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Effect of the antidepressant nefazodone on the density of cells expressing mu-opioid receptors in discrete brain areas processing sensory and affective dimensions of pain

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Abstract

Rationale

The principal use of antidepressants is in the treatment of depression and affective disorders. Antidepressants have also been used as an adjuvant to analgesics in pain treatment. However, in chronic treatment, their antinociceptive and antidepressive effects coexist simultaneously. Antidepressants can interact with the opioid system, which is also involved in regulating nociceptive processing and affective state. Chronic antidepressants could act by increasing mu-opioid receptor expression in many brain areas involved in the regulation of nociception and affective state.

Objectives

The aim of this study was to evaluate the antinociceptive and antidepressant-like effects and the possible variations in mu-opioid receptor expression induced by a chronic nefazodone treatment in brain areas related to pain and affective state.

Methods

Wistar rats were chronically treated with nefazodone (10 and 25 mg/kg IP, twice a day, for 14 days). Twelve hours after the last day 14 dose of nefazodone, a tail-flick test was performed. After the administration of a daily dose of nefazodone, Porsolt’s test was carried out 12 h after last dose. Two hours after completion of 14 days treatment, other animals were processed for mu-opioid receptor immunocytochemistry using polyclonal antisera raised in rabbits. Several brain regions were analyzed: the frontal and cingulate cortex, the dorsal raphe nucleus and the periaqueductal gray.

Results

Chronic nefazodone treatment induced a significant increase in tail-flick latency and a significant decrease in immobility time at total doses of 20 and 50 mg/kg per day (P<0.05). In treated animals, the density of neural cells immunostained for mu-opioid receptor in the frontal and cingulate cortices, dorsal raphe nucleus and periaqueductal gray had increased after chronic nefazodone compared to controls.

Conclusion

Therefore, chronic nefazodone induces antinociceptive and antidepressant-like effects in rats and increases mu-opioid receptor expression in brain areas related to pain and affective state. These results suggest that antidepressants could be effective on somatic and affective dimensions of pain and this action could be related to its influence on the opioid system.

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Acknowledgements

This work was supported by the Spanish Ministry of Health (FIS 01/1055, FIS PI031430), “Plan Andaluz de Investigación (CTS-510),” the Basque Government (GV PI-1999-51) and the University of the Basque Country (UPV 081.123-EA094/99). We would like to thank J.M. Rodríguez Robledo for his technical assistance. All animal use procedures conformed to international European ethical standards (86/609-EEC) and Spanish law (RD 223/1988) for the care and use of laboratory animals.

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Authors and Affiliations

  1. Pharmacology and Neuroscience Research Group (CTS-510), Department of Neuroscience (Pharmacology and Psychiatry), Faculty of Medicine, University of Cadiz, Plaza Fragela 9, 11003, Cádiz, Spain

    Antonio Ortega-Alvaro & Juan Antonio Micó

  2. Department of Physiology, School of Pharmacy, University of the Basque Country, PO Box 450, Vitoria, Spain

    Ignacio Acebes, Gonzalo Saracíbar, Enrique Echevarría & Luis Casis

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  1. Antonio Ortega-Alvaro
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  2. Ignacio Acebes
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  3. Gonzalo Saracíbar
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  6. Juan Antonio Micó
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Correspondence to Juan Antonio Micó.

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Ortega-Alvaro, A., Acebes, I., Saracíbar, G. et al. Effect of the antidepressant nefazodone on the density of cells expressing mu-opioid receptors in discrete brain areas processing sensory and affective dimensions of pain. Psychopharmacology 176, 305–311 (2004). https://doi.org/10.1007/s00213-004-1894-7

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  • DOI: https://doi.org/10.1007/s00213-004-1894-7

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