The
pain modulatory effects of (D-Tyr)L(Me-Phe)QPQRF-
amide ([
1DMe]NPYF), a stable analogue of
neuropeptide FF were studied in rats with a chronic neuropathy induced by unilateral
ligation of two spinal nerves. According to behavioral assessments, intrathecal (i.t.) administration of [
1DMe]NPYF induced mechanical antiallodynic and thermal antinociceptive effects in a parallel and dose-dependent fashion, whereas following administration in the periaqueductal gray (PAG) it produced only mechanical antiallodynia. I.t. or PAG administration of FLFQPQRF, a non-amidated form of
NPFF, or intraplantar injection of [
1DMe]NPYF into the neuropathic paw had no effects. Electrophysiological results indicated that administration of [
1DMe]NPYF suppressed responses of nociceptive spinal dorsal horn neurons in a submodality selective way and without an effect on their spontaneous activity; PAG administration predominantly suppressed brush-evoked responses and i.t. administration heat-evoked responses. The descending inhibitory effect by conditioning electrical stimulation of the PAG was enhanced by i.t. administration of [
1DMe]NPYF. The reversibility of [
1DMe]NPYF-induced effects by
naloxone (1 mg/kg subcutaneously) depended on the submodality of test stimulation and the route of
drug administration. The amplitude of the innocuous H-reflex was not changed by [
1DMe]NPYF administered i.t. in control rats. The present results indicate that [
1DMe]NPYF produces a selective attenuation of
pain in neuropathic animals due to
naloxone-sensitive or -insensitive central mechanisms depending on the submodality of
pain and route of
drug administration. The
amide-group is essential for the [
1DMe]NPYF-induced attenuation of
pain.