δ-Opioid Receptor and Somatostatin Receptor-4 Heterodimerization: Possible Implications in Modulation of Pain Associated Signaling

Rishi K Somvanshi,Ujendra Kumar,Prasun K Datta

doi:10.1371/journal.pone.0085193

Rishi K Somvanshi, Ujendra Kumar + Show 1 more

Open Access

https://doi.org/10.1371/journal.pone.0085193

Copy DOI

Journal: PloS one	Publication Date: Jan 8, 2014
Citations: 28	License type: CC BY 4.0

Affiliation: University of British Columbia

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.

Highlights

The functional consequences of GPCRs heterodimerization in a native system expressing these receptors endogenously, in the central nervous system (CNS) are poorly understood
We observed that all d-Opioid receptor (dOR) positive neurons colocalized with somatostatin receptor 4 (SSTR4) indicating that dOR expression was limited to SSTR4 positive neurons
Consistent observations in three different brain regions revealed that all dOR positive neurons coexpress SSTR4, whereas, some neurons positive to SSTR4 were devoid of dOR like immunoreactivity

Summary

Introduction

The functional consequences of GPCRs heterodimerization in a native system expressing these receptors endogenously, in the central nervous system (CNS) are poorly understood. Opioid receptors (ORs), namely mu (m), delta (d) and kappa (k), are the prominent members of the GPCRs super family [1,2]. The most indispensable function of ORs in CNS is to modulate pain. MOR is more efficient as an analgesic drug target due to its high expression at cell surface, reinstating dOR expression at neuronal membrane enhances receptor mediated analgesic effects [8]. These studies collectively suggest that ORs membrane expression is a prerequisite for receptors analgesic properties [8]. ORs functionally interact with other receptor of the family and display distinct pharmacological and signaling properties [10]

Methods

Results

Conclusion