Impaired defense mechanism against inflammation, hyperalgesia, and airway hyperreactivity in somatostatin 4 receptor gene-deleted mice. Proc Natl Acad Sci USA

Department of Pharmacology and Pharmacotherapy, Institute of Pharmacognosy, Analgesic Research Laboratory of Gedon Richter Plc., University of Pécs, H-7624 Pécs, Hungary.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2009; 106(31):13088-13093. DOI: 10.1073/pnas.0900681106

ABSTRACT We have shown that somatostatin released from activated capsaicin-sensitive nociceptive nerve endings during inflammatory
processes elicits systemic anti-inflammatory and analgesic effects. With the help of somatostatin receptor subtype 4 gene–deleted
mice (sst4−/−), we provide here several lines of evidence that this receptor has a protective role in a variety of inflammatory disease
models; several symptoms are more severe in the sst4 knockout animals than in their wild-type counterparts. Acute carrageenan-induced paw edema and mechanical hyperalgesia, inflammatory
pain in the early phase of adjuvant-evoked chronic arthritis, and oxazolone-induced delayed-type hypersensitivity reaction
in the skin are much greater in mice lacking the sst4 receptor. Airway inflammation and consequent bronchial hyperreactivity elicited by intranasal lipopolysaccharide administration
are also markedly enhanced in sst4 knockouts, including increased perivascular/peribronchial edema, neutrophil/macrophage infiltration, mucus-producing goblet
cell hyperplasia, myeloperoxidase activity, and IL-1β, TNF-α, and IFN-γ expression in the inflamed lung. It is concluded that
during these inflammatory conditions the released somatostatin has pronounced counterregulatory effects through sst4 receptor activation. Thus, this receptor is a promising novel target for developing anti-inflammatory, analgesic, and anti-asthmatic

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    • "The activity of this enzyme correlates with the amount of neutrophils and macrophages and is a widely used biochemical marker for the evaluation of the inflammatory reaction intensity. MPO activity from the lung homogenates was measured with spectrophotometry using H 2 O 2 -3,3 ,5,5 -tetramethyl-benzidine (TMB/H 2 O 2 ) and compared to a human standard MPO preparation as described earlier in detail [18]. All reagents used for this assay were purchased form Sigma, St. Louis, MO, USA. "
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    ABSTRACT: Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (Tac4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions. Since there is no information on its functions in the airways, we investigated its role in endotoxin-induced pulmonary inflammation. Acute pneumonitis was induced in Tac4 gene-deleted (Tac4(-/-)) mice compared to C57Bl/6 wildtypes by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24h later. Semiquantitative histopathological scoring was performed; reactive oxygen species (ROS) production was measured with luminol bioluminescence, myeloperoxidase activity with spectrophotometry, and inflammatory cytokines with Luminex. All inflammatory parameters, such as histopathological alterations (perivascular edema, neutrophil/macrophage accumulation, goblet cell hyperplasia), myeloperoxidase activity, ROS production, as well as interleukin-1beta, interleukin-6 and keratinocyte chemoattractant concentrations were significantly diminished in the lung of Tac4(-/-) mice. However, bronchial hyperreactivity similarly developed in both groups. Interestingly, in LPS-treated Tac4(-/-) mouse lungs, bronchus-associated, large, follicle-like lymphoid structures developed. We provide the first evidence that hemokinin-1 plays a crucial pro-inflammatory role in the lung by increasing inflammatory cell activities, but might be a specific regulator of lymphocyte functions. Copyright © 2014. Published by Elsevier Inc.
    Peptides 12/2014; 64. DOI:10.1016/j.peptides.2014.12.002 · 2.62 Impact Factor
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    • "Thus, this compound has analgesic effects in several pain models [31]. Moreover, sst4 KO mice exhibit an impaired defense against inflammation and hyperalgesia [30]. However, it is assumed that these sst4 not necessarily are located on neurons in DRGs or spinal cord [30]. "
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    ABSTRACT: Somatostatin (SST) and some of its receptor subtypes have been implicated in pain signaling at the spinal level. In this study we have investigated the role of SST and its sst2A receptor (sst2A) in dorsal root ganglia (DRGs) and spinal cord. SST and sst2A protein and sst2 transcript were found in both mouse and human DRGs, sst2A-immunoreactive (IR) cell bodies and processes in lamina II in mouse and human spinal dorsal horn, and sst2A-IR nerve terminals in mouse skin. The receptor protein was associated with the cell membrane. Following peripheral nerve injury sst2A-like immunoreactivity (LI) was decreased, and SST-LI increased in DRGs. sst2A-LI accumulated on the proximal and, more strongly, on the distal side of a sciatic nerve ligation. Fluorescence-labeled SST administered to a hind paw was internalized and retrogradely transported, indicating that a SST-sst2A complex may represent a retrograde signal. Internalization of sst2A was seen in DRG neurons after systemic treatment with the sst2 agonist octreotide (Oct), and in dorsal horn and DRG neurons after intrathecal administration. Some DRG neurons co-expressed sst2A and the neuropeptide Y Y1 receptor on the cell membrane, and systemic Oct caused co-internalization, hypothetically a sign of receptor heterodimerization. Oct treatment attenuated the reduction of pain threshold in a neuropathic pain model, in parallel suppressing the activation of p38 MAPK in the DRGs CONCLUSIONS: The findings highlight a significant and complex role of the SST system in pain signaling. The fact that the sst2A system is found also in human DRGs and spinal cord, suggests that sst2A may represent a potential pharmacologic target for treatment of neuropathic pain.
    Molecular Pain 02/2014; 10(1):12. DOI:10.1186/1744-8069-10-12 · 3.65 Impact Factor
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    • "Neurogenic and non-neurogenic inflammatory processes were significantly reduced upon administration of SSTR4 specific agonist in animal models [22]. Recently, SSTR specific knockout (ko) models have provided new insights for the role of SSTRs in certain pathophysiological conditions such as inflammation and analgesia [22], [23]. Helyes et al., have described that SSTR4 ko mice are more susceptible to inflammation and exhibit sustained pain than wt mice [23]. "
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    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.
    PLoS ONE 01/2014; 9(1):e85193. DOI:10.1371/journal.pone.0085193 · 3.23 Impact Factor
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