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Opioid and chemokine receptor crosstalk: a promising target for pain therapy?

Abstract

Chemokines and opioids are important regulators of immune, inflammatory and neuronal responses in peripheral and central pain pathways. Recent studies have provided insights into the functional interactions between chemokine receptors and opioid receptors, and their role in pain modulation. In this Progress article, we discuss how crosstalk between these two systems might provide a molecular and cellular framework for the development of novel analgesic therapies for the management of acute and/or chronic pain.

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Figure 1: Potential sites of crosstalk between chemokine receptors and opioid receptors in nociceptive pathways.
Figure 2: Neuronal colocalization of CXC-chemokine receptor 4 and μ-opioid receptor in the rat periaqueductal grey and dorsal root ganglion, and relevance to morphine-induced analgesia.
Figure 3: Involvement of CXC-chemokine ligand 12–CXC-chemokine receptor 4 axis in acute and chronic morphine tolerance.
Figure 4: Impact of neuroinflammation in morphine tolerance and hyperalgesia.

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Acknowledgements

This work was supported by the Agence Nationale pour la Recherche, Sorbonne Universités, Université Pierre-et-Marie-Curie, the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Centre National de la Recherche Scientifique (CNRS). The authors thank R. N. Cooper for editorial assistance with this manuscript.

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Correspondence to Annabelle Réaux-Le Goazigo.

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Glossary

Acute pain

A defence mechanism that starts suddenly and that is normally very sharp. It provides a fast alert to potentially dangerous traumas.

Allodynia

A type of pain that is induced by a normally innocuous stimulus.

Central sensitization

An exacerbation of pain perception from noxious stimuli that is associated with the development and maintenance of chronic pain. It is caused by an increase in neuronal excitability and a decrease in inhibition of neuronal activity in the spinal cord.

Chemokines

Small secreted cytokines that were identified on the basis of their ability to induce chemotaxis of leukocytes. Chemokines function as regulators of the immune system, peripheral system and CNS.

Chemotactic

Involving chemotaxis, which is cell movement or cell migration in response to a chemical stimulus.

Chronic pain

Pain lasting more than 3–6 months that is the result of aberrant activity in nociceptive pathways.

Cytokines

Small secreted proteins that are mainly produced by the immune cells that mediate and regulate immunity, inflammation and haematopoiesis.

Hyperalgesia

Exaggerated pain in response to stimuli that are expected to be (moderately) painful.

Innate immune response

Fast-acting, nonspecific immunological actions of an organism that recognize an infection and attempt to clear it from the organism.

Neuropathic pain

A chronic condition that is caused by a lesion or disease of the somatosensory nervous system. A characteristic of neuropathic pain is an abnormal response to somatic sensory stimulation.

Nociceptor

A free nerve ending of thinly myelinated and unmyelinated fibres that responds to intense, noxious stimuli by sending nerve signals to the spinal cord and to the brain.

Opioid-induced hyperalgesia

A paradoxical increase in pain response and reduction in pain threshold that occurs with acute or prolonged use of opioids, or after withdrawal of opioid treatment.

Opioid tolerance

A process of neuro-adaptation to opioid drugs that results in a reduction in analgesic efficacy after repeated doses. Higher doses of opioids are therefore required to maintain a consistent level of pain relief.

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Parsadaniantz, S., Rivat, C., Rostène, W. et al. Opioid and chemokine receptor crosstalk: a promising target for pain therapy?. Nat Rev Neurosci 16, 69–78 (2015). https://doi.org/10.1038/nrn3858

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