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

Naloxone has been used to antagonize opioid effects for many years, even though\r\nat low doses it can exert antinociceptive effects. This 'paradoxical' analgesia\r\nhas been detected after systemic administration of naloxone given alone or in\r\ncombination with opioid drugs. In the present study, we investigated possible\r\nperipheral antinociceptive effects of low doses of naloxone using both an in vivo\r\nand in vitro model of trigeminal nociception. Low doses of naloxone injected\r\nlocally into the rat wiskerpad elicited antinociceptive activity in the rat\r\norofacial formalin test. The block of primary afferents with local administration\r\nof capsaicin suggested that naloxone acts both directly on sensory neurons and\r\nindirectly, by modulating the inflammatory component of the second phase of\r\nformalin test. Naloxone analgesia is maintained in rats made tolerant to the\r\nmu-receptor agonist DAMGO, suggesting the involvement of delta- and kappa-opioid \r\nreceptors. Subsequently, the effects of very low doses of naloxone were tested in\r\nprimary cultures of rat trigeminal neurons activated with bradykinin, in order to\r\nelucidate the mechanisms of action underlying naloxone antinociceptive effects.\r\nNaloxone inhibited bradykinin-evoked CGRP release in two different experimental\r\nparadigms, i.e. primed and unprimed cultures, acting at the level of delta- and\r\nkappa-opioids receptors. These results suggest that low doses of naloxone can\r\ndirectly modulate the activation of the trigeminal neurons by modulating the\r\nactivity of specific opioid receptors, and this effect may be clinically relevant\r\nin combined therapies where an increased analgesic effect is sought through the\r\npotentiation of peripheral mechanisms.