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Catecholaminergic and opioidergic system mediated effects of reboxetine on diabetic neuropathic pain

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Abstract

Rationale

Current data indicate that the noradrenergic system plays a critical role in neuropathic pain treatment. Notably, drugs that directly affect this system may have curative potential in neuropathy-associated pain.

Objectives

The aim of this study was to evaluate the potential therapeutic efficacy of reboxetine, a potent and selective noradrenaline reuptake inhibitor, on hyperalgesia and allodynia responses in rats with experimental diabetes. Furthermore, mechanistic studies were performed to elucidate the possible mode of actions.

Methods

Experimental diabetes was induced by a single dose of streptozotocin. Mechanical hyperalgesia, mechanical allodynia, thermal hyperalgesia, and thermal allodynia responses in diabetic rats were evaluated by Randall–Selitto, dynamic plantar, Hargreaves, and warm plate tests, respectively.

Results

Reboxetine treatment (8 and 16 mg/kg for 2 weeks) demonstrated an effect comparable to that of the reference drug, pregabalin, improving the hyperalgesic and allodynic responses secondary to diabetes mellitus. Pretreatment with phentolamine, metoprolol, SR 59230A, and atropine did not alter the abovementioned effects of reboxetine; however, the administration of α-methyl-para-tyrosine methyl ester, propranolol, ICI-118,551, SCH-23390, sulpiride, and naltrindole significantly inhibited these effects. Moreover, reboxetine did not induce a significant difference in the rat plasma glucose levels.

Conclusions

Our findings indicate that the antihyperalgesic and antiallodynic effects of reboxetine are mediated by the catecholaminergic system; β2-adrenoceptors; D1-, D2/D3-dopaminergic receptors; and δ-opioid receptors. The results suggest that this analgesic effect of reboxetine, besides its neutral profile on glycemic control, may be advantageous in the pharmacotherapy of diabetic neuropathy–induced pain.

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Funding

This research was supported from the Anadolu University Scientific Research Projects Commission (Project no: 1606S549).

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  1. Department of Pharmacology, Faculty of Pharmacy, Anadolu University, 26470, Eskisehir, Turkey

    Nazlı Turan Yücel, Özgür Devrim Can & Ümide Demir Özkay

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  1. Nazlı Turan Yücel
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  2. Özgür Devrim Can
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  3. Ümide Demir Özkay
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Correspondence to Nazlı Turan Yücel.

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Turan Yücel, N., Can, Ö.D. & Demir Özkay, Ü. Catecholaminergic and opioidergic system mediated effects of reboxetine on diabetic neuropathic pain. Psychopharmacology 237, 1131–1145 (2020). https://doi.org/10.1007/s00213-019-05443-5

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