Enhancement of experimental pruritus and mechanically evoked dysesthesiae with local anesthesia

Pain reduces itch-a commonly known effect of scratching the skin. Experimentally produced itch from histamine is sometimes accompanied by secondary sensations of pain. The present study investigated the effects of eliminating this pain, by means of a local anesthetic, on the itch and the enhanced mechanically evoked itch and pain that occur after an intradermal injection of histamine. In ten human subjects, the volar forearm was injected with either 20 microl of 2% chloroprocaine (experimental arm), or 20 microl of saline (control arm). Histamine 10 microl was injected into each bleb, and the resulting magnitude of itch estimated. The borders of three cutaneous areas were mapped within which mechanical stimulation of the skin surrounding the bleb elicited abnormal sensations (dysesthesiae): alloknesis, defined as itch evoked by innocuous stroking, and hyperalgesia and hyperknesis, characterized, respectively, by enhanced pain and enhanced itch evoked by pricking the skin with a fine tipped filament. The magnitude and duration of itch were significantly greater and the areas of dysesthesia significantly larger for the experimental than for the control arm. It is hypothesized that there exist two classes of histamine-sensitive primary afferent neurons. One class is "pruritic", and mediates itch whereas the other is "antipruritic", and evokes a centrally mediated reduction in histamine-evoked itch and dysesthesiae. It is further suggested that the anesthetic blocked the discharges of the antipruritic afferents, preventing the central inhibition from occurring and thereby unmasking the effects of the pruritic afferents.     

Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia

We investigated the effects of tactile allodynia on the itch and mechanically evoked dysesthesiae produced by an intradermal injection of histamine in human volunteers. After an intradermal injection of capsaicin into the volar surface of one forearm, there developed an area of tactile allodynia to stroking and hyperalgesia to pricking the skin. Histamine was then injected simultaneously into the area of allodynia (experimental arm) and into the opposite forearm (control arm). Magnitude estimates of itch were obtained every 15 s for 5 min, and the areas of cutaneous hyperalgesia (pricking-evoked pain), alloknesis (stroking-evoked itch), hyperknesis (pricking-evoked itch) and wheal and flare were measured. The areas of wheal and flare were not significantly different on the two arms. The magnitude of itch and the areas of hyperknesis and alloknesis developed normally on the control arm but were absent or greatly reduced on the experimental arm. Thus, both the itch and the alloknesis and hyperknesis normally induced by histamine were absent or greatly reduced when histamine was injected in an area of capsaicin-induced allodynia. These results are compatible with the hypothesis that activity in capsaicin-sensitive, nociceptive primary afferent neurons evokes a central neuronal inhibitory process that prevents or reduces the itch and mechanically evoked dysesthesiae normally produced by an intradermal injection of histamine.     

Indirect mechanism of histamine-induced nociception in temporomandibular joint of rats

A considerable amount of evidence suggests that temporomandibular joint (TMJ) pain associated with temporomandibular disorder results, at least in part, from an inflammatory episode. Although histamine can cause pain, it is not clear whether this mediator induces nociception in the TMJ. In this study, we investigated the contribution of endogenous histamine to formalin-induced nociception in the TMJ of rats. We also investigated whether the administration of histamine induces nociception in the TMJ and, if so, whether this effect is mediated by an indirect action on primary afferent nociceptors. Local administration of the H1-receptor antagonist pyrilamine prevented formalin-induced nociception in the TMJ in a dose-dependent manner. Local administration of histamine (250 microg) in the TMJ induced nociceptive behavior that was inhibited by co-administration of the lidocaine N-ethyl bromide quaternary salt QX-314 (2%) or the selective H1-receptor antagonist pyrilamine (400 microg). Nociception induced by histamine was also inhibited by pre-treatment with sodium cromoglycate (800 microg) and by co-administration of the 5-HT(3) receptor antagonist tropisetron (400 mug), while pyrilamine (400 mug) did not inhibit nociception induced by 5-hydroxytryptamine (5-HT, 250 microg) in the TMJ. Furthermore, histamine, in a dose that did not induce nociception by itself, strongly enhanced 5-HT-induced nociception. Finally, the administration of a sub-threshold dose of 5-HT (100 microg), but not of histamine (100 microg), elicited nociception in the TMJ previously challenged with the inflammatory agent carrageenan (100 microg). In conclusion, these data suggest that histamine induces TMJ nociception by an indirect mechanism involving endogenous release of 5-HT and activation of 5-HT(3) receptors on sensory afferents. It is proposed that histamine activates the H1 receptor to induce the release of 5-HT which depolarizes the nociceptor by activating 5-HT(3) receptor.     

Selective CB2 agonists with anti-pruritic activity: Discovery of potent and orally available bicyclic 2-pyridones

The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.     

