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. 2025 Mar 4;102:100783. doi: 10.1016/j.curtheres.2025.100783

Reversing Morphine Induced Tolerance: Insights Into Cetirizine and Green Tea Extract Efficacy

Tahereh Eteraf-Oskouei 1, Adel Mahmoudi Gharehbaba 2, Solmaz Asnaashari 3, Zahra Fazli 1, Bohloul Habibi Asl 1,⁎
PMCID: PMC12370155  PMID: 40852197

Abstract

Background

The treatment of chronic pain presents a considerable difficulty, particularly due to opioid dependence, which is marked by tolerance and withdrawal symptoms. Opioids primarily target mu (μ) opioid receptors, providing pain relief while also leading to various side effects. This research aimed to examine the effectiveness of cetirizine and green tea hydroalcoholic extract (EXT) in altering morphine tolerance and improving analgesic effects.

Methods

Adult male mice were divided into nine groups. In order to investigate the analgesic tolerance, animals received morphine on 14 consecutive days. Cetirizine (5, 10, 20 mg/kg, i.p.) and EXT (50, 100, 200 mg/kg, i.p.) were given before a test dose of morphine (9 mg/kg, i.p.). The analgesic effects were evaluated by the hot plate test.

Results

Cetirizine with doses of 5, 10, 20 mg/kg, and 10 mg/kg showed a significant effect in reducing morphine tolerance 30 min (P < 0.0001) and 45 to 60 min (P < 0.0001) after test dose of morphine (9 mg/kg, i.p.) respectively. While the injection of different doses of the extract did not show any effect on tolerance to morphine. In the combined injection of these two drugs, there was no reduction in tolerance to morphine.

Conclusions

Cetirizine but not EXT reversed morphine tolerance. Furthermore, the co-administration of cetirizine and EXT did not yield any significant benefits compared to the individual treatments.

Keywords: Cetirizine, Green tea, Morphine, P-glycoprotein, Tolerance

Introduction

Managing chronic pain remains a complex challenge. Various classes of drugs are used for pain relief, including nonsteroidal anti-inflammatory drugs, anesthetics, N-methyl-d-aspartate receptor antagonists, and opioids. Opioid dependence, a growing clinical and societal issue, is marked by tolerance, withdrawal symptoms, and relapse. However, effectively addressing this condition remains a significant challenge.1

Opioids provide pharmacological benefits by binding to opioid receptors, which are G-protein coupled receptors featuring seven transmembrane domains. These receptors are overexpressed in the brain and spinal cord.2 Three categories have been confirmed: mu (μ, MOR),3 kappa (κ, KOR),4 and delta (δ, DOR),5 each exhibiting distinct central pharmacological effects. μ receptor agonists cause analgesic and euphoric effects, as well as respiratory depression. They are primarily in charge for the physical dependence commonly accompanied with opioids.6 Kappa receptor agonists offer pain relief and have low potential for dependence. However, they are not effective as therapeutic targets due to their tendency to cause strong dysphoric reactions.7 Activation of the δ receptor by agonists is not a favorable option due to the seizure-inducing effects.8 μ-opioid agonists are the first choice in the clinic. However, there is an urgent necessity for strategies to mitigate their side effects.9

There is increasing evidence that efflux transporters in the blood-brain barrier (BBB) may contribute to the development of tolerance to opioids. P-glycoprotein (P-gp), is a member of ATP-binding cassette (ABC) superfamily of transport proteins. It plays a role in multiple processes such as removing harmful substances from cells, absorbing nutrients, moving ions and peptides, and facilitating cell communication.10,11 A total of 48 ABC transporters have been discovered in humans and categorized into 7 subfamilies based on phylogenetic research.12 P-gp, also referred to as ABCB1, is a member of the ABCB subfamily, particularly classified within the MDR/TAP subfamily. It has been extensively studied and is acknowledged as one of the most thoroughly characterized efflux transporters known to date. Several in-depth reviews are available that examine the secondary and tertiary structures of P-gp, as well as its substrate-binding pocket.13, 14, 15 The precise mechanism of P-gp has not yet been completely elucidated. Though, two models—the “hydrophobic vacuum cleaner” and the “flippase”—are widely recognized in the literature. Each model is accompanied by a concise description of its pump function. In the “hydrophobic vacuum cleaner” model, P-gp removes the hydrophobic substrates from the lipid bilayer and releases them into the exterior aqueous environment. On the other hand, in the “flippase” model, substrates are transferred from the inner leaflet of the lipid bilayer to the outer leaflet of the plasma membrane or directly into the extracellular setting.16 Despite various efforts to investigate a structure-activity relationship (SAR) for P-gp, its substrate specificity continues to be extensive. Typically, P-gp substrates possess a significant amount of hydrogen bonds, a nitrogen atom with basic properties, and are lipophilic with a molecular weight lower than 500.10 Chronic exposure to opioids has been found to induce the overexpression of P-gp, which is associated with reduced opioid effectiveness and the development of tolerance. This upregulation occurs through the activation of toll-like receptors and subsequent inflammatory signaling pathways, resulting in increased secretion of pro-inflammatory cytokines that further boost P-gp activity.17

