site. It is likely that clonidine locally blocks the release of norepinephrine via activation of alpha 2 receptors on the sympathetic terminals. This study suggests, therefore, that SMP is mediated via alpha 1-adrenergic receptors located in the affected tissue.     

alpha(2)-adrenergic receptors stimulate oligopeptide transport in a human intestinal cell line

Di- and tripeptides, as well as peptidomimetic drugs such as cephalexin (CFX), are absorbed by enterocytes via the oligopeptide transporter PepT1. We recently showed that the alpha(2)-adrenergic agonist clonidine increases CFX absorption in anaesthetized rats. Herein, we investigated whether alpha(2)-adrenergic receptors can directly affect PepT1 activity in a clone of the differentiated human intestinal cell line Caco-2 (Caco-2 3B) engineered to stably express alpha(2A)-adrenergic receptors at a density similar to that found in normal mucosa. Measurement of CFX fluxes across cell monolayers cultured on transwell filters demonstrated that the alpha(2)-agonists clonidine and UK14304 caused a 2-fold increase of CFX transport in Caco-2 3B cells, but not in Caco-2 (expressing PepT1 but not alpha(2)-adrenergic receptors) or in the HT29 19A clone (expressing alpha(2)-adrenergic receptors but not PepT1). The stimulatory effect of clonidine was abolished by glycyl-sarcosine (a competitor for the transporter) and blocked by yohimbine or RX821002 (alpha(2)-antagonists). Analysis of the kinetics of CFX transport in control and clonidine-treated Caco-2 3B cells showed that clonidine increased V(max) of CFX transport without changing K(m). Clonidine action was abolished by colchicine but not altered by amiloride, demonstrating that microtubule integrity but not Na(+)/H(+) exchanger activity is necessary for the effect of alpha(2)-agonists to occur. In conclusion, clonidine can directly activate alpha(2)-adrenergic receptors located on epithelial cells. The precise molecular mechanisms whereby these receptors modulate PepT1 activity remain to be elucidated but an increased translocation to the apical membrane of preformed cytoplasmic transporter molecules is likely to be involved.     

Synergy between the antinociceptive effects of intrathecal clonidine and systemic morphine in the rat

These experiments tested the hypothesis that intrathecal alpha 2-adrenergic antinociception could be potentiated by the concurrent administration of systemic morphine. Thirty-four male rats, implanted with chronic indwelling intrathecal catheters, received a subcutaneous injection of either morphine sulfate or an equal volume of saline, followed by an intrathecal injection of clonidine HCl or an equal volume of vehicle. Antinociception was assessed using the tail-flick test. Tail-flick latencies following subcutaneous morphine plus intrathecal vehicle, or subcutaneous saline plus intrathecal clonidine were not significantly different from baseline. However, the combination of subcutaneous morphine plus intrathecal clonidine produced a significant antinociceptive effect. Such potentiation may prove to be a useful clinical strategy to help maximize analgesia, minimize side effects and attenuate the development of tolerance.     

A comparison of motor block between ropivacaine and bupivacaine for continuous labor epidural analgesia.

The aim of the present study was to compare the amount of motor block produced by different loading doses of ropivacaine and bupivacaine when delivered in a dilute solution with added opioid. Sixty-eight healthy term primigravid parturients were randomized to receive an initial bolus dose of 10 mL of 1 of the following: 0.25% bupivacaine (high bupivacaine), 0.25% ropivacaine (high ropivacaine), 0.125% bupivacaine (low bupivacaine), or 0.125% ropivacaine (low ropivacaine). Each loading dose had 10 micrograms of sufentanil added to it. All groups received a continuous infusion of a 0.1% study drug infusion with 0.6 microgram/mL of sufentanil at a rate of 8 to 14 mL/h to maintain analgesia. Supplemental doses of 10 mL of a 0.125% study solution with 10 micrograms of sufentanil were given as needed. Pain scores and a modified Bromage scale were used to assess analgesia and motor block. A statistically significant greater percentage of parturients receiving bupivacaine had motor block than those who received ropivacaine, with a marked decrease in the occurrence of motor block in the low ropivacaine group. The pain relief seemed to be less satisfactory in the ropivacaine groups, but the difference was not statistically significant. Ropivacaine produced significantly less motor block than bupivacaine in the 0.25% and the 0.125% loading doses, with the greatest difference seen in the lower concentration loading dose of ropivacaine.     

