Introduction

The pain-suppressive effect of morphine is related to the interaction of this alkaloid with binding sites located in the central nervous system (CNS) and more precisely within structures known for their involvement in the regulation of nociceptive stimuli. Moreover, the wide distribution of opioid receptors in the brain accounts for the multiplicity of pharmacologic responses elicited by morphine administration. Psychic dependence and respiratory depression, which are among the major side effects of narcotics, are related to overstimulation of brain receptors, respectively, in behavioral and bulbar respiratory controls. The reduction in intestinal transit is another drawback frequently associated with chronic morphine treatment. Thus, despite the considerable interest in morphine and surrogates for treatment of severe pain, there is a crucial need for new analgesics to fill the gap between opioid analgesics and antalgics, such as aspirin and paracetamol. Such compounds may be of major interest for the treatment of various pain syndromes (postoperative, neurogenic, osteoarthritic) and more easily used in children, the elderly, and patients with respiratory problems.

Although many factors seem to be involved in pain control, the prevailing role of the opioid μ receptor type in analgesia has hampered the discovery of analgesics devoid of the severe morphine side effects, which were proposed to result from the stimulation of μ receptors. This hypothesis has recently been firmly established using transgenic mice with a deletion of the μ-receptor gene (Matthes et al., 1996).