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In our previous work using the streptozotocin (STZ)\u2010diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3\u00a0months post\u2010STZ and maintained for 6\u00a0months post\u2010STZ. As this time course mimicked that for the temporal development of hyposensitivity to the pain\u2010relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3\u2010methylfuroxan\u20104\u2010carbaldehyde) in STZ\u2010diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ\u2010diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85\u00a0mg\/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were \u226515\u00a0mmol\/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3\u00a0weeks of STZ\u2010diabetes in rats and this was maintained for the study duration. Morphine hyposensitivity developed in a temporal manner with efficacy abolished by 3\u00a0months post\u2010STZ. Administration of dietary <jats:sc>l<\/jats:sc>\u2010arginine (NO precursor) at 1\u00a0g\/d to STZ\u2010diabetic rats according to a 15\u2010week prevention protocol initiated at 9\u00a0weeks post\u2010STZ prevented abolition of morphine efficacy. When given as an 8\u2010week intervention protocol in rats where morphine efficacy was abolished, dietary <jats:sc>l<\/jats:sc>\u2010arginine at 1\u00a0g\/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine hyposensitivity in STZ\u2010diabetic rats.<\/jats:p>","DOI":"10.1111\/1440-1681.12855","type":"journal-article","created":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T10:36:37Z","timestamp":1505817397000},"page":"42-49","source":"Crossref","is-referenced-by-count":6,"title":["Morphine hyposensitivity in streptozotocin\u2010diabetic rats: Reversal by dietary <scp>l<\/scp>\u2010arginine treatment"],"prefix":"10.1111","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2425-1096","authenticated-orcid":false,"given":"Shahrdad","family":"Lotfipour","sequence":"first","affiliation":[{"name":"School of Pharmacy Faculty of Health and Behavioural Sciences The University of Queensland  Brisbane Qld Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2281-3734","authenticated-orcid":false,"given":"Maree 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