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.

The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model

“…Potential interactions of SST receptors with opioid receptors have been suggested (Betoin et al, 1994;Hatzoglou et al, 2005;Maurer et al, 1982;Pfeiffer et al, 2002;Prinster et al, 2005). A recent study showed, that SSTR4 and delta-opioid receptors exist in a heteromeric complex in the spinal cord and function in synergistic manner (Somvanshi and Kumar, 2014). A potential interaction of spinal SSTR4 and opioid receptors was also supported by the results of this study.…”

“…Due to the expression of SSTR4 on rat dorsal root ganglia (Bar et al, 2004), a primarily peripheral site of action for SSTR4 agonists has been proposed (Helyes et al, 1996;Pinter et al, 2002;Szolcsanyi et al, 2004). However, the SSTR4 receptor is also expressed in the rat spinal cord (Somvanshi and Kumar, 2014) and therefore a central site of action cannot be excluded.…”

Molecular Pharmacology ofδ-Opioid Receptors

“…A direct interaction between these receptors in the brain, spinal cord, and heterologous systems is supported by coimmunoprecipitation and FRET studies (Somvanshi and Kumar, 2014). Again, further work is needed to confirm that this hetero-oligomer possesses distinct characteristics and roles in native tissue.…”

Novel Drug-Like Somatostatin Receptor 4 Agonists are Potential Analgesics for Neuropathic Pain

“…The somatotropin release-inhibiting factor 1 (SRIF1) receptor class involves sst 2 , sst 3 and sst 5 mediating important endocrine actions of somatostatin (e.g., inhibition of growth hormone, insulin, glucagon secretion), and the SRIF2 class includes sst 1 and sst 4 [10]. It is well known that sst 4 receptor is present in the dorsal root ganglia cells and spinal cord dorsal horn, and can also mediate analgesic effects along with the δ-opioid receptor [12,13]. We provided several lines of evidence that the broad anti-inflammatory, antinociceptive and anti-hyperalgesic effects of somatostatin are mediated by the sst 4 receptor without influencing endocrine functions [1,4,[14][15][16][17].…”