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. 2025 Jun 5;35(3):269–274. doi: 10.5152/pcp.2025.241005

Exploring the Modulatory Effects of Vitamin B12 on Morphine-Induced Conditioned Place Preference in Rats

Tuğçe Uskur 1, Fatma Ünlü Taşdemir 2, Mehmet Aykut Öztürk 2,3, Haktan Sönmez 2,3, Zeynep Gizem Todurga Seven 2, Selim Gökdemir 2, Burak Baştan 2, Gökhan Faikoğlu 2, Kübra Saygısever Faikoğlu 2, Sibel Özyazgan 2, Dündar Okan Yıllar 4, Ahmet Gökhan Akkan 5,✉
PMCID: PMC12371738  PMID: 40824234

Abstract

Background:

This study aims to investigate the effects of vitamin B12 on morphine-induced conditioned place preference (CPP), a model commonly used to assess the rewarding effects of drugs. Morphine is a potent analgesic widely used for moderate to severe pain, but it also poses a significant risk of addiction. Previous studies suggest that cyanocobalamin (vitamin B12) may enhance the analgesic effects of morphine and reduce tolerance, but its impact on morphine addiction remains unclear.

Methods:

The experiment followed phases of habituation, pre-conditioning, conditioning, and post-conditioning. Adult male Wistar albino rats (250-300 g) were randomly divided into 3 groups (n = 8 per group): control (saline), morphine (10 mg/kg), and a combination group of vitamin B12 (2 mg/kg) with morphine. The effects of saline, morphine, and the morphine-vitamin B12 combination on CPP were assessed. All drugs and saline were administered intraperitoneally (ip).

Results:

Morphine (10 mg/kg) significantly induced CPP compared to the saline group (P < .0001). Vitamin B12 (2 mg/kg) did not produce a statistically significant difference in morphine-induced CPP compared to the control group.

Conclusion:

Morphine induces a significant place preference, and vitamin B12 did not produce a statistically significant difference in reducing this effect. Further research with different doses of vitamin B12 is necessary to fully investigate these effects.

Introduction

Substance addiction is a condition where the continued use of an addictive substance negatively impacts life and health, yet the desire to take the substance cannot be stopped.1 One major type of substance addiction, opioid addiction, is a global issue. Morphine, one of the most commonly used opioid analgesics for pain management, has serious side effects associated with chronic use, such as tolerance to its analgesic effect, potential for physical dependence, and development of withdrawal syndrome. Therefore, morphine addiction remains a significant problem, and numerous studies have been conducted to mitigate it.2,3

Animal models are frequently employed to identify the systems responsible for morphine addiction and to develop new therapeutic approaches. One such model is the conditioned place preference (CPP), a Pavlovian conditioning type of preclinical animal model used in many vertebrates to evaluate the rewarding effects of drugs with potential for reinforcement.4 This paradigm is an important method used in substance addiction research within neuroscience.5 Numerous studies utilizing CPP to investigate the rewarding effect of various drugs can be found in the literature.6-9

Cyanocobalamin (vitamin B12), a water-soluble derivative of the B vitamin group, is involved in various metabolic processes such as blood formation, the synthesis of fatty acids, DNA, and energy production.10 Vitamin B12 is a neurotrophic agent that shows special affinity for neural tissues, contributing to the protection of the nervous system, axonal cell myelination, and peripheral nerve regeneration.11,12 Animal studies also support the numerous beneficial effects of vitamin B12, including nerve regeneration and the inhibition of cyclooxygenase enzymes and other pain signaling pathways.13 Literature reports both animal and clinical studies indicating the antinociceptive effects of B vitamins.14,15 Studies have shown that B complex vitamins containing cyanocobalamin enhance acute morphine antinociception and reduce the development of tolerance to chronic morphine use in mice.16 A 2020 study on a rat neuropathic pain model suggested that treatment with a combination of cyanocobalamin and morphine could result in more effective analgesia by establishing long-term regeneration balance and reducing tolerance development.17

Studies have also indicated the potential effectiveness of B vitamins in substance addiction. A 2018 study demonstrated that serum B12 levels could significantly influence the severity of methamphetamine addiction and potentially play a role in its prognosis.18 Research on mice with morphine-induced addiction and tolerance has shown that the co-administration of B12 and morphine can reduce tolerance to morphine’s analgesic effects and alleviate withdrawal symptoms induced by naloxone.19

In this context, the present study aims to investigate the effects of cyanocobalamin on morphine-induced CPP.