Cetirizine—a nonsedating antihistamine—is sold as a mixture of levocetirizine and dextrocetirizine enantiomers.18 Previous studies have shown that in morphine-tolerant mice, there is an increase in inflammatory cytokines and a disruption in the pain signaling system at the spinal level. This phenomenon is a contributing factor to the diminished analgesic efficacy of morphine when used chronically.19 A study conducted in 2016 revealed that cetirizine inhibits P-gp activity in a dose-dependent manner.20

The polyphenols found in the plant have been extensively shown to have antioxidant and anticancer properties.21 Typically, green tea leaves comprise roughly 36% polyphenols, with catechins representing the primary component.22 This plant contains four types of catechins: epigallocatechin-3-gallate (EGCG) at a concentration of about 59%, EGC at about 19%, epicatechin-3-gallate (ECG) at roughly 6.13%, and epicatechin (EC) at approximately 4.6%.23 In addition, the polyphenols present in green tea also induce a reduction in the expression of P-gp gene.24,25 Several studies have demonstrated the inhibitory impact of green tea on P-gp.26, 27, 28 However, the precise functional mechanism underlying this inhibition remains undetermined.

The effect of cetirizine and EXT on morphine tolerance has not been explored yet. This study aims to evaluate the effectiveness of cetirizine and EXT in reversing morphine tolerance and improving its analgesic effects in an animal model. This evaluation is grounded in previous studies that demonstrate the influence of cetirizine and EXT on the reduction of P-gp overexpression, which is one of the most significant mechanisms contributing to drug tolerance. By targeting this pathway, we seek to assess the potential of cetirizine and green tea in mitigating the analgesic effects of morphine in mice.

Materials and Methods

Materials

Morphine sulfate was purchased from Darou Pakhsh Company (Tehran, Iran). Cetirizine was obtained from Abidi Pharmaceutical Company (Tehran, Iran). Also, green tea purchased from Mahmood Company (Tehran, Iran).

Sample preparation and extraction

In order to obtain the hydroalcoholic extract from green tea, the plant's leaves were initially washed and subsequently dried before being grinded into a fine powder. Afterward, the dry powder (100 g) was immersed in hydroalcoholic and placed on a shaker at room temperature for 24 h. Following the specified duration, the extract underwent filtration. The duration of this process extended over a period of three consecutive days. A rotary evaporator (Heidolph Laborota 4010—Germany) was used to concentrate and remove moisture from the hydroalcoholic extract.29

Total phenolic content (TPC)

The phenolic content of the ethanolic extract was assessed using the Folin–Ciocalteu method. In summary, the extract solution, (1 mg/mL), was mixed with 10% (v/v) Folin–Ciocalteu reagent in distilled water. This mixture was allowed to stand at room temperature for 5 min. Subsequently, sodium carbonate solution (1 mL, 1 M) was added. After a 30-min incubation period, the UV absorbance of the extract was measured at 750 nm. A standard curve was drawn using gallic acid solutions in a 60:40 (v/v) acetone:water mixture, with concentrations of 12.5, 25, 50, and 100 μg/mL. The TPC was then quantified using the calibration curve of gallic acid.30

Animals and treatment

Male albino mice (20–30 g; Pasteur Institute, Tehran, Iran) were randomly divided into 9 distinct groups, with each group comprising 10 mice. The animals were kept under controlled environmental settings, with a standard temperature of 24 ± 0.5°C and a lighting schedule of 12 h of light followed by 12 h of darkness. They had unrestricted access to food and water. The studies were conducted following the guidelines outlined in the Guide for Care and Use of Laboratory Animals of Tabriz University of Medical Sciences, Tabriz, Iran (National Institutes of Health Publication No 85-23, revised 1985). The study was carried out in the Faculty of Pharmacy of Tabriz University of Medical Science (IR.TBZMED.AEC.1401.045).

