Abstract

BELLIDO, I.; CASTRO, M. J.; GOMEZ-LUQUE, A.  and  SANCHEZ DE LA CUESTA, F.. Relationship between the analgesic effect of acute fentanyl and upregulation of brain 5-HT_1A receptors in the rat. Rev. Soc. Esp. Dolor [online]. 2004, vol.11, n.5, pp.270-281. ISSN 1134-8046.

5-HT_1A agonists have analgesic effects. The analgesic effect of µ agonists can be blocked by selective 5-HT_1A antagonists. In order to determine the mechanism that produces the synergies observed between µ and serotoninergic 5-HT_1A receptors in terms of their antinociceptive effect, we determined the analgesic effect of fentanyl after ap-plying a painful thermal and mechanical stimulus in the rat, and related it with the affinity and the maximum density of 5-HT_1A receptors in thirteen brain areas using autoradiographic techniques. Fentanyl showed a dose- and time-dependant analgesic effect with the two nociceptive stimuli. In addition to its analgesic effect, fentanyl caused an up-regulation of 5-HT_1A receptors, since we found a dose-dependant increase of their density, but the same affinity. The highest dose of fentanyl (12.8 µg.kg^-1) caused a statistically significant increase of the density of 5-HT_1A receptors that was positively associated with its analgesic effect on the terminal cortical external (+64%), internal (+69%) and piriform (+113%) frontoparietal areas, the CA1 (+111%) and DGm (+60%) regions of the hippocampus, the amygdalin nuclei PMCo (+101%) and AHiAL (+91%) and the hypo-thalamus (+127%). The analgesic effect of acute fentanyl would be explained, at least, by two mechanisms: its stimulation of opiate neurotransmission acting directly on opiate µ receptors and the increase of 5-HT levels at the central nervous system and the up-regulation of 5-HT_1A receptors at the terminal brain areas, hence facilitating the stimulation of such receptors. Since the post-synaptic 5-HT_1A receptors act as heteroreceptors that inhibit non-serotoninergic neurons and cause neuronal hyperpolarization, fentanyl would facilitate the stimulation of these receptors and would inhibit the neuronal activity in all such terminal areas, preventing the transmission of the nociceptive stimulus. This would explain the reduced analgesic effect of opiate µ agonists that is observed with selective 5-HT_1A antagonists and the increased analgesic effect observed when µ agonists and other drugs capable of increasing 5-HT levels, such as ISRS, are co-administered. Further studies are required in order to accurately determine the mechanism through which the stimulation of µ receptors cause up-regulation of post-synaptic 5-HT_1A receptors and the role of each brain area in the perception of the nociceptive stimulus.

Keywords : µ receptor; 5-HT_1A receptor; Synergies; Fentanyl; Analgesia.

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