.2023 Jan 7;16(1):86.

doi: 10.3390/ph16010086.

Tramadol and Tapentadol Induce Conditioned Place Preference with a Differential Impact on Rewarding Memory and Incubation of Craving

Joana Barbosa^{1 2}, Sandra Leal^{1 3}, Frederico C Pereira⁴, Ricardo Jorge Dinis-Oliveira^{1 2 5 6}, Juliana Faria^{1 2}

Affiliations

¹ TOXRUN-Toxicology Research Unit, University Institute of Health Sciences-CESPU (IUCS-CESPU), 4585-116 Gandra, PRD, Portugal.
² UCIBIO-REQUIMTE-Applied Molecular Biosciences Unit-Network of Chemistry and Technology, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
³ CINTESIS@RISE-Center for Health Technology and Services Research of the Health Research Network, MEDCIDS-Department of Community Medicine, Information and Health Decision Sciences, Faculty of Medicine, University of Porto, Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal.
⁴ Institute of Pharmacology and Experimental Therapeutics/iCBR-Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal.
⁵ Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal.
⁶ MTG Research and Development Lab, 4200-604 Porto, Portugal.

PMID:36678582
PMCID: PMC9864601
DOI: 10.3390/ph16010086

Tramadol and Tapentadol Induce Conditioned Place Preference with a Differential Impact on Rewarding Memory and Incubation of Craving

Joana Barbosa et al. Pharmaceuticals (Basel).2023.

.2023 Jan 7;16(1):86.

doi: 10.3390/ph16010086.

Authors

Joana Barbosa^{1 2}, Sandra Leal^{1 3}, Frederico C Pereira⁴, Ricardo Jorge Dinis-Oliveira^{1 2 5 6}, Juliana Faria^{1 2}

Affiliations

¹ TOXRUN-Toxicology Research Unit, University Institute of Health Sciences-CESPU (IUCS-CESPU), 4585-116 Gandra, PRD, Portugal.
² UCIBIO-REQUIMTE-Applied Molecular Biosciences Unit-Network of Chemistry and Technology, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal.
³ CINTESIS@RISE-Center for Health Technology and Services Research of the Health Research Network, MEDCIDS-Department of Community Medicine, Information and Health Decision Sciences, Faculty of Medicine, University of Porto, Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal.
⁴ Institute of Pharmacology and Experimental Therapeutics/iCBR-Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal.
⁵ Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4099-002 Porto, Portugal.
⁶ MTG Research and Development Lab, 4200-604 Porto, Portugal.

PMID:36678582
PMCID: PMC9864601
DOI: 10.3390/ph16010086

Abstract

Tramadol and tapentadol, synthetic opioids commonly prescribed for moderate-to-severe pain, have a unique pharmacology that optimizes their analgesia and safety. However, they are not devoid of risks, presenting addictive, abuse, and dependence potential. While tramadol-reinforcing properties have been documented by various studies with human and animal models, including conditioned place preference (CPP) assays, no similar studies have been performed with tapentadol. In the present study, we performed CPP assays by intraperitoneally administering Wistar rats with a tramadol/tapentadol therapeutic dose. Animal permanence and the number of entries in the CPP compartments were recorded in the preconditioning phase and then 1 (T1), 7 (T7), and 14 (T14) days after conditioning. Both opioids induced a change in place preference (T1), suggesting that they have short-term reinforcing properties. However, only tramadol was associated with place preference retention (T7 and T14), with an increase in the number of entries in the opioid-paired compartment (T1 and T7), showing that it causes rewarding memory and incubation of craving. The results indicate that at therapeutic doses: (1) both drugs cause short-term rewarding effects and (2) as opposed to tramadol, tapentadol does not cause CPP retention, despite its higher central nervous system activity and stricter scheduling.

Keywords: abuse; conditioned place preference; dependence; drug misuse; incubation of craving; psychopharmacology; rewarding memory; tapentadol; tramadol.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Chemical structures of tramadol and tapentadol. The chemical structures of tramadol (+)- and (−)-enantiomers are depicted. The stereocenters are depicted with asterisks. Atom positions are sequentially numbered.

**Figure 2**
Change in place preference at T1 (a), T7 (b) and T14 (c) time points. Change in preference was assessed by measuring the difference between CPP scores 1 (a), 7 (b) and 14 (c) days after the last drug administration (conditioning phase) and the CPP score in the preconditioning phase. In the conditioning phase, rats received daily intraperitoneal injections of 50 mg/kg tramadol or tapentadol, alternating with normal saline, for 8 days, and were immediately allowed to stay in a pre-determined (drug-paired: non-preferred; saline-paired: preferred) compartment. Control animals received daily intraperitoneal injections of normal saline for the same period. Results were recorded with the PPCWIN software, version 2.0 (Panlab, ref. 76-0011), and are expressed as means ± SD (n = 9). *p < 0.05; **p < 0.01; ***p < 0.001.

**Figure 3**
Number of entries in each compartment (preferred (saline-paired) compartment and non-preferred (drug-paired) compartment) at each time point—preconditioning phase (T0), and 1, 7 and 14 days after the last drug administration (T1, T7 and T14, respectively). In the conditioning phase, rats received daily intraperitoneal injections of 50 mg/kg tramadol (b) or tapentadol (c), alternating with normal saline, for 8 days. Control animals received daily intraperitoneal injections of normal saline for the same period (a). Results were recorded with the PPCWIN software, version 2.0 (Panlab, ref. 76-0011), and are expressed as means ± SD (n = 9). **p < 0.01 compared with T0; #p < 0.05 between the preferred and non-preferred compartment (same time point).

**Figure 4**
Summary of tramadol and tapentadol mechanisms of action and CPP behavioral effects. Arrow thickness depicts the approximate relative intensity of each effect. Regarding tramadol, the parent drug or metabolite enantiomer predominantly responsible for each effect is specified. 5-HT: 5-hydroxytryptamine/serotonin; CB1R: cannabinoid receptor 1; M1:O-desmethyltramadol; MOR: µ-opioid receptors; NA: noradrenaline. Red circumferences with diagonal lines: 5-HT/NA reuptake inhibition; green circumference with triangle: MOR activation.

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References

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Tramadol and Tapentadol Induce Conditioned Place Preference with a Differential Impact on Rewarding Memory and Incubation of Craving

Affiliations

Tramadol and Tapentadol Induce Conditioned Place Preference with a Differential Impact on Rewarding Memory and Incubation of Craving

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Research Materials