Influence of local and neutral anaesthetics on the polymorphic phase preferences of egg yolk phosphatidylethanolamine

(1) The polymorphic phase preferences of egg phosphatidylethanolamine have been examined in the presence of normal alcohols and alkanes of varying chain length, as well as charged amine anaesthetics. (2) It is shown that the charged anaesthetics, ethanol and butanol can stabilize a bilayer arrangement for egg phosphatidylethanolamine. In contrast, longer chain ($\text{C}\text{?6}$) normal alcohols and alkanes induce the hexagonal (H_II) phase. (3) The relative potency of local anaesthetics in vitro (chlorpromazine, dibucaine, tetracaine and procaine) is mirrored by their relative ability to stabilize bilayer structure for hydrated egg phosphatidylethanolamine. Further, the aqueous concentrations of anaesthetic required to affect phospholipid polymorphism is sensitive to the lipid composition. For example, the inclusion of 20 mol% egg phosphatidylserine in egg phosphatidylethanolamine dispersions can reduce the aqueous concentrations of dibucaine required to induce appreciable bilayer stabilization effects from 5.0 mM to 0.5 mM. (4) It is suggested that the ability of amphipatic molecules such as anaesthetics to influence phosphatidylethanolamine polymorphism arises from their molecular shape. The possibility that anaesthetic molecules may exert their effects by virtue of this shape property is raised.     

Histamine H(2) receptor-mediated modulation of local cytokine expression in a mouse experimental tumor model

Accumulating evidence indicates that histamine is involved in the modulation of cytokine expression patterns. We previously reported that daily treatment with the H(2) receptor antagonist, cimetidine, suppressed tumor growth through alteration of the local cytokine expression pattern. In this study, we used a mouse strain genetically lacking histidine decarboxylase (HDC), to evaluate the role of endogenous histamine synthesis on cytokine expression and tumor development. In the mutant mice, cimetidine had no effect on tumor growth, whereas an H(2) agonist, dimaprit, significantly enhanced tumor growth. When the HDC-deficient mice were implanted with mutant CT-26 cells stably expressing HDC, drastic suppression of tumor growth by cimetidine was observed, which was accompanied by augmentation of mRNA expression of LT-beta, TNF-alpha, and IFN-gamma in the tumor tissues. These results suggest that endogenous histamine synthesis in tumor tissues suppresses local tumor immunity via the H(2) receptors, resulting in tumor growth promotion.     

Formation of micelles and membrane action of the local anesthetic tetracaine hydrochloride

The formation of micelles of the local anesthetic tetracaine hydrochloride in aqueous phosphate buffer solution of pH 6.5 and ionic strength ($\text{I}$) 0.10 was examined at 22°C by surface tension and using the fluorescent indicators perylene (peri-dinaphthalene) and 8-anilino-1-naphthalene sulfonic acid, sodium salt (ANS). The critical micelle concentration was located at 0.069, 0.071 and 0.063 M by measurements of surface tension, perylene solubilization and enhancement of ANS fluorescence, respectively. In contrast to other cationic surfactants, the anesthetic monomer did not show evidence of forming a fluorescent molecular complex with ANS under the experimental conditions of this study.The formation of micelles by tetracaine-HCl showed a pronounced effect on lipid membranes by inducing an abrupt decrease in the scattered light of egg lecithin liposomes at an anesthetic concentration roughly similar to its critical micelle concentration. This optical behaviour is characteristic of liposome damage and can be interpreted to mean that the lipids become solubilized into tetracaine-HCl micelles.The ability of this local anesthetic to form micelles can be taken as a manifestation of the same hydrophobic forces that lead to partitioning of the drug into membranes.     

Spatial summation of perceived pressure,sharpness and mechanically evoked cutaneous pain

Psychophysically, spatial summation can be demonstrated as a decrease in threshold accompanying an increased field of stimulation. The present study examined to what extent different mechanically evoked percepts (pressure, sharpness, and pain) show spatial summation. Various probes were used to apply prescribed forces to the dorsal surface of the digits of 19 healthy subjects. The threshold for three perceptual qualities showed differing degrees of spatial summation: sharpness showed no statistically significant spatial summation; pain demonstrated some significant summation (46% on average); pressure showed the greatest degree of spatial summation (76% on average). The lack of significant spatial summation for sharpness threshold is consistent with the theory that perceived sharpness can be evoked by near threshold activity of a single nociceptor. The modest amount of spatial summation for pain implies that distinctly suprathreshold activation of nociceptors is required for mechanically evoked pain perception, and such input summates centrally, but not completely. The greater spatial summation observed for pressure vs. pain thresholds implies a greater degree of central summation for slowly adapting mechanoreceptors vs. nociceptors.     

