Potentiation of Morphine-Induced Antinociception by Propranolol: The Involvement of Dopamine and GABA Systems

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.

Chronic morphine exposure and maternal separation induce impairments in cognition and locomotor activity of male adolescent rats

“…It might be hypothesized that chronic maternal morphine exposure activated a circuit that could not be aroused by MS alone (Figure 2f). It has been shown that there is a cross‐talk between the opioidergic and adrenergic systems (Afify & Andijani, 2017). In addition, the enhancement of body stretching in our study might be explained by a possible combination of opioidergic and adrenergic pathway activation (orderly followed by chronic maternal morphine exposure and MS) (Kestering‐Ferreira et al, 2021), which can be clarified in future molecular studies.…”

Propranolol reduces risk of knee or hip replacement due to osteoarthritis: A propensity score matched cohort study-using data from the Clinical Practice Research Datalink

“…There are several mechanisms by which propranolol may cause analgesia. These include blocking the β2 adrenoreceptors on the peripheral nociceptors, dorsal root ganglia, and superficial dorsal horn [17][18][19] , regulation of periaqueductal grey neurons firing, interference with sensitization in the rostral ventromedial medulla and locus coeruleus 20,21 , and increased analgesic effect of opioids 22 . Propranolol also induces infiltrative cutaneous analgesia and is more potent than lidocaine 23 .…”

The therapeutic potential of ultra-short-acting β-receptor antagonists in perioperative analgesic: Evidence from preclinical and clinical studies

“…β-Adrenergic antagonists can slow down the heart rate and reduce the contractility of the heart muscle by inhibiting the β 1 receptor. Afify and Andijani, (2017 ) demonstrated that the use of β-blockers enhanced the analgesic effect of morphine in a mechanism that involved decreased CO. This phenomenon has been confirmed in clinical studies: one report suggested that perioperative esmolol administration can reduce the intraoperative use of inhalation anesthetic and fentanyl and morphine consumption for the first three postoperative days ( Chia et al, 2004 ).…”

“…OPRs are Gi/o-coupled receptors whose stimulation inhibits AC activity to reduce PKA activation ( Law and Loh, 1999 ). Research shows that β-blockade prevents the stimulatory effect on the AC enzyme, reduces the number of cAMP molecules, enhances the inhibitory effect of opioids on pain transmission, and provides an antinociceptive response ( Afify and Andijani, 2017 ). These findings may be the result of Gs stimulation weakening the impact on Gi/o ( Figure 2 ).…”