Serotonin induces peripheral antinociception via the opioidergic system.

PURPOSE: Studies conducted since 1969 have shown that the release of serotonin (5-HT) in the dorsal horn of the spinal cord contributes to opioid analgesia. In the present study, the participation of the opioidergic system in antinociceptive effect serotonin at the peripheral level was examined. METHODS: The paw pressure test was used with mice (Swiss, males from 35 g) which had increased pain sensitivity by intraplantar injection of PGE2 (2 µg). Serotonin (250 ng), administered locally to the right paw of animals, produces antinociception in this model. RESULTS: The selective antagonists for mu, delta and kappa opioid receptors, clocinnamox clocinnamox (40 µg), naltrindole (60 µg) and nor-binaltorfimina (200 µg), respectively, inhibited the antinociceptive effect induced by serotonin. Additionally, bestatin (400 µg), an inhibitor of enkephalinases that degrade peptides opioids, enhanced the antinociceptive effect induced by serotonin (low dose of 62.5 ng). CONCLUSIONS: These results suggest that serotonin possibly induce peripheral antinociception through the release of endogenous opioid peptides, possible from immune cells or keratinocytes.

Serotonin induces peripheral mechanical antihyperalgesic effects in mice.

The role of serotonin (5-HT) in nociception will vary according to the subtypes of receptors activated. When administered peripherally, it induces pain in humans and in rats by activation of 5-HT1, 5-HT2 and 5-HT3 receptors. In addition, endogenous 5-HT produced in situ, is involved in the nociceptive response induced by formalin in rat's paw inflammation, possibly via 5-HT3 receptors. Moreover, it has been shown that 5-HT released in the dorsal horn of the spinal cord by stimulation of the periaqueductal gray causes activation of inhibitory interneurons, resulting in inhibition of spinal neurons. In the present study we evaluated the effect of serotonin and its receptors at peripheral antinociception. The mice paw pressure test was used in animals that had increased sensitivity by an intraplantar injection of PGE2 (2 µg). We used selective antagonists of serotonin receptors (isamoltan 5-HT1B, BRL 15572 5-HT1D, ketanserin 5-HT2A, ondansetron 5-HT3 and SB-269970 5-HT7). Administration of serotonin into the right hind paw (62.5, 125, 250 and 500 ng and 1 µg) produced a dose-dependent peripheral mechanical antihyperalgesic effect of serotonin in mice. Selective antagonists for 5-HT1B, 5-HT2A, 5-HT3 receptors at doses of 0.1, 1 and 10 µg, reversed the antihyperalgesic effect induced by 250 ng serotonin. In contrast, selective antagonists for 5-HT1D and 5-HT7 receptors were unable to reverse the antihyperalgesic effect induced by serotonin. These results demonstrated for the first time, the peripheral mechanical antihyperalgesic effect of serotonin, and participation of 5-HT1B, 5-HT2A and 5-HT3 receptors in this event.

NSAIDs induce peripheral antinociception by interaction with the adrenergic system.

AIMS: We evaluated the role of adrenergic systems on the peripheral antinociception induced by dipyrone and diclofenac. Mainmethods: The rat pawpressure test, inwhich sensitivity is increased by intraplantar injection of prostaglandin E2, was used to examine the peripheral effects of locally administered drugs. KEY FINDINGS: Dipyrone (10, 20 and 40 µg) and diclofenac (5, 10 and 20 µg) administered locally into the right paw elicited a dose-dependent antinociceptive effect, which was demonstrated to be local; the injection of drugs into the ipsilateral and contralateral hindpaws demonstrated an effect only in the ipsilateral paw because only the treated paw produced an antinociceptive effect. To test the adrenergic system, we used guanethidine (30 mg/kg) to deplete noradrenalin from noradrenergic vesicles. Guanethidine antagonized the peripheral antinociception induced by diclofenac and dipyrone. Yohimbine (2.5, 5, 10, or 20 µg/paw) a nonselective α2-adrenergic receptor antagonist antagonized the peripheral antinociception induced by diclofenac (20 µg/paw) and dipyrone (40 µg/paw). Rauwolscine (Rau; 10, 15, 20 µg), a selective α2C-adrenoreceptor, was able to block the peripheral antinociception induced by NSAIDs. The other specific α2A,B and D-adrenoreceptor antagonists (BRL 44480, imiloxan and RX 821002, respectively) did not modify the peripheral antinociception. However, prazosin (0.5, 1, and 2 µg/paw), an α1 receptor antagonist, and propranolol (0.3, 0.6 or 1.2 µg/paw), a ß-adrenoreceptor antagonist, antagonized the antinociception induced by diclofenac (20 µg/paw) and dipyrone (40 µg/paw). SIGNIFICANCE: Dipyrone and diclofenac produce peripheral antinociception, which involves the release of NA and interaction with α1, α2C and ß-adrenoreceptors.