Abstract
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 (D2 receptor antagonist, 1.5 mg/Kg, IP), and bicuculline (GABAA 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.
Highlights
Pain is an important reflex that warns against a potential damage or injury, and has been the subject of intense study and research
The antinociception obtained with 10 mg/Kg propranolol plus 4 mg/Kg morphine was equal to that induced by 8 mg/Kg of morphine administered alone (%HAC inhibtion were 76% and 80%), respectively, (Figure 2D)
IP administration of morphine (8 mg/Kg) plus propranolol (10 mg/Kg) to mice resulted in maximum possible antinociception (100% inhibition of HAC evoked writhing) compared to 80% in mice treated with morphine alone
Summary
Pain is an important reflex that warns against a potential damage or injury, and has been the subject of intense study and research. Role of Adrenergic System in Morphine-Induced Antinociception system has a pivotal role in regulating the opioid activity. Esmolol (Chia et al, 2004; Collard et al, 2007; Haghighi et al, 2015), atenolol (Zaugg et al, 1999), and labetalol (Xiao et al, 2008) demonstrated analgesic properties and reduced the recurrent postoperative pain. Non-selective β-adrenergic receptor blockers inhibited the development of morphine tolerance in mice (Kihara and Kaneto, 1986; Kaneto and Inoue, 1990); reduced naloxone precipitated opioid withdrawal and might be effective in the treatment of opiate addiction (Harris and Aston-Jones, 1993). The specific mechanisms by which β-blockers potentiate the analgesic effect of opioids remains controversial
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