[(pF)Phe4, Arg14, Lys15]N/OFQ-NH2 (UFP-102) 活化大鼠環導水管灰質N/OFQ受體之定量性研究

Abstract The discovery of a fourth member of the opioid receptor family, opioid receptor-like (ORL-1) recptor in 1994 gave rise to a new camp in opioid research, since this new G-protein coupled receptor though being in logically homogenous to classical opioid receptors’ did not bind opiates with high affinity. A year later, two groups independently identified the endogenous ligand of this receptor, a 17 amino acid neuropeptide named nociceptin or orphanin FQ. This receptor family was officially renamed after its endogenous ligand as nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP) receptor in IUPHAR2002. The NOP receptor and N/OFQ are widely distributed in the central nervous system (CNS), and the periphery. Several studies have implicated the N/OFQ-NOP receptor plays an important role system in pain, anxiety, learning, memory, food intake, diuresis, and drug addition. However, N/OFQ modulation of pain pathways is yet to be completely understood. N/OFQ, unlike traditional opioids which display analgesia effect, elicited both analgesia and hyperalgesia. It has great benefit in understanding the physiological role(s) of N/OFQ in pain regulation by developing NOP receptor ligands, including agonists and antagonists. A novel ligand for the receptor (NOP), [(pF)Phe4, Arg14, Lys15] N/OFQ-NH2 (UFP-102), has been generated by combining in the N/OFQ-NH2 sequence two chemical modifications, [Arg14, Lys15] and [(pF)Phe4], that have been previously demonstrated to increase potency and ability lasting, respectively. The present study, quantitatively investigated the potency of UFP-102 at NOP receptors of rat brain slices containing the midbrain ventrolateral periaquaductal gray (vlPAG), a crucial site for N/OFQ-induced reversal of opioid algesia, using the blind patch-clamp whole cell recording technique. UFP-102 concentration-dependently induced an outward current at resting membrane potential and increased the membrane current elicited by hyperpolarization ramps from -60 to -140 mV in ventrolateral PAG neurons. The current induced by UFP-102 is characterized with inward rectification and has reversal potential near the equilibrium potential of K+ ions according to the Nernst equation. Therefore, UFP-102 activates inwardly rectifying K+ channels. UFP-102 showed similar maximal effects (35 ± 3% and 40 ± 4%, respectively) but higher potency (4- to 5-fold) relative to N/OFQ. UFP-101, a novel selective and competitive antagonist of NOP receptors, concentration-dependently attenuated of K+ current induced by UFP-102 but did not change its reversal potential. It produced a parallel right-shift of the concentration-response curve of UFP-102 but did not alter the extent of UFP-102 induced maximal response. The antagonistic effect of UFP-101 on UFP-102 induced K+ current was surmountable by increasing the UFP-102 concentrations. However, the nonselective opioid receptor antagonist, naloxone, did not attenuated of K+ current induced by UFP-102. The pIC50 of UFP-101 against UFP-102 was 6.52. It is concluded that, in ventrolateral PAG, (1) UFP-102 is a selective agonist of NOP receptor with an EC50 value of 11±2 nM. (2) UFP-102 showed similar maximal effects but higher potency (about 4- to 5-fold) relative to N/OFQ.