Herpetomonas samuelpessoai: Changes in cell shape and induction of differentiation by local anesthetic

Lidocaine, a local anesthetic, induces changes in morphology and motility of Herpetomonas samuelpessoai when incubated under nonproliferative conditions. The cells become rounded and immotile. These effects are dependent on time and temperature of incubation, concentration of lidocaine, and pH. Divalent cations (Ca²⁺, Mg²⁺, Ba²⁺, and Sr²⁺) reversed the effect of lidocaine. Lidocaine also induces the formation of membrane-bound cytoplasmic vacuoles as determined by morphometry applied to electron micrographs. Lidocaine had a dose-dependent effect on the growth of H. samuelpessoai in a chemically defined medium. At concentrations which did not interfere with cell growth, it induces the transformation of promastigote into opisthomastigote via paramastigote. It is suggested that lidocaine may be used as an inductor of differentiation in H. samuelpessoai opening the possibility of obtaining the three developmental stages of this trypanosomatid.     

Changes in Histamine Metabolism in the Brains of Mice with Streptozotocin-Induced Diabetes

Histamine (HA) metabolism in the brain of mice with streptozotocin (STZ)-induced diabetes was examined. The levels of tele-methylhistamine (t-MH), a major metabolite of brain HA, significantly increased 3 and 4 weeks after STZ injection. However, the HA turnover rates in the diabetic mice, determined from the accumulation of t-MH after the administration of pargyline, were not different from the control values when the animals were allowed free access to food. When the mice were starved for 15 h 4 weeks after STZ treatment, the brain levels of L-histidine decreased significantly, whereas HA turnover increased significantly. Such changes were not observed in starved control mice. Histidine decarboxylase or HA N-methyltransferase activity did not change after starvation in either diabetic or control mice. These results show that the histaminergic (HAergic) activity in the brains of diabetic mice remains within normal range as long as the animals are allowed free access to food. However, they also indicate that a marked enhancement of HAergic activity accompanied by a decrease in the brain L-histidine level occurs in starved diabetic mice.     

Effects of local anesthetics and related compounds on the endocytosis and catabolism of asialo-glycoproteins in isolated hepatocytes

The effects of local anesthetics, including procaine and dibucaine, and some related amine compounds, such as dansyl-cadaverine, were studied with respect to their effects on the uptake and degradation of asialo-glycoproteins in isolated hepatocytes 0.5 mM of either dibucaine or dansyl-cadaverine reduced the rates of uptake to 18–19% of control values; other amines were less effective. Dibucaine and dansyl-cadaverine both acted by reducing the surface binding capacity of the cells as well as by reducing the rate of internalization of surface-bound asialo-glycoprotein. All of the compounds that affected the uptake, including dansyl-cadaverine, also reduced the rate of degradation. This effect could be studied separately from their effect on uptake. The concentrations that were required in order to reduce degradation were, in general, 0.5-0.25 of those which caused a reduction in the uptake. Even though dibucaine, lidocaine and dansyl-cadaverine were found to accumulate in the lysosomes, it was concluded from studies with isopycnic centrifugation in sucrose gradients that all three compounds inhibited the rate of transfer of endocytosed protein from endocytic vesicles to lysosomes. This effect could be due to a reduced rate of fusion between endocytic vesicles and lysosomes.     

The inhibition of the serum-stimulated increase of ornithine decarboxylase by ionophores and local anesthetics

The addition of fresh serum-containing growth medium to L1210 mouse leukemic cells in culture resulted in a 5-fold increase in ornithine decarboxylase (l-ornithine carboxy-lyase, EC 4.1.1.17) activity. The presence of microtubule disrupting agents (colchine, vinblastine) or cations (5–10 mM K⁺, Na⁺ or Mg²⁺) abolishes this increase of ornithine decarboxylase activity (Chen, K.Y., Heller, J.S. and Canellakis, E.S. (1976) Biochem. Biophys. Res. Commun. 70, 212–219). Based on these observations we proposed that fluctuation in cellular cation concentrations may act as a link between the membrane structure and ornithine decarboxylase. To test this proposal, we studied the effects of selective membrane perturbing agents such as ionophores and local anesthetics, on the serum-stimulated increase of ornithine decarboxylase activity in L1210 cells. Among the six inonophores tested, valinomycin was the most potent one, with I₅₀ value (concentration that gives 50% inhibition of orthinine decarbocylase activity) of 6·10^?9 M. Dibucaine and tetracaine were also effective inhibitors at 10^?4?10^?5 M. The I₅₀ values of valinomycin on the protein synthesis and RNA synthesis, however, were greater than 1·10^?6 M. These results substantiate the notion that ornithine decarboxylase activity can be regulated at plasma membrane level and such regulation is related to the perturbation of cellular cation pools.     

