stilbenes and Neuralgia

We previously showed that subsequent intrathecal (i.t.) injection of resveratrol (30 μg) significantly reverses morphine-evoked neuroinflammation in morphine-tolerant rats. The present study examined the underlying mechanism.. Male Wistar rats were implanted with two i.t. catheters, one of which was connected to a miniosmotic pump and used for morphine (15 μg/h) or saline infusion for 120 hours. To examine the effects on spinal cord expression of histone deacetylase 1 (HDAC1), the inflammatory cytokine tumor necrosis factor-α (TNF-α), and TNF receptor (TNFR) 1 and TNFR2 during tolerance induction, a tail-flick test was performed prior to infusion and after 24 hours, 48 hours, 72 hours, 96 hours, and 120 hours of infusion.. Resveratrol treatment prior to morphine challenge restored the antinociceptive effect of morphine in morphine-tolerant rats and reversed the morphine infusion-induced increase in HDAC1, TNF-α, and TNFR1 expression. Moreover, chronic morphine infusion increased TNFR1-specific expression in neuron in morphine-tolerant rat spinal cords, and this effect was almost completely inhibited by resveratrol treatment prior to morphine challenge.. Resveratrol restores the antinociceptive effect of morphine by reversing morphine infusion-induced spinal cord neuroinflammation and increase in TNFR1 expression. The reversal of the morphine-induced increase in TNFR1 expression by resveratrol is partially due to reversal of the morphine infusion-induced increase in HDAC1 expression. Resveratrol pretreatment can be used as an adjuvant in clinical pain management for patients who need long-term morphine treatment or with neuropathic pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cytokines; Drug Tolerance; Histone Deacetylase 1; Injections, Spinal; Male; Morphine; Neuralgia; Rats; Rats, Wistar; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Resveratrol; Spinal Cord; Stilbenes; Tumor Necrosis Factor-alpha

Anti-inflammatory activity of resveratrol has been widely studied, while its beneficial effect on the management of neuropathic pain, a refractory chronic syndrome with pro-inflammation implicated in, is very little investigated. In the present study, the effects of different doses and various time window of administration of resveratrol were explored in a neuropathic mouse model of chronic constriction injury (CCI) of the sciatic nerve. It was demonstrated that pretreatment of resveratrol (5, 10, 20 and 40 mg/kg) for 7 consecutive days before CCI did not alleviate neuropathic pain, while it clearly relieved the pain when administrated after CCI and such pain relief effect was more pronounced when administrated right after the peak of pain symptom at day 7 after CCI, as evidenced by the alleviation of thermal hyperalgesia and mechanical allodynia. Such a beneficial effect of resveratrol was in a dose-dependent manner. Mechanistic study showed that resveratrol repressed the expression of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, and promoted the expression of anti-inflammatory cytokine IL-10 at the same time, which was further confirmed in a cell model of microglia. It was also shown that neuropathic pain inversely correlated with pro-inflammatory cytokines, such as TNF-α, IL-1β and IL-6, but not with anti-inflammatory cytokine IL-10 in all experimental mice from Spearman correlation coefficient. Our study reveals that resveratrol displays a significant neuropathic pain relief effect and paved a way for novel treatment of chronic pain.

Topics: Animals; Anti-Inflammatory Agents; Cells, Cultured; Cytokines; Disease Models, Animal; Female; Humans; Hyperalgesia; Mice; Mice, Inbred BALB C; Microglia; Neuralgia; Neurogenic Inflammation; Resveratrol; Sciatic Nerve; Stilbenes; Th1-Th2 Balance

Patients suffering from chronic neuropathic pain are at high risk of co-morbid depression, which burdens healthcare. This work aimed to investigate the effects of resveratrol, a phenolic monomer enriched in red wine and grapes, on pain-related and depressive-like behaviors in mice with mononeuropathy, and explored the mechanism(s). Mice received chronic constriction injury (CCI) of sciatic nerves, and sequentially developed pain-related and depressive-like behaviors, as evidenced by sensory hypersensitivity (thermal hyperalgesia in Hargreaves test and mechanical allodynia in von Frey test) and behavioral despair (prolonged immobility time in forced swim test). Chronic treatment of neuropathic mice with resveratrol (30 mg/kg, p.o., twice per day for three weeks) normalized their thermal hyperalgesia (but not mechanical allodynia) and depressive-like behaviors, and these actions were abolished by chemical depletion of central serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. The anti-hyperalgesia and anti-depression exerted by resveratrol may be pharmacologically segregated, since intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of methysergide, a non-selective 5-HT receptor antagonist, separately abrogated the two actions. Furthermore, the antihyperalgesic action of resveratrol was preferentially counteracted by co-administration of the 5-HT7 receptor antagonist SB-258719, while the anti-depression was abrogated by 5-HT1A receptor antagonist WAY-100635. These results confirm that chronic resveratrol administration exerts curative-like effects on thermal hyperalgesia and co-morbid depressive-like behaviors in mice with mononeuropathy. Spinal and supraspinal serotonergic systems (coupled with 5-HT7 and 5-HT1A receptors, respectively) are differentially responsible for the antihyperalgesic and antidepressant-like properties of resveratrol.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents; Brain; Comorbidity; Constriction, Pathologic; Depression; Disease Models, Animal; Hot Temperature; Hyperalgesia; Male; Mice, Inbred C57BL; Neuralgia; Receptor, Serotonin, 5-HT1A; Receptors, Serotonin; Resveratrol; Sciatic Neuropathy; Spinal Cord; Stilbenes; Touch

