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Opioid Activity in the Locus Coeruleus Is Modulated by Chronic Neuropathic Pain

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Abstract

Pain affects both sensory and emotional aversive responses, often provoking depression and anxiety-related conditions when it becomes chronic. As the opioid receptors in the locus coeruleus (LC) have been implicated in pain, stress responses, and opioid drug effects, we explored the modifications to LC opioid neurotransmission in a chronic constriction injury (CCI) model of short- and long-term neuropathic pain (7 and 30 days after nerve injury). No significant changes were found after short-term CCI, yet after 30 days, CCI provoked an up-regulation of cAMP (cyclic 5′-adenosine monophosphate), pCREB (phosphorylated cAMP response element binding protein), protein kinase A, tyrosine hydroxylase, and electrical activity in the LC, as well as enhanced c-Fos expression. Acute mu opioid receptor desensitization was more intense in these animals, measured as the decline of the peak current caused by [Met5]-enkephalin and the reduction of forskolin-stimulated cAMP produced in response to DAMGO. Sustained morphine treatment did not markedly modify certain LC parameters in CCI-30d animals, such as [Met5]-enkephalin-induced potassium outward currents or burst activity and c-Fos rebound after naloxone precipitation, which may limit the development of some typical opioid drug-related adaptations. However, other phenomena were impaired by long-term CCI, including the reduction in forskolin-stimulated cAMP accumulation by DAMGO after naloxone precipitation in morphine dependent animals. Overall, this study suggests that long-term CCI leads to changes at the LC level that may contribute to the anxiodepressive phenotype that develops in these animals. Furthermore, opioid drugs produce complex adaptations in the LC in this model of chronic neuropathic pain.

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Acknowledgments

We are very grateful to Ms. Raquel Rey-Brea, Mr. José Antonio García Partida, Mr. Santiago Muñoz, and Ms. Paula Reyes Perez for their excellent technical assistance. This work is dedicated in memory of Elsa Valdizán, PhD.

Funding and Disclosure

This work was supported by Spain’s Ministerio de Economía y Competitividad, co-financed by “Fondo Europeo de Desarrollo Regional” FEDER “A way to build Europe” (SAF2015-68647-R, SAF2011-25020); the “Centro de Investigación Biomédica en Red de Salud Mental-CIBERSAM” (Spain, G18); the “Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía” (CTS-510, CTS-7748); the Basque Government (IT 747-13); “Fundación Progreso y Salud de la Junta de Andalucía (PI-0080-2017); Fundación Española del Dolor (PI2015-FED-007); and a 2015 NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (NARSAD 23982).

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  1. Neuropsychopharmacology and Psychobiology Research Group, Department of Neuroscience, University of Cádiz, 11003, Cádiz, Spain

    Meritxell Llorca-Torralba, Lidia Bravo & Juan A. Mico

  2. Instituto de Investigación e Innovación en Ciencias Biomédicas de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Avda. Ana de Viya, 21, 11009, Cádiz, Spain

    Meritxell Llorca-Torralba, Lidia Bravo, Juan A. Mico & Esther Berrocoso

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

    Meritxell Llorca-Torralba, Fuencisla Pilar-Cuéllar, Lidia Bravo, Juan A. Mico, Emilio Garro-Martínez & Esther Berrocoso

  4. Instituto de Biomedicina y Biotecnología de Cantabria, IBBTEC (Universidad de Cantabria, CSIC, SODERCAN), Departamento de Fisiología y Farmacología, Universidad de Cantabria, 39011, Santander, Spain

    Fuencisla Pilar-Cuéllar & Emilio Garro-Martínez

  5. Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country UPV/EHU, 48940, Leioa, Spain

    Cristina Bruzos-Cidon, María Torrecilla & Luisa Ugedo

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

    Esther Berrocoso

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Correspondence to Esther Berrocoso.

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Animal handling and all the procedures were carried out in accordance with the guidelines of the European Commission’s directive (2010/63/EC) and Spanish Law (RD 53/2013) regulating animal research. Furthermore, all the experimental protocols were approved by the Committee for Animal Experimentation at the University of Cadiz (Spain).

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Llorca-Torralba, M., Pilar-Cuéllar, F., Bravo, L. et al. Opioid Activity in the Locus Coeruleus Is Modulated by Chronic Neuropathic Pain. Mol Neurobiol 56, 4135–4150 (2019). https://doi.org/10.1007/s12035-018-1361-9

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