The mice were divided into nine groups to ensure a comprehensive evaluation of the treatments. One group received only saline (10 mL/kg, i.p.) for 14 days, serving as the control group. The remaining groups received morphine at a dose of 25 mg/kg for 14 days to induce morphine tolerance. In the 15th day, 30 min prior to administering the test dose of morphine (9 mg/kg) three groups were pretreated with different dosages of Cetirizine (5–10–20 mg/kg, i.p.), and three groups received different doses of EXT (50–100–200 mg/kg, i.p.). Additionally, one group received a combination of EXT (50 mg/kg, i.p.) and Cetirizine (5 mg/kg, i.p.) to evaluate preventive effects on morphine-induced tolerance. Tolerance was evaluated using hot plate after administration of the test dose of Morphine (9 mg/kg, i.p.). Baseline hot plate test was performed twice in all groups, with a 1-h gap between each test.31,32

Hot plate test

The hot plate test is a frequently employed method for assessing the sensitivity to thermal pain. In this experiment, the mice were placed on a stainless steel surface measuring 23 × 23 cm. The surface was kept at a constant temperature of 54 ± 1 °C and was enclosed by a Plexiglas wall of 20 cm in height. The time it took for the mice to respond was recorded. The nociceptive threshold was assessed 30 min before the treatment, and the latency time was recorded as the predrug latency for each test animal. The latency of the hot plate response was measured when the animal licked its rear paw. A 30-second cut-off time was established to prevent any potential harm to the tissue.

Statistical analysis

Statistical analysis of each data set was performed by Instat software. The results were shown as mean ± SEM for the various groups. The data were analyzed using the unpaired t test and one-way ANOVA followed by Tukey post hoc test. A P value of less than 0.05 was considered statistically significant.

Results

Total phenolic content

The green tea stock solution was analyzed using spectrophotometry, and the resulting data were applied into the equation derived from the calibration curve of gallic acid. The concentration of phenolic compounds at 1 mg/mL was measured. The TPC of the ethanolic extract was ultimately determined to be 54.17%.

Assessment of analgesic effect of morphine in tolerant and nontolerant mice

Figure 1 demonstrates the effect of morphine (25 mg/kg, i.p.) for 14 continuous days on the tolerance induction. In order to ensure equal numbers of injections across both groups, the control group were received saline for two times [saline (10 mL/kg, i.p.) + saline (10 mL/kg, i.p.)]. In contrast, the morphine group received injections of both morphine and saline [morphine (25 mg/kg, i.p.) + saline (10 mL/kg, i.p.)]. The test dose of morphine (9 mg/kg, i.p.) was injected to all groups. Mice that had received daily morphine injections (25 mg/kg, i.p.) for a duration of 14 days demonstrated a statistically significant difference in response to the subsequent test dose of morphine (9 mg/kg, i.p.) when compared to the saline group (*P < 0.05 (F > 4) and ***P < 0.001 (F > 47)).

Figure 1.

Figure 1

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The impact of the test dose of morphine (9 mg/kg, i.p.) on tolerant and nontolerant mice. Results are shown as mean ± SEM. The data were analyzed using the unpaired t test. *P < 0.05 (F > 4) and ***P < 0.001 (F > 47) point to the significant difference between two groups (S = saline; M = morphine). Time refers to the duration measured after the injection of the test dose of morphine.

Effects of administration of cetirizine on morphine-induced tolerance

Figure 2 illustrates the effects of cetirizine (5, 10, and 20 mg/kg, i.p.) 30 min prior to morphine injection on the development of morphine-induced tolerance. The results indicated that cetirizine mitigated the level of tolerance to morphine at certain test intervals. Notably, the 10 mg/kg dose of cetirizine demonstrated more beneficial effects compared to the other dosages. Furthermore, significant effects were observed 30 min after the injection of both the 5 and 20 mg/kg doses of cetirizine.

