Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile.opiate receptor | rewarding behavior | kappa 3 receptor T he utility of opioids in the management of pain is not disputed, but they come at a price. Along with their ability to relieve pain comes a variety of opioid receptor-mediated side effects, including respiratory depression, constipation, physical dependence, and reward behavior felt by many to contribute to their addictive potential. Most of the clinical opioids act through mu receptors, which mediate both analgesia and these side effects. Pharmacological studies have long suggested subtypes of mu receptors (1) and the possibility of dissociating analgesia from respiratory depression (2, 3), physical dependence (4), and the inhibition of gastrointestinal transit (5, 6). However, attempts to develop opiate analgesics that avoid these side effects have not been very fruitful. The isolation of a series of splice variants of the cloned mu opioid receptor from mice ( Fig. 1), rats, and humans with similar splicing patterns (7, 8) reveals a complexity far exceeding the pharmacological classification of mu receptor subtypes (1). However, this complexity has yet to be exploited in generating new classes of opioid analgesics. We now report an unexpected and unusual target for potent opioid analgesic drugs that lack respiratory depression, physical dependence, reward behavior, and significant constipation.
ResultsRecently, we synthesized iodobenzoylnaltrexamide (IBNtxA), a naltrexone derivative (Fig. 2) (9). In vivo, it is a very potent analgesic (ED 50 = 0.48 ± 0.05 mg/kg s.c.) (Fig. 3A and Fig. S1), ∼10-fold more potent than morphine (4.6 ± 0.97 mg/kg s.c.) (10), with a mechanism of action quite distinct from traditional opiates. It was active s.c. as well as orally (Fig. S1), with a peak effect after oral administration that was delayed relative to parenteral administration. In ...