Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

Abstract

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 ...

Truncated mu opioid GPCR variant involvement in opioid-dependent and opioid-independent pain modulatory systems within the CNS

“…The importance of 6TM variants in IBNtxA analgesia has been established (9)(10)(11)(12). We now have extended our studies of these truncated forms of the mu opioid receptor to explore other classes of analgesics.…”

“…Although IBNtxA has affinity for kappa receptors (23), its continued analgesia in a triple KO mouse that lacks kappa, as well as delta and 7TM mu, receptors, strongly argues against a role for a kappa analgesic mechanism (10). A third category of drugs, including levorphanol, butorphanol, and nalbuphine, require both 6TM and 7TM variants for full activity (10). This genetic dissection of mu opioids into three general categories may help explain some of the variability in clinical response to various opioid analgesics and incomplete tolerance.…”

“…Classical mu drugs, like morphine and methadone, act only through full-length 7TM mu variants (1-3) whereas 6TM variants are both necessary and sufficient for other drugs, as illustrated by IBNtxA (4). Although IBNtxA has affinity for kappa receptors (23), its continued analgesia in a triple KO mouse that lacks kappa, as well as delta and 7TM mu, receptors, strongly argues against a role for a kappa analgesic mechanism (10). A third category of drugs, including levorphanol, butorphanol, and nalbuphine, require both 6TM and 7TM variants for full activity (10).…”

Morphine stimulates platelet-derived growth factor receptor-β signalling in mesangial cells in vitro and transgenic sickle mouse kidney in vivo

“…Splice variants of MOP have been suggested to play a physiologically important role through heterodimerization. 40 Multiple bands of MOP observed by us are suggestive of the presence of splice variants and perhaps heterodimerization of MOP with KOP. Although not known in the kidney, OPs are known to act as heterodimers in some cell types 41 and therefore silencing or antagonizing one receptor may abrogate the activity of the other.…”

Review of Preclinical Studies on Treatment of Mucositis and Associated Pain

“…A group led by Pasternak synthesized analgesics to target six-transmembrane isoforms of MOR such as MOR-1K. In their preclinical trials, these new compounds were more potent than morphine and lacked the side effects of respiratory depression and physical dependence seen with traditional opioids (Majumdar et al, 2011). Fink and colleagues took a different approach to develop novel analgesics.…”