Enhancement of pentazocine analgesia by clonidine.

Opiate-adrenergic interactions were investigated by studying the effect of the selective alpha 2-adrenergic agonist, clonidine, on the analgesia produced by intravenous placebo and by the predominantly kappa-opiate agonist, pentazocine, in patients with dental postoperative pain. Clonidine did not affect the pain level when administered with intravenous placebo. When administered with pentazocine, clonidine caused a statistically significant increase in pentazocine analgesia. Comparison is made to other opiate-adrenergic interactions and possible mechanisms are discussed.     

Postoperative analgetische Wirksamkeit intraartikulärer Morphin- oder Ropivacaingabe nach Kniegelenkarthroskopie

INTRODUCTION: Recent studies for postoperative pain relief after arthroscopy by intraarticular morphine or bupivacaine showed controversial results. The aim of the study was to evaluate the analgesic effect of intraarticular morphine and ropivacaine. METHODS: 135 patients were randomized into 9 groups (n=15) after standardized knee-arthroscopy. They received either 1 mg or 5 mg morphine or 150 mg ropivacaine or a combination of 5 mg morphine and 75 mg ropivacaine. Drains were opened either after 10 or 30 minutes. A control-group received isotonic saline. Pain was assesed 1 h and 4 h after surgery, at 8 pm on the day of the operation and at 8am and 4 pm the following two days by a VAS scale. Tramadol consumption as rescue medication was registred. RESULTS: Ropivacaine showed the best pain relief after surgery. After 24 h the pain intensity approximated in all groups and after 48 h there was no difference. Tramadol consumption was highest in the control group and lowest in the ropivacaine group (p<0,05). Ropivacaine showed better pain reduction than morphine. An influence of the time, when drains were opened, could only be demostrated for the 75 mg ropivacain combination group. CONCLUSION: Intraarticular ropivacaine following elective knee-arthroscopy reduces postoperative analgetic consumption significantly and improves patient comfort.     

盐酸罗派卡因复合舒芬太尼硬膜外术后镇痛对产妇泌乳的影响

目的 探讨盐酸罗派卡因复合舒芬太尼硬膜外术后镇痛对产妇泌乳功能的影响.方法 将82例单胎足月妊娠拟行剖宫产的产妇按随机数字表法分为对照组40例和观察组42例,均采用持续硬膜外麻醉,对照组术后视疼痛情况肌内注射哌替啶,观察组术后接含0.125％盐酸罗派卡因+0.5 μg·mL-1舒芬太尼镇痛液的镇痛泵,行术后硬膜外自控镇痛.结果 观察组产妇的初乳时间早于对照组,且日哺乳次数明显多于对照组,2组相比差异有统计学意义(P＜0.05);分娩后观察组的泌乳素水平明显升高,与手术前比较,差异有统计学意义(P＜0.05),且明显高于对照组(P＜0.05).结论 采用盐酸罗派卡因复合舒芬太尼硬膜外自控镇痛可明显减少因疼痛引起的泌乳功能下降,对产妇的康复和新生儿母乳喂养有利.     

Chemical compatibility of regional anesthetic drug combinations.

OBJECTIVE: To define the physical and chemical compatibilities of several classes of drugs that may be used in combination for peridural anesthesia. DESIGN: Morphine, fentanyl, bupivacaine, lidocaine, tetracaine, ketamine, and clonidine were admixed for one hour in five groups of three-drug combinations, plus one group of all seven drugs. The combinations were inspected macroscopically and microscopically to determine physical compatibility. The admixtures were evaluated by gas chromatography/mass spectroscopy (GC/MS) and compared with known standards to determine chemical compatibility. RESULTS: The admixtures showed no physical incompatibility on microscopic or macroscopic evaluation. Chemical compatibility of all mixtures was confirmed by GC/MS. Ion chromatograms of the drugs in admixtures were identical to previously established standards. CONCLUSIONS: The agents evaluated demonstrated physical and chemical compatibility under conditions that would be observed during the administration of peridural anesthesia. Combinations of these drugs therefore could be safely admixed for use in anesthesia.     

