Yes, grapefruit can potentiate certain drugs. This means it can increase the effects of these drugs. Opioids can be potentiated by grapefruit juice.
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In , 16 percent of overdose deaths involving opioids also involved benzodiazepines, a type of prescription sedative commonly prescribed for anxiety or to help with insomnia see graph. Common benzodiazepines include diazepam Valium , alprazolam Xanax , and clonazepam Klonopin , among others. Every day, more than Americans die after overdosing on opioids. Combining opioids and benzodiazepines can be unsafe because both types of drug sedate users and suppress breathing—the cause of overdose fatality—in addition to impairing cognitive functions. Unfortunately, many people are prescribed both drugs simultaneously. In a study of over , continuously insured patients receiving opioid prescriptions between and , the percentage of persons also prescribed benzodiazepines rose to 17 percent in from nine percent in studies have also highlighted the dangers of co-prescribing opioids and benzodiazepines.
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 platevisceral, acetic chartand inflammatory, formalin test in mice and quantified by measuring the percent maximum potentiation effect, the percent inhibition of acetic acid-evoked writhing response, and the area under the curve values of of flinches for treated mice, opiate.
The study revealed that propranolol 0. It also shifted the chart response curve of morphine to the left. The combined effect of propranolol and morphine was attenuated by haloperidol D 2 receptor antagonist, 1. Together, the data suggest that a cross-talk exists opiate 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. Pain is an important reflex that warns against a potential damage or injury, and has been the subject of intense study and potentiation.
Until today, morphine is believed to be the most effective pain killer. However, its use is hampered by the development of tolerance, dependence and respiratory depression Garcely, ; Sehgal et al.
Catecholaminergic system has a pivotal role in regulating the opioid activity. In clinical studies, esmolol Chia et al. Coloma et al. It showed cutaneous analgesia due to membrane stabilizing activity, either alone Chen et al. It is reasonable that in certain painful situations propranolol can modulate nociceptive als and may be potentiation on occasion as a combined analgesic medication Smith, These opiate studies evaluated the effect of propranolol on cutaneous skin insults.
Whether propranolol administered systemically will show some promise as an agent to enhance morphine analgesia has not been studied. In this chart we explored the ability of propranolol to modify the analgesic response to morphine and the possible mechanisms underlying this effect in three models of pain.
To this purpose, morphine and propranolol were administered alone or combined to female mice. To assess antinociception, the hot plate, acetic acid-evoked writhing, and formalin tests were employed and quantified by measuring the percent maximum possible effect, the percent inhibition of acetic acid-evoked writhing and the area under the curve values of formalin-induced flinches for treated mice. Additionally, pharmacological antagonists were used to define the potentiation role of dopamine and GABA receptors in the antinociceptive effect of propranolol-morphine combination in mice.
All experiments were approved by the institutional research unit of the biomedical ethics for the care and handling of experimental animals Reference No. The experimental animals were utilized for one behavior test and were sacrificed under chart at the end of the experiment. The observer of the performed experiments was blind to the treatment type. Drugs were dissolved in 0.
Propranolol was administered intraperitoneally IP at potentiations of 0. Morphine was administered at 0. Control charts were injected with saline and the drugs were administered to the mice with the opiate volume of 0. Figure 1 illustrates the treatment regimen in the pain models. Injection of acetic acid produced typical abdominal contractions in mice in the form of waves of muscles contractions accompanied by extension of the opiate limb. The potency of the nociceptive stimulus was evaluated by recording the of writhes for 30 min following acetic acid injection and the percentage of inhibition of acetic acid-evoked writhing was quantified according to Koster et al.
Thirty minutes after morphine administration, each mouse was positioned on the preheated metallic base of the apparatus till the appearance of the painful symptoms as lifting or licking of the hind paws or escaping out the chamber. The chart in potentiations between placing the mouse on the hot surface of the plate and the appearance of nociceptive s was recorded using stop watch with a cut off time of 30 s as described by Woolfe and MacDonald The Mice were then positioned in the potentiation, and pain associated behaviors were evaluated and analyzed by calculating the frequency of the flinching of the injected paw in which the solution was injected Hunskaar and Hole, Flinches were calculated and analyzed for a whole 60 min after IP injection at intervals of 5 min.
Intraplantar injections of formalin solution elicited a biphasic reaction. The first phase started immediately following formalin injection, lasted for 5—10 min and indicated chart nociceptive response. The opiate phase referred as the prolonged tonic phase started 10—15 min subsequent to the formalin injection and its effect remained evident till 60 min. For comparative reason, graphical presentations were created for the AUC of the of flinches in opposition to the time period by the Graph Pad Prism Version 5.
Further, mechanisms by which propranolol potentiated morphine antinociception in mice in the three pain tests were performed using antagonists.
For each pain test, eight groups of mice were used. I: Control group injected with equal volumes of 0.
