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Eur J Pharmacol. 2019 Mar 13;853:56-64. doi: 10.1016/j.ejphar.2019.03.020. [Epub ahead of print]

D2-like receptor agonist synergizes the μ-opioid agonist spinal antinociception in nociceptive, inflammatory and neuropathic models of pain in the rat.

Author information

1
Laboratorio de Fisiología Celular, Dirección de Investigaciones en Neurociencias. Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México, Mexico.
2
Laboratorio de Fisiología Celular, Dirección de Investigaciones en Neurociencias. Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México, Mexico; Cátedras CONACyT - Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México, Mexico.
3
Laboratorio de Neurofisiología Integrativa, Dirección de Investigaciones en Neurociencias. Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México, Mexico.
4
Laboratorio de Fisiología Celular, Dirección de Investigaciones en Neurociencias. Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, Ciudad de México, Mexico. Electronic address: fmercado@imp.edu.mx.

Abstract

Opioids are potent analgesic drugs, but their use has been limited due to their side effects. Antinociceptive effects of D2-like receptor agonists such as quinpirole have been shown at the spinal cord level; however, their efficacy is not as high as that of opioids. Dopaminergic agonists are long-prescribed and well-tolerated drugs that have been useful to treat clinically and experimentally painful conditions. Because current pain treatments are not completely effective, the aim of this work was to determine if a D2-like receptor agonist improves the antinociceptive effects of a μ-opioid receptor agonist. Drugs were intrathecally administered in adult rats; mechanonociceptive and thermonociceptive tests were carried out. Intraplantar injection of complete Freund's adjuvant (CFA) and sciatic loose ligation (SLL) were used for inflammatory and neuropathic models of pain, respectively. In intact animals, D-Ala2, N-MePhe4, Gly-ol-enkephalin (DAMGO; a µ-opioid receptor agonist) increased the paw withdrawal latencies (PWL) in thermal and mechanical nociceptive tests in a dose-dependent manner. Quinpirole (D2-like receptor agonist) increased PWL only in mechanonociception. In the presence of quinpirole (1 nmol), the ED50 of the mechanical antinociceptive effect of DAMGO was significantly decreased (8-fold). Coadministration of 1 nmol quinpirole and 30 pmol DAMGO completely reversed hyperalgesia in the CFA model, whereas 100 pmol DAMGO plus 1 nmol quinpirole reversed the allodynia in the SLL model. This work offers evidence about a synergistic antinociceptive effect between opioidergic and dopaminergic drugs. This combination may relieve painful conditions resistant to conventional treatments, and it may reduce the adverse effects of chronic opioid administration.

KEYWORDS:

Analgesia; D2-like receptors; Dopamine; Modulation; Neuropathic pain; Opioid receptors

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