Antinociceptive Synergistic Interaction Between Clonidine and Ouabain on Thermal Nociceptive Tests in the Rat

The antinociceptive effect produced by spinal injection of clonidine (an alpha(2)-adrenergic agonist) is mediated by a cholinergic mechanism. We aimed in the current study to evaluate the antinociceptive interaction between intrathecally administered ouabain, an inhibitor of Na(+), K(+)-ATPase, and clonidine. We used rats chronically implanted with lumbar intrathecal catheters to examine the ability of intrathecal clonidine and ouabain and the mixtures of clonidine-ouabain to alter tail-flick latency. To characterize the interaction, isobolographic analysis was performed. Intrathecal clonidine (0.5-10 microg) and ouabain (0.1-5 microg) produced significant dose- and time-dependent antinociception in the tail-flick tests. The median effective dose (ED(50)) values for intrathecally administered ouabain and clonidine were 2.3 microg and 4.7 microg, respectively. The experimental point for the ouabain-clonidine combination decreased significantly (P < .05) below the lines of additivity. Isobolographic analysis exhibited a synergistic interaction after the coadministration of ouabain and clonidine. No motor impairment was observed in the animals after intrathecal administration of the combination of ouabain and clonidine or clonidine alone. Intrathecal pretreatment with atropine but not yohimbine blocked the antinociceptive effect of ouabain and attenuated its interaction with spinal clonidine. These results suggest that the synergistic interaction of ouabain and clonidine were probably mediated, at least in part, via an enhancement of cholinergic transmission in the spinal nociceptive processing system. PERSPECTIVE: Although intrathecal clonidine produces pronounced analgesia, antinociceptive doses of intrathecal clonidine produce several side effects, including hypotension, bradycardia, and sedation. This article presents antinociceptive synergistic interaction between clonidine and ouabain on thermal nociceptive tests in the rat.     

罗哌卡因联合舒芬太尼在潜伏期分娩镇痛中的应用

[目的]观察罗哌卡因与舒芬太尼联合应用于潜伏期分娩镇痛对产程、分娩方式和新生儿的影响.[方法]选择100例无阴道分娩和腰硬联合麻醉禁忌证的初产妇,随机等分为两组(n=50).A组在宫口开至1～2 cm时采用腰硬联合分娩镇痛:蛛网膜下腔注入罗哌卡因3 mg,硬膜外腔连接自控镇痛泵,镇痛液为0.5 μg/mL舒芬太尼+0....     

Evidence against alpha-adrenoceptors mediating relaxation in rat thoracic aortae: alpha-agonists relaxation depends on interaction with alpha-adrenoceptors

In rat aorta, the presence of functional alpha(2)-adrenoceptors (alpha(2)-AR) was investigated in ring preparations preconstricted with alpha(1)-adrenergic and non- alpha(1)-adrenergic agonists. Particularly, the hypothetical interference of alpha(2)-AR agonists with alpha(1)-AR-mediated vasoconstriction was evaluated. Relaxant and contractile responses to alpha(2)-AR agonists were obtained. In endothelium-intact and endothelium-denuded aortic rings preconstricted with phenylephrine (1 x 10(-6) m), the imidazoline derivatives, clonidine and UK14304, induced relaxations with similar order of potencies (-log EC(50)) and maxima relaxant effects respectively. Pretreatment with the NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME) had no effect on the relaxant responses to clonidine and UK14304. In phenylephrine-constricted rings with endothelium, relaxations to clonidine and UK 14304 were not antagonized by the selective alpha(2)-AR antagonist, rauwolscine (< or =1 x 10(-6) m). Clonidine and UK 14304 induced only contractions on endothelium-intact and endothelium-denuded aortic rings contracted with prostaglandin F(2alpha) (3 x 10(-7) m). Moreover, clonidine and UK 14304-induced relaxation of endothelium-denuded arteries precontracted with methoxamine but not with serotonin. Finally, the concentration-contraction curves to clonidine and UK 14304 in endothelium-denuded aortic rings were significantly shifted to the right by the alpha(1D)-AR selective antagonist, BMY 7378, and rauwolscine. The pA(2) and pK(B) values for BMY 7378 and rauwolscine, respectively, against endothelium-independent actions of clonidine and UK 14304 were characteristic of an effect on the alpha(1D)-AR. The other selective alpha(2)-AR agonist tested BHT 933 (an azepine derivative), lacks considerable relaxant and contractile effects in rat aorta. The results provide no evidence for the presence of functional alpha(2)-AR in rat aorta. Respectively, the relaxant and contractile effects of the imidazoline derivatives, clonidine and UK 14304, may be due to an adjustable (in relation to the agonist-dependent active state of the alpha(1)-AR), inhibitory and excitatory, interaction with alpha(1)-ARs.     

