Involvement of Enhanced Gene Expression of Anti-Opioid Systems in Morphine Tolerance and Dependence

Abstract

Chronic morphine application induces such side effects as tolerance and physical dependence, which have been speculated to be developed through neuronal plasticity of the central nervous system. Based on the assumption that the reduction of morphine analgesia during chronic treatment is mediated through anti-opioid systems in brain, several attempts have been done to characterize morphine analgesic tolerance by use of blocking agents for anti-opioid systems.¹ Glutamaterigic system using NMD A receptor (NMDAR) was the first to be demonstrated as an anti-opioid system to develop morphine tolerance and dependence.² On the other hand, nociceptin/orphanin FQ (N/OFQ) was discovered to be an endogenous ligand for opioid receptor-like orphan receptor, ORL1, which is now called NOPR.^{3, 4} From the initial pharmacological studies N/OFQ has been reported to be an anti-opioid peptide.^{5, 6} Using this idea, we have firstly clarified that N/OFQ system through NOPR is also involved in the development of morphine tolerance and dependence, by use of NOPR^-/- mice, which lack the gene encoding NOPR.^{7, 8} However, as it is often observed that knock-out mice develop some compensatory changes during development and growth, we have studied the involvement of NOPR in such mechanisms by use of specific antagonist (J-113397).⁹ Here, we report the characterization and their possible molecular mechanisms of both NMDAR and NOPR systems involved in the development of morphine tolerance and dependence.