Inhibition of opioid release in the rat spinal cord by serotonin 5-HT1A receptors

Neurotransmitter receptors that inhibit the release of opioid peptides in the spinal cord may play an important role in modulating pain. Serotonin is an important neurotransmitter in bulbospinal descending pathways, and 5-HT1 receptors have been shown to inhibit synaptic transmission. Our goal was to determine whether 5-HT1A receptors inhibit opioid release in the spinal cord. Opioid release was evoked from rat spinal cord slices by electrically stimulating one dorsal horn, and measured in situ through the internalization of μ-opioid receptors in dorsal horn neurons. Stimulation with 1000 square pulses at 500 Hz produced internalization in 60% of the μ-opioid receptor neurons in the stimulated dorsal horn, but not in the contralateral one. The selective 5-HT1A receptor agonist 8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) inhibited the evoked μ-opioid receptor internalization by about 50%, with an approximate IC50 of 50 nM. The effect of 8-OH-DPAT was attributed to inhibition of opioid release and not of the receptor internalization process, because 8-OH-DPAT did not inhibit the internalization induced by incubating the slices with a μ-opioid receptor agonist (endomorphin-2, 100 nM). The selective 5-HT1A receptor antagonist WAY100135 (10 μM) blocked the inhibition produced by 1 μM 8-OH-DPAT. These results show that 5-HT1A receptors inhibit opioid release in the spinal dorsal horn, probably from a subpopulation of enkephalin-containing presynaptic terminals. Therefore, 5-HT1A receptors likely decrease the analgesia produced by endogenously released opioids.