Differential Efficacies of Somatostatin Receptor Agonists for G-Protein Activation and Desensitization of Somatostatin Receptor Subtype 4-Mediated Responses

Somatostatin released from the capsaicin-sensitive sensory nerves mediates analgesic and anti-inflammatory effects via the somatostatin sst4 receptor without endocrine actions. Therefore, sst4 is considered to be a novel target for drug development in pain including chronic neuropathy, which is an emerging unmet medical need. Here, we examined the in silico binding, the sst4-linked G-protein activation on stable receptor expressing cells (1 nM to 10 μM), and the effects of our novel pyrrolo-pyrimidine molecules in mouse inflammatory and neuropathic pain models. All four of the tested compounds (C1–C4) bind to the same binding site of the sst4 receptor with similar interaction energy to high-affinity reference sst4 agonists, and they all induce G-protein activation. C1 is the more efficacious (γ-GTP-binding: 218.2% ± 36.5%) and most potent (EC50: 37 nM) ligand. In vivo testing of the actions of orally administered C1 and C2 (500 µg/kg) showed that only C1 decreased the resiniferatoxin-induced acute neurogenic inflammatory thermal allodynia and mechanical hyperalgesia significantly. Meanwhile, both of them remarkably reduced partial sciatic nerve ligation-induced chronic neuropathic mechanical hyperalgesia after a single oral administration of the 500 µg/kg dose. These orally active novel sst4 agonists exert potent anti-hyperalgesic effect in a chronic neuropathy model, and therefore, they can open promising drug developmental perspectives.

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Region-dependent G-protein activation by μ-, δ1- and δ2-opioid receptor agonists in the brain: Comparison between the midbrain and forebrain

Life Sciences ◽

10.1016/s0024-3205(99)00422-1 ◽

1999 ◽

Vol 65 (16) ◽

pp. PL233-PL239 ◽

Cited By ~ 4

Author(s):

Minoru Tsuji ◽

Minoru Narita ◽

Hirokazu Mizoguchi ◽

Michiko Narita ◽

Masahiro Ohsawa ◽

...

Keyword(s):

G Protein ◽

Opioid Receptor ◽

Protein Activation ◽

Receptor Agonists ◽

G Protein Activation ◽

Opioid Receptor Agonists ◽

The Brain

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Region-dependent G-protein activation by κ-opioid receptor agonists in the mouse brain

Neuroscience Letters ◽

10.1016/j.neulet.2003.09.034 ◽

2004 ◽

Vol 356 (2) ◽

pp. 145-147 ◽

Cited By ~ 6

Author(s):

Hirokazu Mizoguchi ◽

Randy J. Leitermann ◽

Minoru Narita ◽

Hiroshi Nagase ◽

Tsutomu Suzuki ◽

...

Keyword(s):

G Protein ◽

Opioid Receptor ◽

Mouse Brain ◽

Protein Activation ◽

Receptor Agonists ◽

G Protein Activation ◽

Opioid Receptor Agonists

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Faculty Opinions recommendation of Re-examining the 'Dissociation Model' of G protein activation from the perspective of Gβγ signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738875770.793579982 ◽

2020 ◽

Author(s):

Philip Wedegaertner

Keyword(s):

G Protein ◽

Protein Activation ◽

G Protein Activation ◽

Dissociation Model

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Opioid-Activated Postsynaptic, Inward Rectifying Potassium Currents in Whole Cell Recordings in Substantia Gelatinosa Neurons

Journal of Neurophysiology ◽

10.1152/jn.1998.80.6.2954 ◽

1998 ◽

Vol 80 (6) ◽

pp. 2954-2962 ◽

Cited By ~ 49

Author(s):

S. P. Schneider ◽

W. A. Eckert ◽

A. R. Light

Keyword(s):

Membrane Potential ◽

G Protein ◽

Potassium Currents ◽

Substantia Gelatinosa ◽

Opioid Agonist ◽

Membrane Hyperpolarization ◽

Whole Cell ◽

Protein Activation ◽

G Protein Activation ◽

Whole Cell Recordings

Schneider, S. P., W. A. Eckert III, and A. R. Light. Opioid-activated postsynaptic, inward rectifying potassium currents in whole cell recordings in substantia gelatinosa neurons. J. Neurophysiol. 80: 2954–2962, 1998. Using tight-seal, whole cell recordings from isolated transverse slices of hamster and rat spinal cord, we investigated the effects of the μ-opioid agonist (d-Ala2, N-Me-Phe4,Gly5-ol)-enkephalin (DAMGO) on the membrane potential and conductance of substantia gelatinosa (SG) neurons. We observed that bath application of 1–5 μM DAMGO caused a robust and repeatable hyperpolarization in membrane potential ( V m) and decrease in neuronal input resistance ( R N) in 60% (27/45) of hamster neurons and 39% (9/23) of rat neurons, but significantly only when ATP (2 mM) and guanosine 5′-triphosphate (GTP; 100 μM) were included in the patch pipette internal solution. An ED50 of 50 nM was observed for the hyperpolarization in rat SG neurons. Because G-protein mediation of opioid effects has been shown in other systems, we tested if the nucleotide requirement for opioid hyperpolarization in SG neurons was due to G-protein activation. GTP was replaced with the nonhydrolyzable GTP analogue guanosine-5′- O-(3-thiotriphosphate) (GTP-γ-S; 100 μM), which enabled DAMGO to activate a nonreversible membrane hyperpolarization. Further, intracellular application of guanosine-5′- O-(2-thiodiphosphate) (GDP-β-S; 500 μM), which blocks G-protein activation, abolished the effects of DAMGO. We conclude that spinal SG neurons are particularly susceptible to dialysis of GTP by whole cell recording techniques. Moreover, the depletion of GTP leads to the inactivation of G-proteins that mediate μ-opioid activation of an inward-rectifying, potassium conductance in these neurons. These results explain the discrepancy between the opioid-activated hyperpolarization in SG neurons observed in previous sharp electrode experiments and the more recent failures to observe these effects with whole cell patch techniques.

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