Spinal and local peripheral antiallodynic activity of Ro64-6198 in neuropathic pain in the rat.
The nociceptin system seems to be involved in modulation of acute nociceptive stimulation and in chronic pain processes, e.g. inflammation and neuropathy. In the present study, we examined the analgesic effect of a new opioid receptor-like (ORL1) receptor agonist, Ro64-6198, and compared it with the effect of endogenous ORL1 receptor agonist, nociceptin/orphanin FQ (N/OFQ), in a model of neuropathic pain in the rat. Ro64-6198 was injected intrathecaly (i.t.), intraplantarly (i.pl.) and subcutaneously (s.c.), and responses of neuropathic rats were measured in tactile (von Frey) and thermal (cold water) allodynia tests. Ro64-6198 did not change the pain threshold in naive animals, but exhibited antiallodynic activity in neuropathic rats. This effect was observed after i.t. and i.pl. but not after s.c. administration. Moreover, the observed antiallodynic potency of Ro64-6198 was weaker in comparison with N/OFQ after i.t. administration of either agonist, but almost equal after i.pl. injection. Selective antagonists of the ORL1 receptor, [Phe1Psi(CH2-NH)Gly2]NC(1-13)NH2 (PhePsi) and [N-Phe1]-NC(1-13)NH2 (NPhe), inhibited the antiallodynic actions of Ro64-6198 which indicated that the spinal and peripheral antinociceptive effects were mediated by ORL1 receptors. Therefore, besides spinal, also peripheral ORL1 receptors may be targeted by drugs designed for the long-term treatment of chronic pain.
Obara
Ilona
I
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland.
Przewlocki
Ryszard
R
Przewlocka
Barbara
B
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000209:etiology; D018847:Opioid Peptides / Q000494:pharmacology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000819:agonists*; D020426:Sciatic Neuropathy / Q000150:complications / Q000188:drug therapy; D013116:Spinal Cord / Q000187:drug effects*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors; D000094942:Nociceptin Receptor
D007093:Imidazoles; D018847:Opioid Peptides; D010446:Peptide Fragments; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; C408068:Ro 64-6198; C114149:nociceptin (1-13)-NH2, Phe(1)-psi(CH2-NH)-Gly(2)-; C000722285:Oprl1 protein, rat