Curcumin attenuates thermal hyperalgesia in a diabetic mouse model of neuropathic pain

Abstract

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus is recognised as one of the most difficult types of pain to treat. A lack of the understanding of its aetiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of the newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect of curcumin and its effect on tumour necrosis factor-α (TNF-α) and nitric oxide (NO) release in streptozotocin induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia along with increased plasma glucose and decreased body weights as compared with control mice. Chronic treatment with curcumin (15, 30 and 60 mg/kg body weight; p.o.) for 4 weeks starting from the 4th week of streptozotocin injection significantly attenuated thermal hyperalgesia and the hot-plate latencies. Curcumin also inhibited the TNF-α and NO release in a dose dependent manner. These results indicate an antinociceptive activity of curcumin possibly through its inhibitory action on NO and TNF-α release and point towards its potential to attenuate diabetic neuropathic pain.

Introduction

Neuropathic pain is generally considered to be one of the most common complications of diabetes, affecting both types of diabetes equally (Clark and Lee, 1995, Guy et al., 1985). It is mostly characterised by pain that can occur spontaneously as a result of exposure to mild painful stimuli, i.e., hyperalgesia (Brown and Asbury, 1984). Although neuronal loss or alteration of neurotransmitters (Greene et al., 1987) have been reported to be responsible for the changed pain perception, the exact etiologic factors remains unexplored. Several new drugs such as nonsteroidal anti-inflammatory drugs, antidepressants, anticonvulsants and opioids are currently under investigation in the management of diabetic neuropathic pain (James et al., 1999), but the treatment with these drugs is limited because of their partial effectiveness and potential toxicity (Arner and Meyerson, 1998, Courteix et al., 1993).

Renewed interest has been observed in recent years on the multiple activities of natural flavonoids. Curcumin, a yellow pigment from Curcuma longa, is a major component of turmeric and exhibits anticarcinogenic and anti-inflammatory properties including an inhibitory effect on the production of interleukin-8 (IL-8), interleukin-1β (IL-1β) and TNF-α by lipopolysaccharide stimulated monocytes and alveolar macrophages (Chan, 1995). Curcumin most likely inhibits cell proliferation, cell-mediated cytotoxicity and cytokine production by inhibiting nuclear factor-kappaB (NF-κB) target genes involved in induction of these immune responses (Gao et al., 2004). Studies have revealed that increased concentration of TNF-α correlates well with increased concentrations of NF-κB as observed in Caco-2 cell lines (Mao et al., 2004). Low concentrations of curcumin have also been found to inhibit nitric oxide production, as measured by the amount of nitrite released into the culture medium (Johnston and DeMaster, 2003). Together with the ability of curcumin to inhibit NO and TNF-α release which cause nitrosative stress in diabetes and promote pain and inflammatory signals, respectively, the present study was designed to evaluate the effect of curcumin in diabetic neuropathic pain and an attempt was made to look for the participation of NO and TNF-α in curcumin's antinociceptive effect.