L-Arginine supplementation prevents allodynia and hyperalgesia in painful diabetic neuropathic rats by normalizing plasma nitric oxide concentration and increasing plasma agmatine concentration

Eur J Nutr. 2018 Oct;57(7):2353-2363. doi: 10.1007/s00394-017-1508-x. Epub 2017 Jul 19.


Purpose: Neuropathic pain is a common diabetic complication. It is characterized by symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. L-Arginine is a common precursor of many metabolites of biological interest, in particular, nitric oxide (NO), ornithine, and hence polyamines. In central nervous system, NO, glutamate, and polyamines share an N-methyl-D-aspartate (NMDA) receptor-mediated effect. We hypothesized that a variation in arginine metabolism caused by diabetes may contribute to development and maintenance of neuropathic pain and to the worsening of clinical and biological signs of diabetes.

Methods: We examined whether oral L-arginine supplementation (2.58 ± 0.13 g/l in drinking water for 3 weeks) could improve the development of neuropathic pain and the clinical, biological, and metabolic complications of diabetes in streptozocin (STZ)-induced diabetic (D) rats.

Results: STZ administration induced classical symptoms of type 1 diabetes. Diabetic rats also displayed mechanical hypersensitivity, tactile, and thermal allodynia. Plasma citrulline and NO levels were increased in diabetic hyperalgesic/allodynic rats. L-Arginine supplementation failed to reduce hyperglycaemia, polyphagia, and weight loss. Moreover, it abolished hyperalgesia and allodynia by normalizing NO plasma concentration and increasing plasma agmatine concentration.

Conclusions: L-Arginine supplementation prevented the development of mechanical hyperalgesia, tactile, and thermal allodynia in painful diabetic neuropathy with concomitant reduction of NO and increased agmatine production, offering new therapeutic opportunities for the management of diabetic neuropathic pain.

Keywords: Agmatine; Allodynia; Hyperalgesia; L -Arginine; Neuropathic pain; Nitric oxide; STZ-D rats.

MeSH terms

  • Administration, Oral
  • Agmatine / blood*
  • Animals
  • Arginine / pharmacology*
  • Diabetes Mellitus, Experimental / complications
  • Diabetic Neuropathies / prevention & control*
  • Hyperalgesia / prevention & control*
  • Neuralgia / prevention & control
  • Nitric Oxide / blood*
  • Rats
  • Rats, Sprague-Dawley
  • Streptozocin


  • Nitric Oxide
  • Streptozocin
  • Agmatine
  • Arginine