Adiponectin-Mediated Analgesia and Anti-Inflammatory Effects in Rat.

Tommaso Iannitti,Sharron Dolan,Annette Graham,Theodore John Price

doi:10.1371/journal.pone.0136819

Abstract

The adipose tissue-derived protein, adiponectin, has significant anti-inflammatory properties in a variety of disease conditions. Recent evidence that adiponectin and its receptors (AdipoR1 and AdipoR2) are expressed in central nervous system, suggests that it may also have a central modulatory role in pain and inflammation. This study set out to investigate the effects of exogenously applied recombinant adiponectin (via intrathecal and intraplantar routes; 10–5000 ng) on the development of peripheral inflammation (paw oedema) and pain hypersensitivity in the rat carrageenan model of inflammation. Expression of adiponectin, AdipoR1 and AdipoR2 mRNA and protein was characterised in dorsal spinal cord using real-time polymerase chain reaction (PCR) and Western blotting. AdipoR1 and AdipoR2 mRNA and protein were found to be constitutively expressed in dorsal spinal cord, but no change in mRNA expression levels was detected in response to carrageenan-induced inflammation. Adiponectin mRNA, but not protein, was detected in dorsal spinal cord, although levels were very low. Intrathecal administration of adiponectin, both pre- and 3 hours post-carrageenan, significantly attenuated thermal hyperalgesia and mechanical hypersensitivity. Intrathecal administration of adiponectin post-carrageenan also reduced peripheral inflammation. Intraplantar administration of adiponectin pre-carrageenan dose-dependently reduced thermal hyperalgesia but had no effect on mechanical hypersensitivity and peripheral inflammation. These results show that adiponectin functions both peripherally and centrally at the spinal cord level, likely through activation of AdipoRs to modulate pain and peripheral inflammation. These data suggest that adiponectin receptors may be a novel therapeutic target for pain modulation.

Highlights

Adiponectin, an anti-inflammatory adipokine lowered in plasma in individuals with obesity, is known to have significant anti-inflammatory, anti-atherogenic, anti-apoptotic, and insulinsensitising properties [1, 2]
Recent work in this laboratory reported that adiponectin, adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) mRNAs are expressed in rat spinal cord [18], suggesting that a local adiponectin signalling system may exist at this level
Adiponectin, AdipoR1 and AdipoR2 mRNA were constitutively expressed in spinal cord

Summary

Introduction

Adiponectin, an anti-inflammatory adipokine lowered in plasma in individuals with obesity, is known to have significant anti-inflammatory, anti-atherogenic, anti-apoptotic, and insulinsensitising properties [1, 2]. Evidence that intra-articular administration of adiponectin reduces the severity of collagen-induced arthritis in mouse [6], through modulation of tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and matrix metalloproteinase (MMP)-3 in joint tissue, suggested that adiponectin may play a role in pain pathophysiology. The seven-transmembrane domain adiponectin receptors AdipoR1 and AdipoR2 are widely distributed in brain [13,14,15,16,17], where they are involved in regulation of energy homeostasis, food intake and autonomic functions [10] Recent work in this laboratory reported that adiponectin, AdipoR1 and AdipoR2 mRNAs are expressed in rat spinal cord [18], suggesting that a local adiponectin signalling system may exist at this level. The aim of this study was to investigate whether adiponectin has anti-inflammatory and anti-hyperalgesic effects when administered centrally at the spinal level, compared to peripheral administration, in a well characterised rodent model of peripheral inflammation

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