Material and Methods

Animals

The study involved 24 adult male Wistar Albino rats, each weighing between 250 and 300 grams, obtained from the Üsküdar University Experimental Research Unit (ÜSKÜDAB). The animals were kept in groups of 4 per Plexiglas cage, under controlled conditions with a constant temperature of 22-25°C and 60%-70% humidity, maintaining a 12-hour light/12-hour darkness cycle. Food and water were provided ad libitum. All experiments were conducted during the light phase of the cycle, between 10:00 am and 2:00 pm. To acclimate the rats to the experimental conditions, they were habituated to the laboratory environment and handling 1 week prior to the commencement of the experiments. This research was conducted in accordance with the guidelines set forth in the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health (NIH, Publication No. 85-23, revised 1985), and it received approval from the Local Ethics Committee for Animal Experiments at Üsküdar University (Approval no.: 13; Date: 2019).

Inclusion and Exclusion Criteria

Inclusion Criteria:

  • Adult male Wistar Albino rats.

  • Body weight within the range of 250-300 grams at the start of the experiment.

  • Rats that were in good health with no visible signs of illness or injury.

  • Rats that had not been previously involved in any other experimental procedures.

Exclusion Criteria:

  • Rats with a body weight outside the range of 250-300 grams.

  • Rats showing signs of illness, injury, or stress during the acclimation period.

  • Any rats that exhibited abnormal behavior prior to the commencement of the experiment.

  • Rats that had previously participated in any other experiments.

Drugs

Morphine hydrochloride and vitamin B12 were acquired from Macfarlan Smith Ltd., Edinburgh, UK, and Deva Holding Company, Istanbul, Türkiye, respectively. Both drugs were dissolved in 0.9% saline to prepare the solutions fresh each morning. The dosages were administered intraperitoneally in a consistent volume, calculated as 0.5 mL for every 250 grams of the animal’s body weight. Control animals were administered saline only.

Apparatus

The CPP apparatus utilized in this study consisted of a Plexiglas chamber, measuring 60 × 30 × 30 cm, with walls that were opaque and colored black and white. The chamber was divided into 2 compartments, each featuring a removable droppings tray placed 2.5 cm below the floor. For distinct tactile stimuli, compartment “A” was equipped with a stainless steel mesh floor (4 × 4 mm), while compartment “B” contained a floor made of stainless steel grid rods (3 mm in diameter) spaced 7 mm apart.

Procedure

The apparatus was thoroughly cleaned between sessions using a 70% ethanol solution diluted by half (resulting in a 35% ethanol solution) to ensure effective disinfection while minimizing olfactory cues. After cleaning with the ethanol solution, the surfaces were wiped again with sterile water and allowed to dry completely to further reduce any potential impact on the animals’ behavior. This procedure was implemented to ensure that the animals’ behavior was based solely on the conditioning stimuli rather than any residual odors.

Preliminary trials assessed the baseline preference of naive animals between the grid and mesh surfaces, indicating a predisposition for the grid. To accommodate this inherent bias, a biased experimental design was adopted, pairing drugs with the less preferred mesh compartment. This is consistent with standard practice in place conditioning studies that use a biased apparatus, aligning with methodologies from prior research,20-22 but with minor modifications.

The experiment was structured into several phases: habituation, pre-testing, conditioning, and preference testing. Rats had unrestricted access to both sides of the enclosure during preconditioning, with identical tactile stimuli on both sides. A rat was considered to have entered a side once both forepaws touched that texture.

The study involved 3 groups, each consisting of 8 rats. Following pre-testing, animals were randomly assigned to control, morphine (10 mg/kg), or a combination group (10 mg/kg morphine plus 2 mg/kg vitamin B12). Treatments were administered intraperitoneally 15 minutes apart, based on the designated floor type, before placing the animals in the apparatus. The 19-day conditioning phase included a 2-day break after the fourth session. Rats were habituated from days 1 to 7 to minimize novelty effects. The bias of the apparatus was revalidated on day 8 through a 15-minute free exploration to determine initial floor preferences. Conditioning sessions were 40 minutes long, with saline paired with the grid floor on specific days and drugs with the mesh floor on alternate days. The post-test on day 11, 24 hours after the last conditioning session, involved placing the rats in the center of the box post-saline injection for 15 minutes to record the time spent on the mesh floor, assessing the rewarding or aversive effects of the drugs.