Figure 2.

Figure 2

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Effects of administration of the cetirizine (5, 10, 20 mg/kg, i.p.) on morphine-tolerant animals on the 15th day. Results are shown as mean ± SEM. The data are compared with ANOVA followed by Tukey post-hoc test; ***P < 0.0001 (F > 19) versus saline + morphine control group (S = saline; M = morphine; Cet = cetirizine). Time refers to the duration measured after the injection of the test dose of morphine.

Effects of administration of EXT on morphine-induced tolerance

The results presented in Figure 3 indicate that there is no significant difference in the results when administering EXT at doses of 50, 100, and 200 mg/kg, 30 min prior to a morphine test dose on the 15th day in mice, in comparison to the control group.

Figure 3.

Figure 3

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Effects of administration of EXT (50, 100, 200 mg/kg, i.p.) on morphine-tolerant animals on the 15th day. Results are shown as mean ± SEM (M = morphine; EXT = green tea, extract). Time refers to the duration measured after the injection of the test dose of morphine.

Effect of co-administration of cetirizine and EXT on Morphine-induced tolerance

Figure 4 depicts the effects of pretreatment with both cetirizine (5 mg/kg, i.p.) and EXT (50 mg/kg, i.p.) in comparison to their individual effects. The findings indicate that the co-administration of these two medications did not yield any significant impact when compared to the effects observed with the individual administration of each medication.

Figure 4.

Figure 4

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The impact of co-administration of cetirizine and EXT on morphine-tolerant mice on the 15th day. Results are expressed as mean ± SEM (M = morphine; Cet = cetirizine; EXT, green tea, extract). Time refers to the duration measured after the injection of the test dose of morphine.

Discussion

Morphine is a well-known opioid analgesic commonly used to treat moderate to severe pain, especially in cancer patients and those recovering from surgery. However, its clinical application is often restricted due to substantial concerns about the development of tolerance to its pain-relieving effects and the risk of adverse effects, including dependence.33

Several theories elucidate the mechanisms underlying the development of tolerance, including traditional concepts such as receptor desensitization and internalization, as well as alterations in downstream signaling pathways.34

P-gp plays a critical role in limiting the absorption of various compounds with diverse structures and functions, including most anticancer drugs. Consequently, it is significantly involved in the phenomenon of multidrug resistance.35 Prolonged administration of morphine leads to elevated expression levels of the P-gp gene, as morphine is a substance that is actively transported by P-gp.17

Cetirizine is a second-generation antihistamine commonly utilized to alleviate allergic symptoms, including rhinitis and urticaria. It acts as a selective antagonist of the H1 histamine receptor, which is responsible for various physiological reactions linked to allergies.18 The drug functions by competitively blocking the binding of histamine to H1 receptors, thereby inhibiting histamine-induced responses such as vasodilation, increased vascular permeability, and sensory nerve activation. This mechanism leads to a decrease in symptoms like itching, sneezing, and nasal congestion. In contrast to first-generation antihistamines, cetirizine has a reduced ability to penetrate the BBB, resulting in fewer central nervous system side effects, such as drowsiness.36

Histamine H1 receptors are known to play a critical role in both somatic and visceral pain perception.37 Studies indicate that the activation of these receptors can modulate nociceptive responses.38 Findings suggest that the co-administration of cetirizine with morphine enhances morphine-induced antinociception,39 which may be mediated through the activation of central opioid receptors. This interaction highlights the potential role of the histaminergic system in pain modulation and the enhancement of morphine's analgesic effects.

The physicochemical characteristics of cetirizine, as highlighted in the literature, may provide insights into its potential to inhibit P-gp. In their study, Ekins et al40 aimed to identify the functional groups associated with active P-gp inhibitor molecules, examining 27 compounds that inhibit digoxin transport in Caco-2 cells in vitro. Their findings indicated that effective P-gp inhibition requires the presence of two hydrophobic groups, a hydrogen-bond acceptor group, and an aromatic core. The chemical structure of cetirizine, contains one hydrogen bond donor, five hydrogen bond acceptors, and eight rotatable bonds. The log octanol/water partition coefficients (log P and log D) for cetirizine are recorded at 4.48 and 1.04, respectively, at a pH of 7.4.

