P.1.c.047 Hippocampal nociceptin receptors and memory: possible implications for "anti-alcohol" effects of nociceptin ligands

Abstract

The opioid system comprises four receptor subtypes: μ (MOP), κ (KOP), δ (DOP), now called the ‘classical’ opioid receptors, and the ‘non-classical’ nociceptin/orphanin FQ peptide (N/OFQ) receptor (NOP). Selective endogenous peptides, cleaved from larger precursor proteins, have been identified for all subtypes. Both classical and non-classical opioid receptors couple to inhibitory, pertussis toxin-sensitive G-proteins. Opioid receptors activate the same major intracellular pathways, which include: closing of voltage-sensitive calcium channels; opening of potassium channels and subsequent cellular hyperpolarization; and inhibition of cyclic AMP production through inhibition of the enzyme adenylate cyclase. All current, clinically used opioids work through activation of the MOP receptor. In an experimental setting, co-administration of MOP and DOP agonists has been shown to have a synergistic analgesic action. Administration of DOP-receptor antagonists has also been shown to reduce tolerance, physical dependence and other side effects of MOP-receptor agonists, without detriment to their analgesic action. In animal models NOP agonists are analgesic when administered spinally and have a pronociceptive/anti-analgesic (or anti-opioid) effect supraspinally. NOP knockout mice show a partial loss of tolerance to morphine and there is an up-regulation of N/OFQ production in chronic morphine tolerant mice. Analgesic tolerance that develops from repeated exposure to morphine is markedly attenuated in NOP knockout mice. The development of ligands with mixed action at MOP, DOP and NOP receptors offer new opportunities for opioid pharmacology.