J-2156, a small molecule somatostatin type 4 receptor agonist, alleviated hindpaw hypersensitivity in the streptozotocin-induced rat model of painful diabetic neuropathy but with a 2-fold decrease in potency at an advanced stage in the model, mimicking morphine
Copyright © 2024 Kuo, Imam, Li, Lin, Raboczyj, Bohmer, Nicholson, Corradini and Smith..
There is a large unmet need for novel pain-killers to improve relief of painful diabetic neuropathy (PDN). Herein, we assessed the efficacy of the somatostatin type 4 (SST4) receptor agonist, J-2156, for relief of PDN in rats. Diabetes was induced with streptozotocin (STZ; 70 mg/kg) and bilateral hindpaw hypersensitivity was fully developed by 8-week post-STZ. In the intervals, 8-12-weeks (morphine-sensitive phase; Phase 1) and 16-18-weeks (morphine-hyposensitive phase; Phase 2) post-STZ, rats received a single dose of intraperitoneal (i.p.) J-2156 (10, 20, 30 mg/kg), gabapentin (100 mg/kg i.p.), subcutaneous morphine (1 mg/kg) or vehicle. Hindpaw withdrawal thresholds (PWTs) were assessed using von Frey filaments pre-dose and at regular intervals over 3-h post-dose. In Phase 1, J-2156 at 30 mg/kg evoked significant anti-allodynia in the hindpaws with maximal effect at 1.5 h compared with 1 h for gabapentin and morphine. The durations of action for all three compounds were greater than 3 h. The corresponding mean (±SEM) extent and duration of anti-allodynia (ΔPWT AUC) for gabapentin did not differ significantly from that for J-2156 (30 mg/kg) or morphine. However, in Phase 2, the ΔPWT AUC for morphine was reduced to approximately 25% of that in Phase 1, mirroring our previous work. Similarly, the mean (±SEM) ΔPWT AUC for J-2156 (30 mg/kg) in Phase 2 was approximately 45% of that for Phase 1 whereas for gabapentin the mean (±SEM) ΔPWT AUCs did not differ significantly (p > 0.05) between the two phases. Our findings further describe the preclinical pain relief profile of J-2156 and complement previous work in rat models of inflammatory pain, neuropathic pain and low back pain. SST4 receptor agonists hold promise as novel therapeutics for the relief of PDN, a type of peripheral neuropathic pain that is often intractable to relief with clinically used drug treatment options.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Frontiers in pharmacology - 15(2024) vom: 28., Seite 1346801 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Kuo, A [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Anti-allodynia |
|---|
| Anmerkungen: |
Date Revised 07.02.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.3389/fphar.2024.1346801 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM368073882 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM368073882 | ||
| 003 | DE-627 | ||
| 005 | 20240207232344.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240206s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3389/fphar.2024.1346801 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1283.xml |
| 035 | |a (DE-627)NLM368073882 | ||
| 035 | |a (NLM)38318132 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Kuo, A |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a J-2156, a small molecule somatostatin type 4 receptor agonist, alleviated hindpaw hypersensitivity in the streptozotocin-induced rat model of painful diabetic neuropathy but with a 2-fold decrease in potency at an advanced stage in the model, mimicking morphine |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 07.02.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Copyright © 2024 Kuo, Imam, Li, Lin, Raboczyj, Bohmer, Nicholson, Corradini and Smith. | ||
| 520 | |a There is a large unmet need for novel pain-killers to improve relief of painful diabetic neuropathy (PDN). Herein, we assessed the efficacy of the somatostatin type 4 (SST4) receptor agonist, J-2156, for relief of PDN in rats. Diabetes was induced with streptozotocin (STZ; 70 mg/kg) and bilateral hindpaw hypersensitivity was fully developed by 8-week post-STZ. In the intervals, 8-12-weeks (morphine-sensitive phase; Phase 1) and 16-18-weeks (morphine-hyposensitive phase; Phase 2) post-STZ, rats received a single dose of intraperitoneal (i.p.) J-2156 (10, 20, 30 mg/kg), gabapentin (100 mg/kg i.p.), subcutaneous morphine (1 mg/kg) or vehicle. Hindpaw withdrawal thresholds (PWTs) were assessed using von Frey filaments pre-dose and at regular intervals over 3-h post-dose. In Phase 1, J-2156 at 30 mg/kg evoked significant anti-allodynia in the hindpaws with maximal effect at 1.5 h compared with 1 h for gabapentin and morphine. The durations of action for all three compounds were greater than 3 h. The corresponding mean (±SEM) extent and duration of anti-allodynia (ΔPWT AUC) for gabapentin did not differ significantly from that for J-2156 (30 mg/kg) or morphine. However, in Phase 2, the ΔPWT AUC for morphine was reduced to approximately 25% of that in Phase 1, mirroring our previous work. Similarly, the mean (±SEM) ΔPWT AUC for J-2156 (30 mg/kg) in Phase 2 was approximately 45% of that for Phase 1 whereas for gabapentin the mean (±SEM) ΔPWT AUCs did not differ significantly (p > 0.05) between the two phases. Our findings further describe the preclinical pain relief profile of J-2156 and complement previous work in rat models of inflammatory pain, neuropathic pain and low back pain. SST4 receptor agonists hold promise as novel therapeutics for the relief of PDN, a type of peripheral neuropathic pain that is often intractable to relief with clinically used drug treatment options | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a J-2156 | |
| 650 | 4 | |a SST4 receptor | |
| 650 | 4 | |a anti-allodynia | |
| 650 | 4 | |a morphine | |
| 650 | 4 | |a pain relief | |
| 650 | 4 | |a painful diabetic neuropathy (PDN) | |
| 650 | 4 | |a rat model | |
| 700 | 1 | |a Imam, M Z |e verfasserin |4 aut | |
| 700 | 1 | |a Li, R |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, L |e verfasserin |4 aut | |
| 700 | 1 | |a Raboczyj, A |e verfasserin |4 aut | |
| 700 | 1 | |a Bohmer, A E |e verfasserin |4 aut | |
| 700 | 1 | |a Nicholson, J R |e verfasserin |4 aut | |
| 700 | 1 | |a Corradini, L |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, M T |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Frontiers in pharmacology |d 2010 |g 15(2024) vom: 28., Seite 1346801 |w (DE-627)NLM208568891 |x 1663-9812 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2024 |g day:28 |g pages:1346801 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3389/fphar.2024.1346801 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2024 |b 28 |h 1346801 | ||