Alpha1-adrenergic receptors augment P2X3 receptor-mediated nociceptive responses in the uninjured state.

In the present study, the adrenergic receptor (AR) subtype mediating adrenergic augmentation of P2X(3) receptor-mediated nociceptive responses on sensory nerve endings was examined by using selective AR receptor agonists and antagonists in Sprague Dawley rats in the uninjured state. Local administration of alphabeta-methyleneATP (ligand for P2X3/P2X2/3 receptors) into the plantar hind paw produced few pain behaviors when given alone in this strain of rats; combination with adrenaline (alpha1- and alpha2-AR agonist) and phenylephrine (alpha1-AR agonist) but not clonidine or UK 14,304 (alpha2-AR agonists) increased flinching behaviors. Flinching produced by noradrenaline (NA)/alphabeta-methyleneATP was suppressed by low doses of prazosin (alpha1-AR antagonist), and this reduction was selective compared with yohimbine (alpha2-AR antagonist). Prazosin also reduced flinching produced by phenylephrine/alphabeta-methyleneATP. Using thermal threshold determinations, adrenaline and phenylephrine but not clonidine or UK 14,304, mimicked the action of NA in augmenting reductions in thermal thresholds produced by alphabeta-methyleneATP. Terazosin (another alpha1-AR antagonist) inhibited hyperalgesia produced by NA/alphabeta-methyleneATP. These results provide evidence for alpha1-AR involvement in adrenergic augmentation of P2X3/P2X2/3 receptor-mediated responses on sensory nerve endings in the uninjured state in Sprague Dawley rats. PERSPECTIVE: This study indicates the alpha1-adrenergic receptor subtype mediates adrenergic augmentation of the activation of sensory nerves by purinergic P2X3 receptors (respond to ATP) in the periphery. Observations are potentially relevant to chronic pain conditions in which sympathetic nerves influence sensory nerves.     

alpha2A-adrenoceptor stimulation reduces capsaicin-induced glutamate release from spinal cord synaptosomes.

Glutamate (Glu) is involved in excitatory neurotransmission and nociception and plays an essential role in relaying noxious stimuli in the spinal cord. Intrathecal or epidural injection of alpha2-adrenergic agonists produces potent antinociceptive effects, alters spinal neurotransmitter release, and effectively treats acute nociceptive and chronic neuropathic pain. Although it is generally believed that alpha2-adrenergic receptor stimulation reduces excitatory neurotransmitter release from peripheral afferents, the subtype of receptor causing this effect and its specificity to nociceptive neurotransmission have been inadequately studied. We therefore examined the pharmacology of adrenergic agents to inhibit Glu release in spinal cord from stimulation with capsaicin, a specific agonist for receptors on nociceptive afferents. Capsaicin evoked Glu release in synaptosomes from normal rat dorsal spinal cord in a concentration-dependent manner. Glu release from 30 microM capsaicin was inhibited by adrenergic agonists with a relative potency of clonidine = dexmedetomidine > norepinephrine > ST91 > phenylephrine = 0, consistent with an action on alpha2A/D subtype receptors. Also consistent with this interpretation was the observation that inhibition of capsaicin-induced Glu release by clonidine or dexmedetomidine was blocked by the alpha2A/D antagonist BRL44408 but not by the alpha2B/C-preferring antagonist ARC239. Similar results were obtained in perfused spinal cord slices. These data suggest that capsaicin-evoked Glu release, likely reflecting stimulation of C fiber terminals, can be inhibited by activation of the alpha2A/D subtype, and this action of adrenergic agonists may reflect in part their efficacy in the treatment of acute pain.     

