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The function of alpha-2-adrenoceptors in the rat locus coeruleus is preserved in the chronic constriction injury model of neuropathic pain

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Abstract

Rationale

Peripheral neuropathic pain is a chronic condition that may produce plastic changes in several brain regions. The noradrenergic locus coeruleus (LC) is a crucial component of ascending and descending pain pathways, both of which are frequently compromised after nerve injury.

Objectives

The objective of the study was to examine whether chronic constriction injury (CCI), a model of neuropathic pain, alters noradrenergic activity in the rat LC.

Methods

Activity in the LC was assessed by electrophysiology and microdialysis, while protein expression was monitored in western blots and by immunohistochemistry.

Results

The pain threshold had dropped in injured rats 7 days after inducing neuropathy. While alpha-2-adrenoceptors mediate activity in the LC and in its terminal areas, no alterations in either spontaneous neuronal activity or extracellular noradrenaline levels were observed following CCI. Moreover, alpha-2-adrenoceptor activity in the LC of CCI rats remained unchanged after systemic administration of UK14,304, RX821002 or desipramine. Accordingly, extracellular noradrenaline levels in the LC were similar in CCI and control animals following local administration of clonidine or RX821002. In addition, there were no changes in the expression of the alpha-2-adrenoceptors, Gαi/z subunits or the regulators of G-protein signaling. However, pERK1/2 (phosphorylated extracellular signal-regulated kinases 1/2) expression augmented in the spinal cord, paragigantocellularis nucleus (PGi) and dorsal raphe nucleus (DRN) following CCI.

Conclusions

Neuropathic pain is not accompanied by modifications in tonic LC activity after the onset of pain. This may indicate that the signals from the PGi and DRN, the excitatory and inhibitory afferents of the LC, cancel one another out.

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Acknowledgements

The authors would like to thank Mrs Raquel Rey-Brea, Mr Jesus Gallego-Gamo and Mrs Beatriz Fraile for their excellent technical assistance. This study was supported by grants from the “Fondo de Investigación Sanitaria” (PI070687, PI10/01221, PI080417); MICINN (SAF 2009–08460); CIBERSAM (G09, G18, G16); Junta de Andalucía, Consejería de Innovación, Ciencia y Empresa (CTS-510, CTS-4303); Cátedra Externa del Dolor Fundación Grünenthal-University of Cadiz; FP7-PEOPLE-2010-RG (268377); the Basque Government (IT199/07); and an FPU fellowship (AP2007-02397). The authors would also like to thank Conselho de Reitores das Universidades Portuguesas (CRUP) for financing the collaboration between the Spanish and Portuguese authors (project Acção Integrada E-42/07).

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Authors and Affiliations

  1. Neuropsychopharmacology Research Group, Department of Neuroscience, University of Cadiz, 11003, Cadiz, Spain

    Cristina Alba-Delgado, Gisela Borges & Juan A. Mico

  2. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain

    Cristina Alba-Delgado, Pilar Sánchez-Blázquez, Jorge E. Ortega, Igor Horrillo, Juan A. Mico, J. Javier Meana & Esther Berrocoso

  3. Departamento de Biologia Experimental, Faculdade de Medicina do Porto and Instituto de Biologia Molecular e Celular (IBMC), Universidade do Porto, 4200-319, Porto, Portugal

    Gisela Borges & Fani Neto

  4. Instituto Cajal, Consejo Superior de Investigaciones Científicas, 28002, Madrid, Spain

    Pilar Sánchez-Blázquez

  5. Department of Pharmacology, University of the Basque Country, 48940, Bizkaia, Spain

    Jorge E. Ortega, Igor Horrillo & J. Javier Meana

  6. Neuropsychopharmacology Research Group, Psychobiology Area, Department of Psychology, University of Cadiz, 11510, Cadiz, Spain

    Esther Berrocoso

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  1. Cristina Alba-Delgado
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Correspondence to Esther Berrocoso.

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Alba-Delgado, C., Borges, G., Sánchez-Blázquez, P. et al. The function of alpha-2-adrenoceptors in the rat locus coeruleus is preserved in the chronic constriction injury model of neuropathic pain. Psychopharmacology 221, 53–65 (2012). https://doi.org/10.1007/s00213-011-2542-7

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