MDAN-21, , a bivalent opioid ligand containing a mu-opioid receptor agonist (derived from oxymorphone) linked to the delta-opioid receptor antagonist (related to naltrindole) by a spacer of 21 atoms, was reported to have potent analgesic properties in mice. Tolerance, physical dependence, and conditioned place preference were not evident in that species. The finding that bivalent ligands in this series, with spacers 19 atoms or greater, were devoid of tolerance and dependence led to the proposal that MDAN-21 targets heteromeric mu-delta-opioid receptors. The present study focused on its effects in nonhuman primates (Macaca mulatta), a species with a physiology and behavioral repertoire not unlike humans. With regard to opioids, this species usually better predicts clinical outcomes. MDAN-21 substituted for morphine in morphine-dependent monkeys in the remarkably low dose range 0.006–0.032？mg/kg, subcutaneously. Although MDAN-21 failed to produce reliable thermal analgesia in the dose range 0.0032–0.032？mg/kg, intramuscularly, it was active in the same dose range and by the same route of administration, in the capsaicin-induced thermal allodynia assay. The results suggest that MDAN-21 may be useful in the treatment of opioid dependence and allodynia. The data provide additional evidence that opioid withdrawal is associated with sensitized pain. 1. Introduction The alkaloid morphine has been used in the treatment of pain, cough, and diarrhea. Unfortunately, unpleasant and/or potentially dangerous side effects such as respiratory depression, nausea, vomiting, and constipation can accompany its use. Psychological and physiological processes such as abuse, tolerance, and physical dependence have been associated with chronic use and limit the utility of morphine and other mu-opioid agonists in the treatment of chronic pain. In a continuing search for potent analgesics free of these undesirable side effects, many analogues of morphine and numerous semisynthetic and synthetic derivatives have been introduced. The evolution of this search was summarized in a succinct review of the exciting but vain quest for the Holy Grail of opioid research [1]. Results of an investigation of the effects of leucine and methionine enkephalin on morphine-induced analgesia suggested an interaction between mu- and delta-opioid receptors [2]. Over a decade later, investigators found that naltrindole, a selective delta-opioid receptor antagonist, blocked the morphine tolerance without diminishing its antinociceptive potency [3]. These reports and the finding that G-protein-coupled
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