甲磺酸罗哌卡因复合舒芬太尼用于剖宫产术后镇痛浓度的临床研究

目的观察舒芬太尼复合不同浓度的甲磺酸罗哌卡因用于剖宫产术后硬膜外自控镇痛术(PCEA)的效果及甲磺酸罗哌卡因的最佳有效浓度。方法 90例产妇在硬-腰联合麻醉(CSEA)下行剖宫产手术的患者,手术后行PCEA术后镇痛,在同样的阿片类药物剂量(30μg舒芬太尼)的背景下,依照给予不同浓度的甲磺酸罗哌卡因,随机分为3组;A组(n=30),0.2℅甲磺酸罗哌卡因100 ml;B组(n=30),0.15℅甲磺酸罗哌卡因100 ml;C组(n=30),0.1℅甲磺酸罗哌卡因100 ml。观察指标:术后4 h、12 h、48 h患者VAS疼痛评分,改良Bromage评分,恶心、呕吐、瘙痒、尿潴留、排气时间延长、延迟性呼吸抑制等副作用。结果①不同浓度的罗哌卡因各时间点VAS无统计学差异(P>0.05)。②下肢肌力恢复情况:术后4 h结果显示,3组间差异无统计学意义(P>0.05)。手术后12 h和48 h显示,C组与A、B两组相比,对下肢肌力影响最小,差异有统计学意义(P<0.05)。③在副作用项目中,C组在尿潴留、排气时间延长上与其它两组比较发生率明显减低,差异有统计学意义(P<0.05)。结论 0.1℅甲磺酸罗哌卡因复合枸橼酸舒芬太尼用于剖宫产术后镇痛效果良好,副作用少,且运动阻滞程度最小,因此更适合应用于剖宫产术后PCEA术后镇痛。     

The 90% Effective Dose of Sufentanil for Epidural Analgesia in the Early First Stage of Labor: A Double-blind,Sequential Dose-Finding Study

PurposeEpidural analgesia in the latent phase of the first stage of labor has been recognized and accepted by anesthesiologists worldwide. However, there is no unified consensus on the exact dosage of sufentanil with the combination of ropivacaine in the induction of epidural analgesia in the early first stage of labor. In this sequential dose-finding study, the 90% effective dose (ED₉₀) of sufentanil for epidural administration in the early first stage of labor was estimated to minimize the adverse effects of using higher doses.MethodsForty parturients with cervical dilatation of 2 to 4 cm who requested epidural analgesia were enrolled in this study. Parturients received 15 mL of a combination of ropivacaine 13 mg and the test dose of sufentanil. The initial dose of sufentanil in epidural administration was 1 μg, and the dose of sufentanil for the next parturient was based on the response of the preceding participant as per a biased coin up-and-down design. The primary outcome was the dose of sufentanil that resulted in successful epidural administration by maintaining the parturients’ visual analog scale scores at ≤30 mm in the first 15, 30, and 45 minutes of induction. The ED₉₀ and 95% CIs were estimated using isotonic regression methods and bootstrapping.FindingsThe estimated ED₉₀ of sufentanil in epidural administration in the early first stage of labor was 1.91 μg (95% CI, 1.82–2.35 μg) in this sequential dose-finding study.ImplicationsSufentanil at a dosage of 2 μg is recommended for the administration of epidural analgesia in parturients in the early first stage of labor. ChiCTR.org.cn identifier: 1900021683.     

