A novel gabapentin analogue assuages neuropathic pain response in chronic sciatic nerve constriction model in rats

Ahmad, Nisar; Subhan, Fazal; Islam, Nazar Ul; Shahid, Muhammad; Ullah, Naseem; Ullah, Rahim; Akbar, Shehla; Amin, Muhammad Usman; Khurram, Muhammad; Ullah, Ihsan; Sewell, Robert David Edmund

doi:10.1016/j.bbr.2021.113190

Cited by 7 publications

(1 citation statement)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, there were no overt signs of sedation at any of the doses of J-2156 administered and CNS side-effects would not be expected as J-2156 has a limited ability to cross the blood-brain-barrier (BBB) ( Schuelert et al, 2015 ). Nevertheless, in future work beyond the scope of this investigation, we intend to formally assess the effects of J-2156 relative to gabapentin and morphine on motor incoordination as quantitative measures of sedation using the rotarod test as described by others ( Ahmad et al, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

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

Kuo,

Imam,

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%