Peripheral antinociceptive effects of low doses of naloxone in an in vivo and in vitro model of trigeminal nociception

Alessandro Capuano, Alice De Corato, Mariangela Treglia, Giuseppe Tringali, Diego Currò, Cinzia Dello Russo, Pierluigi Navarra

Research output: Contribution to journalArticle

Abstract

Naloxone has been used to antagonize opioid effects for many years, even though at low doses it can exert antinociceptive effects. This 'paradoxical' analgesia has been detected after systemic administration of naloxone given alone or in combination with opioid drugs. In the present study, we investigated possible peripheral antinociceptive effects of low doses of naloxone using both an in vivo and in vitro model of trigeminal nociception. Low doses of naloxone injected locally into the rat wiskerpad elicited antinociceptive activity in the rat orofacial formalin test. The block of primary afferents with local administration of capsaicin suggested that naloxone acts both directly on sensory neurons and indirectly, by modulating the inflammatory component of the second phase of formalin test. Naloxone analgesia is maintained in rats made tolerant to the μ-receptor agonist DAMGO, suggesting the involvement of δ- and κ-opioid receptors. Subsequently, the effects of very low doses of naloxone were tested in primary cultures of rat trigeminal neurons activated with bradykinin, in order to elucidate the mechanisms of action underlying naloxone antinociceptive effects. Naloxone inhibited bradykinin-evoked CGRP release in two different experimental paradigms, i.e. primed and unprimed cultures, acting at the level of δ- and κ-opioids receptors. These results suggest that low doses of naloxone can directly modulate the activation of the trigeminal neurons by modulating the activity of specific opioid receptors, and this effect may be clinically relevant in combined therapies where an increased analgesic effect is sought through the potentiation of peripheral mechanisms.

Original languageEnglish
Pages (from-to)784-792
Number of pages9
JournalNeuropharmacology
Volume58
Issue number4-5
DOIs
Publication statusPublished - Mar 2010

Keywords

  • Naloxone
  • Opioid antagonists
  • Peripheral antinociception
  • Primary cultures of rat trigeminal ganglia neurons
  • Rat orofacial formalin test

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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