Functional characterization of the 6-transmembrane form of mu-opioid receptor OPRM1 (2009)

Undergraduate: Philip Cheng

Faculty Advisor: Luda Diatchenko
Department: Chemistry

---

Morphine is one of the most widely used analgesics for the treatment of acute and chronic pain. The mu-opioid receptor (OPRM1) is a principal target for endogenous and exogenous opiates. The analgesic effects of opioids are often offset by their undesirable side-effects: nausea, constipation, tolerance, dependence and opioid induced hypersensitivity to pain (hyperalgesia). The OPRM1 receptor belongs to a class of heptahelical G-protein coupled receptors. We have identified a novel alternatively spliced form of OPRM1 receptor in humans which includes the newly identified exon 13 and coded for 6-transmembrane (6TM) domains. The extracellular N-terminus and first cytoplasmic domain (coded by exon 1) are missing in this isoform. Instead, it was found to possess a cytoplasmic N-terminus followed by 6TM domains and a C-terminus that does not differ from the 7TM isoform. The goal of the study was to functionally characterize the novel, alternatively spliced isoform of OPRM1 in terms of its expression in the human central nervous system (CNS) and its function in an in vitro model. We hereby report that this novel 6TM isoform of OPRM1 is expressed by most regions of the human CNS and upon ligation of morphine exhibits an increase in cellular cAMP levels, increased Ca++ influx and increased production of NO. We propose that these properties are consistent with the pro-nociceptive state observed during morphine tolerance, dependence and opioid induced hyperalgesia.