title: δ-opioid receptor and somatostatin receptor-4 heterodimerization: possible implications in modulation of pain associated signaling.
abstract: Pain relief is the principal action of opioids. Somatostatin (SST), a growth hormone inhibitory peptide is also known to alleviate pain even in cases when opioids fail. Recent studies have shown that mice are prone to sustained pain and devoid of analgesic effect in the absence of somatostatin receptor 4 (SSTR4). In the present study, using brain slices, cultured neurons and HEK-293 cells, we showed that SSTR4 and δ-Opioid receptor (δOR) exist in a heteromeric complex and function in synergistic manner. SSTR4 and δOR co-expressed in cortical/striatal brain regions and spinal cord. Using cultured neuronal cells, we describe the heterogeneous complex formation of SSTR4 and δOR at neuronal cell body and processes. Cotransfected cells display inhibition of cAMP/PKA and co-activation of SSTR4 and δOR oppose receptor trafficking induced by individual receptor activation. Furthermore, downstream signaling pathways either associated with withdrawal or pain relief are modulated synergistically with a predominant role of SSTR4. Inhibition of cAMP/PKA and activation of ERK1/2 are the possible cellular adaptations to prevent withdrawal induced by chronic morphine use. Our results reveal direct intra-membrane interaction between SSTR4 and δOR and provide insights for the molecular mechanism for the anti-nociceptive property of SST in combination with opioids as a potential therapeutic approach to avoid undesirable withdrawal symptoms.
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada.
authors.forename: Rishi K
authors.initials: RK
authors.lastname: Somvanshi
authors.affiliation: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada.
authors.forename: Ujendra
authors.initials: U
authors.lastname: Kumar
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D061251:Primary Cell Culture; D055503:Protein Multimerization; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism*; D017481:Receptors, Somatostatin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013004:Somatostatin / Q000378:metabolism* / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000701:Analgesics, Opioid; D017465:Receptors, Opioid, delta; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; D013004:Somatostatin; D009020:Morphine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3