Statistical Analysis

The data were shown as mean ± SEM and analyzed using GraphPad Prism (Version 5.0). For comparisons between 2 groups, the unpaired Student’s t-test was utilized. Comparisons within groups were performed using one-way ANOVA with Tukey’s post-hoc test to account for multiple comparisons.8,9 The significance threshold was established at α = 0.05 (P < .05) for all statistical tests. The Shapiro–Wilk test was used to assess the normality of the data for each experimental group (control, morphine 10 mg/kg, and B12 + morphine 10 mg/kg). The results indicated that all data sets followed a normal distribution (P > .05 for all groups). This analysis approach allowed for the rigorous assessment of the effects of morphine and the combination treatment (morphine plus vitamin B12) on CPP, compared to control conditions.

Results

The initial place preferences of the animals in compartments A and B are illustrated in Figure 1. In the pretest phase, the animals allocated a significantly greater amount of time to the grid floor (mean = 781.1 ± 16.17 seconds) in comparison to the mesh floor (mean = 118.83 ± 16.17 seconds, P < .001). This indicates a clear bias in the apparatus, as demonstrated by the rats’ significantly longer time spent in the grid floor compartment.

Figure 1.

Figure 1.

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Compartment preferences of all animals upon pretesting (*P < .001, Student’s t-test).

Figure 2 illustrates the impact of morphine (10 mg/kg) on the acquisition of CPP. Administration of morphine (10 mg/kg, intraperitoneally) resulted in a significant increase in the time rats spent in the drug-paired compartment (mean = 797.5 ± 12.6 seconds) compared to the saline-paired compartment (mean = 386.8 ± 32.4 seconds, P < .001, Student’s t-test). This finding confirms the rewarding properties of morphine, as evidenced by the animals’ clear preference for the drug-paired environment.

Figure 2.

Figure 2.

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Effect of morphine on the acquisition of conditioned place preference (*P < .001 relative to saline group, Student’s t-test; n = 8 for each group).

Vitamin B12 (2 mg/kg) (mean = 704.3 ± 76.7 seconds) did not produce a statistically significant change in morphine-induced CPP Figure 3. (Combination: 2 mg/kg vitamin B 12 plus 10 mg/kg morphine; *P < .001 relative to control group, Student’s t-test; n = 8 rats).

Figure 3.

Figure 3.

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Effect of combination treatment on morphine-induced conditioned place preference (combination: 2 mg/kg vitamin B 12 plus 10 mg/kg morphine; *P < .001 relative to control group, Student’s t-test; n = 8 for each group).

Discussion

This research represents the initial exploration into the impact of vitamin B12 on CPP induced by morphine. Consistent with previous studies in the literature, these experiments demonstrated that morphine produces a strong place preference.8 The findings align with prior studies showing that morphine significantly enhances reward-related behaviors, as evidenced by its ability to produce conditioned place preference in rodents. It was observed that the combination groups, where vitamin B12 was administered 15 minutes before morphine, did not significantly reduce morphine-associated place preference. However, further dose-response studies are needed to achieve statistically significant results. It is known that B vitamins do not have the potential to induce place preference in animals. Therefore, to avoid the use of additional animals, a vitamin B12 control group was not studied. Additionally, a study conducted by Ghazanfari et al19 in 2014 investigated the behavioral effects of vitamin B12 in mice and found no significant effect in the locomotor activity test. This test primarily evaluates general activity levels and, although it was not used to measure vitamin B12’s effects on reward-related behavioral changes, it provides data supporting that vitamin B12 does not create behavioral effects. The findings consider the effects of vitamin B12 on morphine-induced CPP in a separate context and highlight its potential to intervene in opioid addiction.