Clonidine and para-aminoclonidine, partial agonists for the alpha2-adrenergic receptor on intact human blood platelets

Human blood platelets display alpha2-adrenergic receptors, which promote platelet aggregation and inhibit the adenylate cyclase. We investigated the effects of the antihypertensive agent clonidine and its analogue para-aminoclonidine on this receptor in the intact human platelet to determine their pharmacological effects and their ability to bind to the receptor by radioligand displacement. Both agents potentiated platelet aggregation induced by a submaximal concentration of ADP. Epinephrine-induced aggregation, on the other hand, was antagonized by clonidine and para-aminoclonidine in a dose-dependent fashion. Both agents inhibited the accumulation of cyclic AMP in platelets exposed to prostaglandin E1 and a phosphodiesterase inhibitor, but to a lesser extent than the inhibition caused by epinephrine. Both antagonized this excess inhibitory action of epinephrine. Clonidine and para-aminoclonidine blocked the binding of [3H]yohimbine (a selective alpha 2-adrenergic antagonist) to intact platelets with half-maximal effects at 0.3 and 0.7 microM, respectively. No evidence for the existence of a second class of binding sites with high affinity for clonidine was seen in intact platelets, either by this technique or by direct binding of [3H]clonidine. It is concluded that these two agents are partial agonists for the alpha 2-adrenergic receptors on blood platelets and that this receptor exists predominantly in the low-affinity state in the intact cell.     

Alpha 2-adrenergic modulation of glucagon and insulin secretions in sheep.

To investigate the effects of alpha 2-adrenergic receptors on the secretions of pancreatic glucagon and insulin, clonidine, midaglizole and yohimbine were intravenously administered in four conscious sheep. Clonidine infusion at a dosage of 1.0 nmol/kg/min produced hyperglucagonemia, hypoinsulinemia and hyperglycemia. Midaglizole or yohimbine was infused for 30 min, at doses of 5, 10 and 50 nmol/kg/min during the clonidine infusion. The highest yohimbine infusion (50 nmol/kg/min) blocked the clonidine-induced responses of glucagon, insulin and glucose. On the other hand, the midaglizole (50 nmol/kg/min) infusion brought about no statistical effect on the clonidine-induced responses of glucagon, insulin and glucose. The alpha 2-adrenergic antagonistic effect of midaglizole was clearly less than that of yohimbine in the present experiments. It is concluded that the glucagon secretion is enhanced and the insulin release is inhibited by alpha 2-adrenergic stimulation in conscious sheep.     

Perioperative administration of the alpha2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression

The development of chronic pain after surgery is not rare. Nerve injury from complete or partial nerve section during surgery leads to macrophage recruitment and release of pro-inflammatory cytokines, leading in turn to sensitization. Macrophages also express alpha2-adrenoceptors, and we previously demonstrated a prolonged reduction in hypersensitivity following peri-neural injection of the alpha2-adrenoceptor agonist, clonidine, in rats with chronic nerve injury. The current study tested whether peri-neural clonidine at the time of injury could also prevent development of hypersensitivity. Rats underwent partial ligation of one sciatic nerve, and peri-neural saline, clonidine or a combination of clonidine and the alpha2A-adrenceptor-preferring antagonist, BRL44408, were administered before wound closure and, in some animals, also 24 and 48 h later. The single clonidine injection reduced hypersensitivity for only 5 h, whereas repeated injection for three days reduced hypersensitivity for 28 days. Peri-neural clonidine reduced the increase in tissue content of the proinflammatory cytokines IL-1beta and particularly TNFalpha in sciatic nerve, DRG and spinal cord while increasing concentrations of the anti-inflammatory cytokine TGF-beta1. Clonidine's effects on behavior and TNFalpha content were blocked by BRL44408. We conclude that peri-neural administration of clonidine at the site and time of injury reduces the degree of hypersensitivity in part by altering the balance of pro- and anti-inflammatory cytokines through activation of alpha2A-adrenoceptors. These results support testing of whether clonidine, as an adjuvant in continuous peripheral nerve blocks in settings of known major nerve injury, such as limb amputation, might prevent the development of chronic pain.