Polli et al41 investigated the effect of P-gp on the brain concentrations of cetirizine and hydroxyzine, concluding that P-gp significantly affects the brain concentration of cetirizine, which acts as a P-gp substrate, while hydroxyzine does not exhibit this relationship. Their comparative analysis of the physicochemical properties of both compounds suggested that the disparity in substrate activity correlates with their log Doct (pH = 7.4) values. Specifically, cetirizine has a log Doct of 1.04, in contrast to hydroxyzine's value of 2.87. The carboxylic group in cetirizine is capable of interacting with basic nitrogen through folded conformers, a feature attributed to its molecular structure, which contributes to its relatively high lipophilicity at physiological pH.

In this context, it has been shown that cetirizine can decrease both the activity and expression of P-gp in both in vitro and in vivo settings. This inhibitory effect is directly correlated with the dosage of cetirizine administered. Therefore, when co-administering cetirizine with drugs that are substrates of P-gp, it is essential to take into account cetirizine's inhibitory influence on P-gp.20 Furthermore, research has established a connection between the enhancement of morphine's analgesic effects and its inhibitory properties.20 In line with the aforementioned research, in the present study pretreatment with Cetirizine (5, 10, 20 mg/kg, i.p.) 30 min before daily morphine administration reduced tolerance to morphine.

In alignment with the findings of our study, another investigation revealed that the administration of cetirizine to rats exposed to morphine enhanced the analgesic effects induced by morphine.39 In that study, this effect of cetirizine was attributed to P-gp inhibition. However, further investigations will be necessary to fully understand the underlying mechanisms.

The polyphenols found in the plant have been shown to possess both antioxidant and anticancer properties.21 Typically, green tea leaves contain about 36% polyphenols, with catechins being the most significant component.22 Additionally, the polyphenols present in green tea have been shown to reduce the gene expression of P-gp.24,25

Conversely, prolonged administration of morphine has been associated with increased oxidative stress through two primary mechanisms: (1) It stimulates the oxidative metabolism of dopamine and xanthine, resulting in heightened production of free radicals and reactive oxygen species.42 (2) It decreases the levels of antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione-S-transferase.43

Several studies suggest that antioxidants play a role in diminishing morphine tolerance by mitigating oxidative stress. These antioxidants can be sourced from a variety of foods, including fruits, vegetables, and dietary supplements. Additionally, EXT is acknowledged as a powerful antioxidant within the realm of pharmacology.44

In the current study, the EXT, despite its content of various polyphenols, did not influence morphine tolerance. This suggests that the EXT amounts utilized in this investigation were likely inadequate to significantly affect P-gp at the BBB, leading to no notable alterations in morphine distribution within the central nervous system. Further research is required to gain a deeper understanding of the underlying mechanisms. Moreover, the simultaneous administration of cetirizine and EXT did not produce significant effects when compared to the separate administration of cetirizine and EXT.

Conclusion

Cetirizine effectively reversed morphine tolerance, whereas EXT did not significantly impact on the efficacy of morphine in this context. Further research is needed to elucidate the mechanisms underlying opioid tolerance and the role of efflux transporters in this process.

Ethics approval and consent to participate

The proposal and consent form were approved by the ethical committee of the Faculty of Pharmacy at Tabriz University of Medical Science (IR.TBZMED.AEC.1401.045).

Availability of data and material

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Author contributions

Tahereh Eteraf-Oskouei and Bohloul Habibi Asl: Conceptualization, supervision, review and editing. Adel Mahmoudi Gharehbaba: Writing—review and editing. Solmaz Asnaashari: Advisor in pharmacognosy. Zahra Fazli: Performed the study.

Declaration of competing interest

The authors declare there is no conflict of interest.

Acknowledgments

Funding

The current research was funded and granted by Tabriz Medical Sciences University (grant number: 1401.045).

Acknowledgments

This work is a part of a Pharm. D thesis, supported by Tabriz University of Medical Sciences, Tabriz, Iran.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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