title: The furoxan nitric oxide donor, PRG150, evokes dose-dependent analgesia in a rat model of painful diabetic neuropathy.
abstract: Painful diabetic neuropathy (PDN) is a type of peripheral neuropathic pain that is often intractable. Elevated nitric oxide (NO) from neuronal and non-neuronal sources in the somatosensory system is implicated in the pathobiology of peripheral neuropathic pain. However, in diabetes, nitrergic nerve degeneration to deplete NO bioactivity appears causal in the pathogenesis of irreversible autonomic neuropathy, another long term complication of diabetes. Hence, this study hypothesized that progressive NO depletion may underpin the pathobiology of PDN and that NO donors may alleviate PDN. Diabetes was induced in rats with intravenous streptozotocin (STZ) at 70 mg/kg and confirmed if blood glucose levels (BGLs) on day 10 post-STZ were ≥15 mmol/L. Analgesic efficacy of subcutaneous (s.c.) bolus doses of the furoxan NO donor, PRG150 was assessed in the STZ-diabetic rat model of PDN at 10-, 14- and 24-weeks post-STZ relative to the sydnominine NO donor, SIN-1 and its prodrug, molsidomine. PRG150 produced dose-dependent analgesia in STZ-diabetic rats whereas SIN-1 and molsidomine evoked neuro-excitatory side-effects, but not analgesia. The 1000-fold larger doses of PRG150 needed to produce analgesia at 14- and 24-weeks (800 pmol/kg) c.f. 10-weeks (8 fmol/kg) post-STZ in rats, suggest that progressive NO depletion is also causal in PDN. Importantly, doses of PRG150 up to 10 000 fold higher than the analgesic dose did not produce hypotension in rats. The 50-fold greater release of NO by SIN-1 c.f. PRG150 in vitro, may underpin the neuro-excitatory rather than analgesic effects of SIN-1/molsidomine. PRG150 is worthy of further investigation as a potential novel analgesic for PDN.
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Qld, Australia.|School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Lillian Y
authors.initials: LY
authors.lastname: Huang
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Qld, Australia.|School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Debbie Y
authors.initials: DY
authors.lastname: Tsui
authors.affiliation: Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Williams
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Qld, Australia.|School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Wyse
authors.affiliation: Centre for Integrated Preclinical Drug Development, The University of Queensland, Brisbane, Qld, Australia.|School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Maree T
authors.initials: MT
authors.lastname: Smith
keywords: 3-methylfuroxan-4-carbaldehyde; 3-morpholinosydnonimine; NO donor; impaired NO bioactivity; nitric oxide; nitric oxide synthase; painful diabetic neuropathy