L. Li, S. Rui-Bin, Q. Bo-Yi Beijing Institute of Pharmacology and Toxicology, Beijing, China

Opioids, widely used in the clinical management of pain, have not been substituted by other analgesics for nearly 200 years. Their clinical practice, however, is greatly limited because of their powerful potential to induce tolerance and dependence. People have been fighting for a long time to find powerful analgesics like opioids without their capacity of inducing tolerance and dependence, but so far nobody has success in this research field. Recently, it has been revealed that some agents, which are not able to interact with opioid receptors, play an important role in regulating the pharmacological actions of opioids. Some of these agents show biphasic modulation on opioid functions, which enhance opioid analgesia but inhibit tolerance to and substance dependence on opioids. These agents at least include imidazoline receptor agonist agmatine, N-methyl-D-aspartate (NMDA) receptor antagonists, NOS inhibitors, and voltage-dependent calcium channel blockers. We would like to call these agents— which do not interact with opioid receptors but which do have biphasic modulation on opioid functions—biphasic opioid function modulator (BOFM). The concept is going to set up a new field to research on the mechanisms of opioid tolerance and dependence, to set up a new field to research and develop new drugs for treatment of opioid tolerance and dependence, and to set up a new way to develop powerful analgesics with lower or no potential to induce tolerance and dependence by a complex of BOFM with opioids. Agmatine is an endogenous biological active substance, a neurotransmitter, and a modulator, the biological and pharmacological actions of which are closely associated with imidazoline and NMDA receptors. It was first demonstrated by Kolesnikov and his colleagues that agmatine enhanced morphine analgesia and inhibited morphine tolerance in mice. In the last 10 years, more and more accumulated results reported by our laboratory and others point out that agmatine has obvious action on opioid functions, which is a very good example for BOFM. Agmatine has an analgesic action in a dose-dependent manner in some weak experimental models and inhibits tolerance to and substance dependent on opioids in vivo and in vitro. The mechanisms related to its above modulator actions on opioid functions might be associated with inhibition of anincrease in release of monoamine, an increase in NOS activity in different brain areas of morphine dependent animals induced by naloxone, and an inhibition of desensitization and abolishment of cAMP over-shooting. In addition, like exogenous, endogenous agmatine is also able to influence pain threshold and inhibit tolerance to and substance dependence on opioids. These results indicate that agmatine is a good example for biphasic opioid function modulator, and imidazoline receptors and endogenous agmatine might form a new modulation system on opioid functions.