Longitudinal study of painful diabetic neuropathy in the Zucker diabetic fatty rat model of type 2 diabetes: Impaired basal G-protein activity appears to underpin marked morphine hyposensitivity at 6 months

Otto, Kathleen J., Wyse, Bruce D., Cabot, Peter J. and Smith, Maree T. (2011) Longitudinal study of painful diabetic neuropathy in the Zucker diabetic fatty rat model of type 2 diabetes: Impaired basal G-protein activity appears to underpin marked morphine hyposensitivity at 6 months. Pain Medicine, 12 3: 437-450. doi:10.1111/j.1526-4637.2011.01067.x


Author Otto, Kathleen J.
Wyse, Bruce D.
Cabot, Peter J.
Smith, Maree T.
Title Longitudinal study of painful diabetic neuropathy in the Zucker diabetic fatty rat model of type 2 diabetes: Impaired basal G-protein activity appears to underpin marked morphine hyposensitivity at 6 months
Journal name Pain Medicine   Check publisher's open access policy
ISSN 1526-2375
1526-4637
Publication date 2011-03
Sub-type Article (original research)
DOI 10.1111/j.1526-4637.2011.01067.x
Volume 12
Issue 3
Start page 437
End page 450
Total pages 14
Place of publication Malden, MA, U.S.A.
Publisher Blackwell Science
Collection year 2012
Language eng
Formatted abstract
Objectives. 
Epidemiological studies in patients with type 1 and type 2 diabetes show that hyperglycemia is associated with the development of long-term microvascular complications, including painful diabetic neuropathy (PDN). However, as the prevalence of type 2 diabetes in humans far exceeds that of type 1, the present study was undertaken as a 22-week longitudinal investigation commencing at 7 weeks of age, to assess the utility of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes for the study of PDN.

Design.
Behavioral methods were used to characterize temporal changes in hindpaw sensitivity as well as morphine potency in these animals. The effect of long-term diabetes on µ-opioid receptor function and mRNA expression levels in the spinal cord was also assessed.

Results.
Diabetes developed spontaneously in ZDF rats with marked hyperglycemia (blood glucose levels ≥ 15 mM) evident by 11 weeks of age, which was maintained until study completion at 29 weeks. In ZDF rats, there was progressive development of mechanical allodynia in the hindpaws such that it was fully developed by 6 months of age. Concurrently, there was temporal loss of opioid sensitivity in these animals such that marked morphine hyposensitivity was evident at 6 months. In the spinal cord, basal G-protein function was significantly impaired at 29 weeks of age, resulting in apparently reduced agonist-stimulated µ-opioid receptor function compared with the prediabetic state.

Conclusions.
Together, our findings suggest that impaired basal G-protein activity underpins morphine hyposensitivity in PDN.

Clinical Relevance. 
Clinical management of diabetic neuropathic pain has been challenging. This study provides a mechanistic explanation regarding the effectiveness, or lack thereof, of opioid analgesia in the treatment of diabetic neuropathic pain.
Keyword Painful Diabetic Neuropathy
Mechanical Allodynia
Morphine Hyposensitivity
Zucker Diabetic Fatty Rats
Opioid Receptor
Impaired Basal G-Protein Activity
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
School of Pharmacy Publications
Centre for Integrated Preclinical Drug Development Publications
 
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Created: Mon, 21 Feb 2011, 12:45:27 EST by Professor Maree Smith on behalf of School of Pharmacy