Truncated Mu Opioid Receptor Splice Variants As Targets For Powerful Pain Relief With Reduced Side Effects

Relief from pain is a major goal of all branches of medicine, and poorly controlled pain is associated with substantial economic and human burden. Mu opioid receptors are targets for strong pain relief, mediating the analgesia of widely used analgesic drugs like morphine, hydrocodone, oxycodone, methadone, and fentanyl. Unfortunately, these drugs are associated with numerous side effects such as constipation, respiratory depression, physical dependence, abuse, and addiction. The mu opioid receptor gene undergoes extensive alternative splicing, although the physiological relevance of many of these splice variants is only now becoming clear. In particular, some of these splice variants produce truncated receptors possessing only 6 transmembrane domains, short of the canonical 7 transmembrane domain structure conserved across the G-protein coupled receptor superfamily. Initial studies suggested that these receptors were expressed in low levels relative to full length variants, and could not bind mu agonist drugs when they were transiently expressed in cell lines, calling into question their importance in opioid receptor pharmacology. Here, we show that these truncated receptors are in fact targets for a new analgesic drug, IBNtxA, which is a potent pain reliever in mice and rats, yet exhibits a dramatically improved side effect profile over current clinically-used mu analgesics. IBNtxA shows only mild constipation, does not depress respiration or produce physical dependence, and shows neither rewarding nor aversive behavior in a conditioned place preference assay. We also examined the pharmacology and regional distribution of this target in rat brain using a radioiodinated form of the drug. Photoaffinity labels based on the structure of IBNtxA were also synthesized and characterized, and we present evidence consistent with the labeling of truncated mu opioid receptor splice variants in mouse brain. Other pain relievers were also found to require these truncated receptors for their analgesic effects, such as the clinically used opioid buprenorphine, as well as kappa1 agonists and clinically used alpha2 agonists. Importantly, dose- or use-limiting side effects for each of these drugs were found to be present in knockout animals lacking the truncated splice variant isoforms, suggesting that the desired analgesic properties can be separated from their unwanted side effects