NOCICEPTIN (ORPHANIN FQ), AN ENDOGENOUS LIGAND FOR THE ORL, (OPIOID-RECEPTOR-LIKE(1))RECEPTOR, MODULATES RESPONSES OF TRIGEMINAL NEURONS EVOKED BY EXCITATORY AMINO-ACIDS AND SOMATOSENSORY STIMULI

1. This is the first in vivo electrophysiological evidence demonstrati ng the effects of hr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-Gln ( nociceptin or orphanin FQ), an endogenous Ligand for the orphan ORL(1) receptor, on nociceptive neurons in the CNS. The effects of nocicepti n were tested on the responses of neurons recorded in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in the rat. 2. Nociceptin applied microiontophoretically produced a pred ominantly long-lasting (5-30 min) inhibitory modulation of the N-methy l-D-aspartic acid (NMDA)-evoked responses of 24 of 31 nociceptive and 12 of 12 nonnociceptive neurons. Excitatory or biphasic effects of noc iceptin were also observed in 6 of 43 neurons. Responses evoked by lph a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) were reduc ed in eight of nine nociceptive and nonnociceptive neurons. 3. The inh ibitory effect of nociceptin was not modality specific; responses to b oth noxious and nonnoxious stimuli were reduced. 4. Although naloxone applied iontophoretically blocked or reduced the peak inhibitory effec t of [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-Enkephalin (DAMGO) or )-3,4-dich oloro-N-methyl-N-(2-1-pyrrolidinyl-cyclo hexyl)-benzene acetamide (U50 , 488H), it did not produce a significant alteration in the peak inhib itory effect of nociceptin. 5. Nociceptin administered intracerebroven tricularly produced a long-lasting (20-35 min) reduction in the NMDA-e voked responses of three of three nociceptive neurons. 6. Nociceptin p roduces a predominantly antinociceptive action in the trigeminal syste m.