Critical evaluation of the streptozotocin model of painful diabetic neuropathy in the rat.
Streptozotocin (STZ)-induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy to assess the efficacies of potential analgesic agents. We have established this model, and here we question whether the changes in nocifensive reflex activity, used as a measure of hyperalgesia, are genuinely indicative of peripheral neuropathy or may rather be attributed to the extreme poor health of the animals. For comparison we have examined animals with peripheral neuropathy induced by partial ligation of the sciatic nerve. Diabetic animals were chronically ill, with reduced growth rate, polyuria, diarrhoea, and had enlarged and distended bladders. Indicative of their poor health, diabetic animals showed markedly reduced motor activity. In contrast, following partial sciatic nerve ligation rats showed none of these adverse effects and their motor activity was not different to naive animals. Diabetic animals displayed marked mechanical hyperalgesia, and some thermal hypoalgesia. Morphine and L-baclofen partially reversed established STZ-induced mechanical hyperalgesia, whilst the NK-1 receptor-antagonist RP-67580, the NMDA-antagonists MK801 and ketamine, and the nitric oxide synthase inhibitor L-NAME were without significant effect. Morphine and L-baclofen produced greater reversal of mechanical hyperalgesia following partial nerve ligation, although RP67580 and MK801 showed little or no activity. These data confirm previous findings that STZ-induced diabetes in rats produces long-lasting mechanical, but not thermal hyperalgesia. In our experience this mechanical hyperalgesia is largely resistant to a range of pharmacological tools. However, we feel that the profound ill-health of the animals, together with the poor activity of a range of potential analgesic drugs, must raise questions on the predictive value of these animals as a model for the human condition of chronic diabetic pain seen in patients receiving long-term insulin treatment, as well as ethical concerns on the use of the animals themselves.
Fox
Alyson
A
Novartis Institute for Medical Sciences, 5 Gower Place, London WC1E 6BN, UK Novartis Pharma Corporation, East Hannover, NJ, USA.
Eastwood
Christopher
C
Gentry
Clive
C
Manning
Donald
D
Urban
Laszlo
L
D000818:Animals; D001418:Baclofen / Q000009:adverse effects / Q000627:therapeutic use; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000209:etiology; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology*; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D009020:Morphine / Q000009:adverse effects / Q000627:therapeutic use; D010146:Pain / Q000209:etiology; D010147:Pain Measurement; D017288:Pain Threshold; D010523:Peripheral Nervous System Diseases / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000601:surgery; D013311:Streptozocin
D007328:Insulin; D013311:Streptozocin; D009020:Morphine; D001418:Baclofen