Abnormal histone acetylation occurs during neuropathic pain through an epigenetic mechanism. Silent information regulator 1 (sir2 or SIRT1), a NAD-dependent deacetylase, plays complex systemic roles in a variety of processes through deacetylating acetylated histone and other specific substrates. But the role of SIRT1 in neuropathic pain is not well established yet. The present study was intended to detect SIRT1 content and activity, nicotinamide (NAM) and nicotinamide adenine dinucleotide (NAD) in the spinal cord using immunoblotting or mass spectroscopy over time in mice following chronic constriction injury (CCI) or sham surgery. In addition, the effect of intrathecal injection of NAD or resveratrol on thermal hyperalgesia and mechanical allodynia was evaluated in CCI mice. Finally, we investigated whether SIRT1 inhibitor EX-527 could reverse the anti-nociceptive effect of NAD or resveratrol. It was found that spinal SIRT1 expression, deacetylase activity and NAD/NAM decreased significantly 1, 3, 7, 14 and 21 days after CCI surgery as compared with sham group. In addition, daily intrathecal injection of 5 µl 800 mM NAD 1 h before and 1 day after CCI surgery or single intrathecal injection of 5 µl 90 mM resveratrol 1 h before CCI surgery produced a transient inhibitory effect on thermal hyperalgesia and mechanical allodynia in CCI mice. Finally, an intrathecal injection of 5 µl 1.2 mM EX-527 1 h before NAD or resveratrol administration reversed the anti-nociceptive effect of NAD or resveratrol. These data indicate that the reduction in SIRT1 deacetylase activity may be a factor contributing to the development of neuropathic pain in CCI mice. Our findings suggest that the enhancement of spinal NAD/NAM and/or SIRT1 activity may be a potentially promising strategy for the prevention or treatment of neuropathic pain.

Topics: Animals; Down-Regulation; Hyperalgesia; Male; Mice; Mice, Inbred Strains; NAD; Neuralgia; Niacinamide; Resveratrol; Sirtuin 1; Spinal Cord; Stilbenes

The present study investigated whether combination of resveratrol and 4-amino 1,8 naphthalimide (4-ANI) is effective in the development of diabetic neuropathy (DN). After 6 weeks of diabetes induction, rats were treated for 2 weeks with resveratrol and 4-amino 1,8 naphthalimide (4-ANI) either alone or in combination. Experimental end points included functional, behavioural and biochemical parameters along with PAR immunohistochemistry and were performed at the end of treatment. Combination of resveratrol (10 mg/kg) and 4-ANI (3 mg/kg) attenuated conduction and nerve blood flow deficits and resulted in amelioration of diabetic neuropathic pain. Significant reversal of biochemical alterations (peroxynitrite, MDA and NAD levels) were also observed, as well as PAR accumulation in the sciatic nerve. This study suggests the beneficial effect of combining resveratrol and 4-ANI in experimental diabetic neuropathy.

Topics: 1-Naphthylamine; Animals; Antioxidants; Diabetic Neuropathies; Male; Malondialdehyde; NAD; Naphthalimides; Neural Conduction; Neuralgia; Neuroprotective Agents; Oxidative Stress; Pain Measurement; Peroxynitrous Acid; Poly Adenosine Diphosphate Ribose; Quinolones; Rats; Rats, Sprague-Dawley; Resveratrol; Sciatic Nerve; Stilbenes

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, has been recognized as one of the most difficult types of pain to treat. The underlying mechanisms of painful symptoms may be closely associated with hyperglycaemia but a lack of the understanding of its proper 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 resveratrol on diabetic neuropathic pain and to examine its effect on serum tumour necrosis factor-alpha (TNF-alpha) and whole brain nitric oxide (NO) release. Four weeks after a single intraperitoneal injection of streptozotocin (STZ, 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 when compared with control mice. Daily treatment with resveratrol (5, 10 and 20 mg/kg body weight; p.o.) for 4 weeks starting from the 4th week of STZ injection significantly attenuated thermal hyperalgesia. Resveratrol also decreased the serum TNF-alpha levels and whole brain NO release in a dose-dependent manner. These results point towards the potential of resveratrol in attenuating diabetic neuropathic pain.

Topics: Analgesics, Non-Narcotic; Animals; Brain; Diabetes Mellitus, Experimental; Hot Temperature; Hyperalgesia; Male; Mice; Mice, Inbred Strains; Neuralgia; Nitric Oxide; Pain Threshold; Phytoalexins; Resveratrol; Sesquiterpenes; Stilbenes; Terpenes; Tumor Necrosis Factor-alpha

Topics: Humans; Neuralgia; Stilbenes; Trigeminal Neuralgia