B vitamins, besides supporting cellular and metabolic functions, are important coenzymes due to their roles in neurochemical synthesis and specific effects on brain function.23 Vitamin B12, 1 of the 8 B vitamins classified according to their solubility and coenzyme functions in water, is known to have synergistic effects when used with opioids in pain treatment.10,19,16,15 Beyond its role in metabolic processes, vitamin B12 demonstrates neuroprotective effects by reducing oxidative stress and preserving neural integrity.24,25 These properties make it a valuable candidate for addressing opioid addiction and related neurological consequences. In particular, vitamin B12 has been shown to enhance the analgesic effects of morphine and prevent the onset of morphine tolerance, which makes it an attractive candidate for opioid addiction management.19 Chronic use (14 days) of cyanocobalamin has been shown to produce an antinociceptive effect in mice and enhance the effect of morphine.10 When used together with morphine, cyanocobalamin can reduce the tolerance to morphine’s antinociceptive effects10,19 and prevent the onset of morphine addiction, as well as alleviate withdrawal symptoms.19

Recent studies further highlight that cyanocobalamin not only exhibits dose-dependent antinociceptive and anti-inflammatory effects in acute and chronic pain models but also enhances the antinociceptive efficacy of morphine during chronic treatment, suggesting its potential to mitigate tolerance to morphine’s analgesic effects.10

The mechanisms by which vitamin B12 modulates these effects are thought to involve its interaction with NMDA (N-Methyl-D-aspartate) receptors and its ability to regulate homocysteine metabolism. NMDA receptors play a central role in opioid addiction and tolerance. Studies indicate that inhibiting NMDA receptors can enhance opioid efficacy and slow the development of tolerance.26 Vitamin B12 indirectly modulates NMDA receptor activity by reducing homocysteine levels, which are known to increase neurotoxicity and contribute to addictive behaviors.23 By converting homocysteine to methionine, vitamin B12 may alleviate these neurotoxic effects, supporting its role in combating addiction.23 In addition to NMDA receptor modulation, homocysteine regulation appears critical, as elevated homocysteine levels have been associated with increased susceptibility to addictive behaviors and neurodegeneration.27,28

Compared to the studies by Ghazanfari et al. (2014), Hosseinzadeh et al. (2012), and Deng et al. (2017), our research focuses on the specific behavioral outcomes of morphine-induced CPP under the influence of vitamin B12. While prior research emphasized antinociceptive and withdrawal-related effects, our findings uniquely highlight behavioral modulation within a reward-based paradigm.

Considering the information in the literature and the data from this research, a detailed examination of the effects of vitamin B12 at different doses on morphine-induced CPP indicates that it could enlighten the role of vitamin B12 in combating opioid addiction and open doors to the development of innovative treatment methods in this field.

Limitations

While the findings of this study provide valuable insights, several limitations should be considered. The relatively small sample size may limit the statistical power and generalizability of the results. The use of a single dose restricts the ability to fully assess the effects of vitamin B12 on morphine-induced CPP, suggesting that studies with varying doses are needed. Additionally, the exclusive use of male rats limits the generalizability of the findings across genders. Finally, although the study proposes potential mechanisms such as NMDA receptor modulation and homocysteine metabolism, direct mechanistic studies were not conducted. These limitations highlight the need for further research to provide a more comprehensive evaluation.

In conclusion, the results of this study suggest that Vitamin B12 may have an effect on reducing the rewarding properties of morphine. However, further research, including studies with different doses of Vitamin B12, is necessary to confirm and better understand these effects.

Funding Statement

The authors declared that this study has received no financial support.

Footnotes

Ethics Committee Approval: This study was approved by the Ethics Committee of Üsküdar University (Approval no.: 13; Date: 2019).

Informed Consent: N/A

Peer-review: Externally peer-reviewed.

Authors Contributions: Concept – T.U.; Design – T.U.; Supervision – S.Ö., D.O.Y., A.G.A.; Resources – T.U.; Materials – F.Ü., M.A.Ö., H.S., Z.G.T.S., S.G., B.B.; Data Collection and/or Processing – F.Ü., M.A.Ö., H.S., Z.G.T.S., S.G., B.B.; Analysis and/or Interpretation – T.U., M.A.Ö., G.F., K.S.F.; Literature Search – T.U.; Writing Manuscript – T.U., M.A.Ö., G.F., K.S.F.; Critical Review – S.Ö., D.O.Y., A.G.A.

Acknowledgements: The authors would like to express their sincere gratitude to Üsküdar University for providing the experimental animals used in this study. Their support and contributions were crucial to the successful completion of this research.

Declaration of Interests: The authors have no conflict of interest to declare.

Data Availability Statement:

We declare the availability of the data in this article

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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

We declare the availability of the data in this article

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