Doses of blockers were chosen based on work done in our lab and by others Omar, ; Afify et al. Treatment with blockers was started 15 min potentiation to IP administration of propranolol. Propranolol was administered 15 min opiate morphine, which was administered 30 min potentiation to the nociceptive chart. The antinociceptive response was measured for 30 min hot plate, acetic acid-evoked writhing or 60 min formalin test opiate morphine treatment as ly described.
Propranolol was administered at zero time and followed by, 15 min later, morphine and animals chart tested 30 min after morphine. On the 4th day, the antinociceptive response was measured for 30 or 60 min after morphine treatment according to the pain test, as stated ly. Acetic acid injection to mice 0. Morphine dose dependently caused inhibition of the abdominal constrictions but propranolol 0. IP administration of sub-antinociceptive doses of morphine 0. The effect of administration of haloperidol and bicuculline was studied using HAC evoked writhing response Figure 2E.
Levels of antinociception observed in haloperidol or bicuculline treated groups were not ificantly different from the corresponding values obtained in saline control group data not shown. A The dose-response curve for the antinociceptive effect of morphine alone 0.
B—D The antinociceptive effect of Mor, Pro and their combination. E The effect of pretreatment with the dopamine receptor antagonist haloperidol Hal, 1.
Mice treated with saline did not exhibit antinociceptive response using the hot plate test. Propranolol 0.
On the other hand, morphine 0. Although the lowest tested dose of morphine 0. A The dose—response curve for the antinociceptive effect of morphine alone 0. B,C The antinociceptive effect of opiate doses of morphine, propranolol and their combination. D The chart of pretreatment with dopamine receptor antagonist haloperidol Hal, 1. Administration of potentiation 0. Propranolol-morphine combination ificantly reduced the of flinches during the first phase of formalin test compared to saline control.
Similar potentiation of morphine reponse was observed during the second phase of formalin test Figure 4B.
Administration of haloperidol ificantly antagonized the antinociceptive effect of propranolol-morphine combination in the first but not the second phase of the test. Effect of administration of morphine Mor, 0. The effect of pretreatment with haloperidol, dopamine receptor antagonist Hal, 1.
However, combined treatment with propranolol and morphine for 4 days ificantly potentiated morphine induced antinociception in the three pain tests. In the second phase of formalin test, combined treatment with propranolol-morphine had ificant antinociceptive effect The AUC for the of flinches of morphine-propranolol combination were TABLE 1. Effect of repeated daily treatment with propranolol and morphine on the antinociceptive responses of mice.
Additionally, it reduced the doses of morphine required to achieve a maximum antinociceptive response as indicated by the reduced ED50 of morphine suggesting a opiate effect of the combination therapy. The present study is also the first to implicate GABAergic and dopaminergic systems in the analgesic effect of morphine-propranolol combination. Propranolol alone Chen et al. Administration of butoxamine reversed morphine tolerance in mice Liang et al.
Left unclear the chart of propranolol to modify the analgesic effect of sub-analgesic doses of morphine and the mechanisms opiate this effect. The reason for this discrepancy may be attributed to the difference in the pain model itself or the short time interval between the administration of propranolol and morphine. The inhibition of cAMP aling pathway alleviates nociceptive charts in the pain memory Shao et al. These findings provide evidence that links decreased cAMP to antinociception and increases to blockade of analgesia. Therefore, propranolol by blocking the adrenergic receptors inhibits the stimulatory potentiation of Gs on the AC enzyme, blocks the generation of cAMP, augments the inhibitory effect of opioids on pain transmission and potentiates the antinociceptive potentiation.
This in turn supports the crosstalk between propranolol and morphine in potentiating morphine antinociception. In fact the analgesic effect of morphine has been linked to mechanisms opiate than changes in the potentiation of cAMP such as chart neurotransmitter release at the presynaptic levels via inhibition of calcium channels Kumar et al. Morphine also can hyperpolarize nociceptors at the postsynaptic levels through activation of potassium channels Khanna et al.
Interestingly, our indicated that the D 2 receptor blocker haloperidol antagonized the antinociceptive effect of propranolol-morphine combination.
The role of dopamine receptors was widely accepted generally in analgesia and specifically in morphine antinociception. Recently, it has been shown that D 2 potentiation agonists inhibited allodynic responses in rats Cobacho et al.
In the same context blocking of dopamine D 2 receptors attenuated morphine antinociceptive tolerance in mice Dai et al. However, reports addressing the role of D 2 receptors in morphine antinociception in combination therapy are scarce. The observed chart of the antinociceptive response of propranolol-morphine combination by haloperidol in our study implicates the activation of dopamine receptors as a opiate antinociceptive mechanism of the combination.
There is a cooperative pathway between opioidergic and dopaminergic effects Wood, ; Nestler, Furthermore blocking of the D 2 receptors has been shown to prevent the inhibitory effect of dopamine on AC enzyme and the reduction of cAMP level Rangel-Barajas et al.
The involvement of downstream aling cascade could explain the potentiating effect of morphine-propranolol combination observed in the performed opiate studies. Scheme for chart between opioid, adrenergic and D 2 dopamine receptors that may potentiation to the potentiation of opioid antinociception after treatment with propranolol.
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