3-nitrotyrosine and Neuralgia

Exposure to hand-transmitted vibration in the work-place can result in the loss of sensation and pain in workers. These effects may be exacerbated by pre-existing conditions such as diabetes or the presence of primary Raynaud's phenomena. The goal of these studies was to use an established model of vibration-induced injury in Zucker rats. Lean Zucker rats have a normal metabolic profile, while obese Zucker rats display symptoms of metabolic disorder or Type II diabetes. This study examined the effects of vibration in obese and lean rats. Zucker rats were exposed to 4h of vibration for 10 consecutive days at a frequency of 125 Hz and acceleration of 49 m/s(2) for 10 consecutive days. Sensory function was checked using transcutaneous electrical stimulation on days 1, 5 and 9 of the exposure. Once the study was complete the ventral tail nerves, dorsal root ganglia and spinal cord were dissected, and levels of various transcripts involved in sensorineural dysfunction were measured. Sensorineural dysfunction was assessed using transcutaneous electrical stimulation. Obese Zucker rats displayed very few changes in sensorineural function. However they did display significant changes in transcript levels for factors involved in synapse formation, peripheral nerve remodeling, and inflammation. The changes in transcript levels suggested that obese Zucker rats had some level of sensory nerve injury prior to exposure, and that exposure to vibration activated pathways involved in injury and re-innervation.

Topics: Animals; Biophysics; Chemokine CCL2; Disease Models, Animal; Ganglia, Spinal; Gene Expression Regulation; Hyperalgesia; Interleukin-1beta; Male; Metabolic Syndrome; Neuralgia; Nitric Oxide Synthase Type I; Rats; Rats, Zucker; Receptors, Adrenergic, alpha-2; RNA, Messenger; Time Factors; Transcutaneous Electric Nerve Stimulation; Tyrosine; Vibration

Our laboratory has shown that λ-carrageenan-induced peripheral inflammatory pain (CIP) can alter tight junction (TJ) protein expression and/or assembly leading to changes in blood-brain barrier xenobiotic permeability. However, the role of reactive oxygen species (ROS) and subsequent oxidative stress during CIP is unknown. ROS (i.e., superoxide) are known to cause cellular damage in response to pain/inflammation. Therefore, we examined oxidative stress-associated effects at the blood-brain barrier (BBB) in CIP rats. During CIP, increased staining of nitrosylated proteins was detected in hind paw tissue and enhanced presence of protein adducts containing 3-nitrotyrosine occurred at two molecular weights (i.e., 85 and 44 kDa) in brain microvessels. Tempol, a pharmacological ROS scavenger, attenuated formation of 3-nitrotyrosine-containing proteins in both the hind paw and in brain microvessels when administered 10 min before footpad injection of λ-carrageenan. Similarly, CIP increased 4-hydroxynoneal staining in brain microvessels and this effect was reduced by tempol. Brain permeability to [(14)C]sucrose and [(3)H]codeine was increased, and oligomeric assemblies of occludin, a critical TJ protein, were altered after 3 h CIP. Tempol attenuated both [(14)C]sucrose and [(3)H]codeine brain uptake as well as protected occludin oligomers from disruption in CIP animals, suggesting that ROS production/oxidative stress is involved in modulating BBB functional integrity during pain/inflammation. Interestingly, tempol administration reduced codeine analgesia in CIP animals, indicating that oxidative stress during pain/inflammation may affect opioid delivery to the brain and subsequent efficacy. Taken together, our data show for the first time that ROS pharmacological scavenging is a viable approach for maintaining BBB integrity and controlling central nervous system drug delivery during acute inflammatory pain.

Topics: Acute Disease; Aldehydes; Analgesics, Opioid; Animals; Antioxidants; Blood-Brain Barrier; Capillary Permeability; Carbon Radioisotopes; Codeine; Cyclic N-Oxides; Cysteine Proteinase Inhibitors; Hyperalgesia; Male; Membrane Proteins; Neuralgia; Neuritis; Occludin; Oxidative Stress; Rats; Rats, Sprague-Dawley; Spin Labels; Sucrose; Tight Junctions; Tyrosine; Xenobiotics

Two reactive oxygen species (ROS), nitric oxide (NO(.)) and superoxide ((.)O2), contribute to persistent pain. Using three different animal models where ROS mediate pain, this study examined whether NO(.) and (.)O2 converge to peroxynitrite (ONOO(-)) or whether each has an independent signaling pathway to produce hyperalgesia. The hyperalgesia after spinal nerve ligation was attenuated by removing (.)O2 by TEMPOL or inhibiting NO(.) production by L-NAME, but not by removing peroxynitrite with FeTMPyP. Nitric oxide-induced hyperalgesia was not affected by removing (.)O2 but was reduced by a guanyl cyclase inhibitor. Superoxide-induced hyperalgesia was not affected by inhibiting NO(.) production but was suppressed by a protein kinase C inhibitor. The data suggest that NO(.) and (.)O2 operate independently to generate pain.

Topics: Animals; Antimycin A; Cyclic N-Oxides; Disease Models, Animal; Enzyme Inhibitors; Hyperalgesia; Male; Metalloporphyrins; Mice; Mice, Inbred C57BL; Neuralgia; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitroso Compounds; Pain Measurement; Peroxynitrous Acid; Reactive Oxygen Species; Signal Transduction; Spin Labels; Superoxides; Tyrosine

We carried out a partial ligation of the sciatic nerve in rats to induce nerve injury and neuropathic hyperalgesia. We showed that nitrotyrosine, a marker of peroxynitrite activity, was formed after partial nerve injury. Double-labelling immunohistochemistry showed that nitrotyrosine-immunoreactive cells were mainly macrophages and Schwann cells. Daily treatment with uric acid, a scavenger of peroxynitrite, decreased nitrotyrosine formation in the injured sciatic nerve, and produced concomitant alleviation of thermal hyperalgesia and Wallerian degeneration. These results provide the first evidence that peroxynitrite is formed after partial nerve injury, and contributes to the initiation of thermal hyperalgesia and Wallerian degeneration. We hypothesize that uric acid alleviates hyperalgesia and Wallerian degeneration by inhibiting oxidative damage caused by peroxynitrite and possibly also by decreasing the production of other inflammatory mediators such as prostaglandins.

Topics: Animals; Hyperalgesia; Hyperthermia, Induced; Immunohistochemistry; Male; Nerve Compression Syndromes; Nerve Crush; Nerve Degeneration; Neuralgia; Nitrates; Peripheral Nerve Injuries; Peripheral Nerves; Rats; Rats, Wistar; Tyrosine; Uric Acid