高龄患者腹腔镜直肠癌根治术不同麻醉方法的比较

目的观察比较3种麻醉方法对高龄腹腔镜直肠癌根治术患者的呼吸循环功能和麻醉效果的影响。方法将45例高龄腹腔镜直肠癌根治术患者随机分成3组,每组15例。EA组,连续硬膜外阻滞麻醉组;GA组,静吸复合全身麻醉组;EGA组,小剂量硬膜外阻滞复合静吸全身麻醉组。观察3组麻醉开始前(T0)、麻醉诱导期(T1)、气管插管时(T2)、拔除气管导管时(T3)的HR、SBP、DBP、MAP、PETCO2、ECG,GA组与EGA组同时监测异氟醚MAC、气道压、手术结束自主呼吸恢复时间、自主呼吸潮气量达标、拔管时间、肌松情况及患者麻醉苏醒时间。结果 EA组有13例麻醉效果优良,SpO295%,PETCO2维持在正常范围;EGA组术毕自主呼吸恢复时间、潮气量达标、拔管时间均明显短于GA组(P0.01)。EA组在麻醉10～15 min后血压下降程度与GA组、EGA组麻醉诱导期血压下降相似(P0.05),EGA组在气管插管/拔管期血压波动不明显,而GA组血压显著升高(P0.01);EA组与GA组麻醉效果相似,EGA组麻醉效果优于GA组(P0.05)。结论 EGA组椎管内局麻药用量、全麻维持药用量、肌松药用量等均相应减少,呼吸循环功能较为稳定,术毕麻醉苏醒快,自主呼吸恢复和潮气量达标迅速,多数患者术毕即可拔除气管导管,是高龄腹腔镜直肠癌根治术患者理想的麻醉方法。     

The effect of epinephrine in local anesthesia on the survival of full- and split-thickness skin grafts: an experimental study

The effect of local anesthesia containing epinephrine on the survival of split- and full-thickness skin grafts remains unclear. In this blinded study, Xylocaine with or without epinephrine was injected subdermally prior to harvesting of split-thickness and full-thickness skin grafts on the dorsum of rabbits. After procurement, the grafts were placed back into their original donor sites. Statistical analysis of graft survival 7 days postoperatively revealed a significant decrease in survival for the full-thickness skin grafts treated with Xylocaine with epinephrine as compared with similar grafts without epinephrine (p less than 0.0005). No significant difference was noted for split-thickness skin-graft survival in grafts treated with Xylocaine with and without epinephrine (p greater than 0.1).     

The effect of neutral and charged micelles on the acid-base dissociation of the local anesthetic tetracaine

The influence of surfactant micelles on the acid-base dissociation of the charged tertiary amino group of the local anesthetic, tetracaine, has been investigated. From measurements of tetracaine fluorescence as a function of bulk pH, apparent $\text{p}\text{K}$ values of 6.88, 7.58 and 9.92 were found in the presence of cationic, neutral and anionic micelles, respectively, in 10 mM NaCl. These values are considerably displaced with respect to the $\text{p}\text{K}$ in aqueous solution which is 8.26. Such large shifts can be attributed to the effect of the surface polarity and electrical potential on the dissociation behavior of the anesthetic bound to micelles. It can be expected that the acid-base dissociation of a local anesthetic adsorbed to nerve fibers will also be affected by the properties of the membrane surface. Thus, it is suggested that the influence of the interfacial region on the $\text{p}\text{K}$ of surface-bound molecules should not be disregarded when estimating the proportion of charged and uncharged forms of local anesthetics interacting with axonal membranes.     

Multiple sites of inhibition of mitochondrial electron transport by local anesthetics

Local anesthetics and alcohols were found to inhibit mitochondrial electron transport at several points along the chain. The anesthetics employed were the tertiary amines procaine, tetracaine, dibucaine, and chlorpromazine, and the alcohols were n-butanol, n-pentanol, n-hexanol, and benzyl alcohol. Uncoupled sonic submitochondrial particles from beef heart and rat liver were studied. We report the following: (1) All of the anesthetics were found to inhibit each of the segments of the electron transport chain assayed; these included cytochrome c oxidase, durohydroquinone oxidase, succinate oxidase, NADH oxidase, succinate dehydrogenase, succinate-cytochrome c oxidoreductase, and NADH-cytochrome c oxidoreductase. (2) NADH oxidase and NADH-cytochrome c oxidoreductase required the lowest concentrations of anesthetic for inhibition, and cytochrome c oxidase required the highest concentrations. (3) We conclude that there are several points along the chain at which inhibition occurs, the most sensitive being in the region of Complex I (NADH dehydrogenase). (4) Beef heart submitochondrial particles are less sensitive to inhibition than are rat liver particles. (5) Low concentrations of several of the anesthetics gave enhancement of electron transport activity, whereas higher concentrations of the same agents caused inhibition. (6) The concentrations of anesthetics (alcohol and tertiary amine) which gave 50% inhibition of NADH oxidase were lower than the reported concentrations required for blockage of frog sciatic nerve.