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Martínez García, Miguel ángelAuthorRivera, C RodriguezAuthorHerradon, EAuthorGonzalez, AAuthorMolina-Alvarez, MAuthorGoicoechea, CAuthorLopez-Miranda, VAuthorSanchez-Robles, E MCorresponding AuthorGiron, RAuthor

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December 24, 2024
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Modulation of morphine antinociceptive and rewarding effect by mirtazapine in an animal model of osteoarthritic pain

Publicated to: European Journal Of Pharmacology. 987 177165- - 2025-01-15 987(), DOI: 10.1016/j.ejphar.2024.177165

Authors: Paniagua, N; García, MM; Rivera, CR; Pascual, D; Herradón, E; González, A; Molina-Alvarez, M; Goicoechea, C; López-Miranda, ; Sánchez-Robles, EM; Girón, R

Affiliations

Rey Juan Carlos Univ URJC, CSIC,Sci Res Super Council, Associated R D I Unit,Inst Med Chem IQM, Dept Basic Hlth Sci,Area Pharmacol Nutr & Bromatol, Alcorcon, Spain - Author
Rey Juan Carlos Univ, High Performance Res Grp Expt Pharmacol PHARMAKOM, Alcorcon, Spain - Author

Abstract

People with chronic pain mitigate their suffering by the action of opioids. Adverse reactions aside, opioids are not exempt from potential complications like addiction and abuse, which have posed a global public health problem lately. Finding new therapeutic strategies to improve analgesia and to reduce opioid side effects has become a priority. In this regard, the association of different adjuvant therapies has been postulated. Despite preclinical and clinical evidence supporting the use of antidepressants as analgesics, it is not clear whether they could help reduce the risk of addiction in combination with opioids. To further explore this idea a model of chronic osteoarthritis pain was employed, and a combination of mirtazapine and morphine was used in a chronic regimen in male and female rats. The effects on the development of tactile allodynia, movement-evoked pain, reward, analgesic tolerance, naloxone-induced withdrawal symptoms, impaired locomotor activity and anxiety were evaluated under a 25-day experimental protocol. Additionally, protein expression of mu-opioid receptors and clusterin (related with substance abuse) was evaluated in plasma and in brain structures of the reward system. Chronic morphine caused analgesic tolerance, reward and naloxone-induced withdrawal symptoms. The combination reduced the analgesic tolerance and prevented the development of withdrawal symptoms but showed sex-based differences regarding reward. Increased levels of clusterin in plasma were observed in females treated with morphine, but not with combined therapy. The combination of mirtazapine and morphine could be a promising strategy to improve the management of long-term opioid treatment and its risk of abuse, especially in females.

Keywords

Analgesics, opioidAnimalsAntidepressantAntidepressantsClusterinConditioned place preferenceDependenceDisease models, animalDrug toleranceExpressionFemaleHyperalgesiaLocomotor sensitizationMaleMirtazapineMorphineMusculoskeletal painOpioidOpioidsOsteoarthritisRaRatRatsRats, wistarReceptorReceptors, opioid, muRewardSex dimorphismSex-differencesSubstance withdrawal syndromeWithdrawal

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal European Journal Of Pharmacology due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2025, it was in position 54/352, thus managing to position itself as a Q1 (Primer Cuartil), in the category Pharmacology & Pharmacy.

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-12-17:

  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 9 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

    Leadership analysis of institutional authors

    There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author () and Last Author (Girón Moreno, María del Rocío).

    the author responsible for correspondence tasks has been Sánchez Robles, Eva María.

    Awards linked to the item

    Funding and disclosure This work has been supported by the Government Delegation for the National Drugs Plan of the Ministry of Health of the Spanish Government (2020I062) . The authors declare no conflict of interest.