Afify Elham A, Andijani Najlaa M
Department of Pharmacology, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Front Pharmacol. 2017 Nov 10;8:794. doi: 10.3389/fphar.2017.00794. eCollection 2017.
Tolerance to the analgesic effect of morphine is a major clinical problem which can be managed by co-administration of another drug. This study investigated the ability of propranolol to potentiate the antinociceptive action of morphine and the possible mechanisms underlying this effect. Antinociception was assessed in three nociceptive tests (thermal, hot plate), (visceral, acetic acid), and (inflammatory, formalin test) in mice and quantified by measuring the percent maximum possible effect, the percent inhibition of acetic acid-evoked writhing response, and the area under the curve values of number of flinches for treated mice, respectively. The study revealed that propranolol (0.25-20 mg/Kg, IP) administration did not produce analgesia in mice. However, 10 mg/Kg propranolol, enhanced the antinociceptive effect of sub-analgesic doses of morphine (0.2, 1, and 2 mg/Kg, IP) in the three nociceptive tests. It also shifted the dose response curve of morphine to the left. The combined effect of propranolol and morphine was attenuated by haloperidol (D receptor antagonist, 1.5 mg/Kg, IP), and bicuculline (GABA receptor antagonist, 2 mg/Kg, IP). Repeated daily administration of propranolol (10 mg/Kg, IP) did not alter the nociceptive responses in the three pain tests, but it significantly potentiated morphine-induced antinociception in the hot plate, acetic acid-evoked writhing, and in the second phase of formalin tests. Together, the data suggest that a cross-talk exists between the opioidergic and adrenergic systems and implicate dopamine and GABA systems in this synergistic effect of morphine-propranolol combination. Propranolol may serve as an adjuvant therapy to potentiate the effect of opioid analgesics.
对吗啡镇痛作用产生耐受性是一个主要的临床问题，可通过联合使用另一种药物来解决。本研究调查了普萘洛尔增强吗啡镇痛作用的能力以及该作用潜在的机制。在小鼠的三种伤害感受性试验（热刺激，热板法）、（内脏刺激，醋酸法）和（炎症刺激，福尔马林试验）中评估镇痛作用，并分别通过测量最大可能效应百分比、醋酸诱发扭体反应的抑制百分比以及处理组小鼠退缩次数曲线下面积值进行量化。研究表明，腹腔注射普萘洛尔（0.25 - 20 mg/Kg）未在小鼠中产生镇痛作用。然而，10 mg/Kg的普萘洛尔在三种伤害感受性试验中增强了亚镇痛剂量吗啡（0.2、1和2 mg/Kg，腹腔注射）的镇痛作用。它还使吗啡的剂量反应曲线向左移动。氟哌啶醇（D受体拮抗剂，1.5 mg/Kg，腹腔注射）和荷包牡丹碱（GABA受体拮抗剂，2 mg/Kg，腹腔注射）减弱了普萘洛尔和吗啡的联合作用。每天重复腹腔注射普萘洛尔（10 mg/Kg）并未改变三种疼痛试验中的伤害感受性反应，但它显著增强了热板试验、醋酸诱发扭体试验以及福尔马林试验第二阶段中吗啡诱导的镇痛作用。总之，数据表明阿片能系统和肾上腺素能系统之间存在相互作用，并且多巴胺和GABA系统参与了吗啡 - 普萘洛尔组合的这种协同作用。普萘洛尔可作为一种辅助治疗来增强阿片类镇痛药的效果。
