A preconditioning nerve lesion inhibits mechanical pain hypersensitivity following subsequent neuropathic injury.

BACKGROUND: A preconditioning stimulus can trigger a neuroprotective phenotype in the nervous system - a preconditioning nerve lesion causes a significant increase in axonal regeneration, and cerebral preconditioning protects against subsequent ischemia. We hypothesized that a preconditioning nerve lesion induces gene/protein modifications, neuronal changes, and immune activation that may affect pain sensation following subsequent nerve injury. We examined whether a preconditioning lesion affects neuropathic pain and neuroinflammation after peripheral nerve injury. RESULTS: We found that a preconditioning crush injury to a terminal branch of the sciatic nerve seven days before partial ligation of the sciatic nerve (PSNL; a model of neuropathic pain) induced a significant attenuation of pain hypersensitivity, particularly mechanical allodynia. A preconditioning lesion of the tibial nerve induced a long-term significant increase in paw-withdrawal threshold to mechanical stimuli and paw-withdrawal latency to thermal stimuli, after PSNL. A preconditioning lesion of the common peroneal induced a smaller but significant short-term increase in paw-withdrawal threshold to mechanical stimuli, after PSNL. There was no difference between preconditioned and unconditioned animals in neuronal damage and macrophage and T-cell infiltration into the dorsal root ganglia (DRGs) or in astrocyte and microglia activation in the spinal dorsal and ventral horns. CONCLUSIONS: These results suggest that prior exposure to a mild nerve lesion protects against adverse effects of subsequent neuropathic injury, and that this conditioning-induced inhibition of pain hypersensitivity is not dependent on neuroinflammation in DRGs and spinal cord. Identifying the underlying mechanisms may have important implications for the understanding of neuropathic pain due to nerve injury.

Oral pre-treatment with epigallocatechin gallate in 6-OHDA lesioned rats produces subtle symptomatic relief but not neuroprotection.

Much recent work is investigating the role of oxidative stress and inflammatory mechanisms in the aetiology of neurodegeneration in Parkinson's disease. The present study evaluated whether the green tea constituent epigallocatechin gallate (EGCG) which has both anti-oxidant and anti-inflammatory properties, exerts neuroprotection and symptomatic effects when administered orally as a pre-treatment prior to 6-hydroxydopamine (6-OHDA) lesions. Groups of rats were given either 1mg/kg, 2mg/kg EGCG or vehicle solution for 14 days. Sham or 6-OHDA surgery was performed on day 11 of the drug administration protocol. Behavioural analysis was conducted before drugs/vehicle solution, again during the treatment period and then repeated at fortnightly intervals for 2 months post-operatively. Whilst some subtle behavioural improvements in postural abnormalities and ability to cross a narrow beam were observed in lesioned rats after EGCG (vs. vehicle) there was no evidence of neuroprotection on post-mortem quantification of degree of nigral dopaminergic neuronal loss when comparing the lesioned groups given the various treatments.

Contusive spinal cord injury evokes localized changes in NADPH-d activity but extensive changes in Fos-like immunoreactivity in the rat.

The histological detection of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d), a marker for nitric oxide-producing cells, was used to evaluate ongoing changes in the neural biochemistry of the rat spinal cord 1 week following contusive spinal cord injury (SCI). In addition, the immunohistochemical detection of the immediate-early gene c-fos was used to identify basal patterns of neural activity at this time. The numbers and laminar locations of NADPH-d- and c-fos-positive cells were examined in spinal segments adjacent to the site of injury (T12-S3) as well as those distant from the injury (C3-C5) in both SCI and un-injured rats. Our data show that contusive SCI results in a significant reduction in NADPH-d labelling in the superficial dorsal horn, and a significant increase in NADPH-d expression in small bipolar neurons and large motoneurons in the ventral horn at the site of the injury. In spinal segments distant to the injury site (C3-C5), NADPH-d activity did not differ from that of uninjured controls. Furthermore, significant reductions in the levels of c-fos expression were observed in SCI rats, in spinal segments both at and distant to the site of injury for all spinal laminae. The only exception was a dramatic increase observed in the sacral parasympathetic nucleus. These data suggest that increased NADPH-d expression is related to conditions specific to the site of injury, whereas the changes in c-fos expression probably indicate more global changes in neuronal activity following SCI.

Use of the narrow beam test in the rat, 6-hydroxydopamine model of Parkinson's disease.

Batteries of behavioural tests provide a method by which researchers may examine specific functional pathways. The narrow beam test examines the ability of a rat to cross a narrow, elevated beam of wood or other material. In order to determine the utility of the narrow beam test in the study of Parkinsonism, it was of interest to characterise the performance of animals at this task. Rats were placed at one end of a 105 cm long, elevated beam and both the time it took to begin crossing the beam, as well as the total time taken to cross the beam, were measured. The effects of training, time of day and 6-hydroxydopamine lesion on beam performance were examined. Rats reached maximal performance at the task within a single test session and time of day had no effect on beam performance. Parkinsonian rats demonstrated a four-fold increase in both the latency to initiate the task and the total time to cross the beam (p < 0.05).

Pain hypersensitivity in rats with experimental autoimmune neuritis, an animal model of human inflammatory demyelinating neuropathy.

Experimental autoimmune neuritis (EAN) is a T cell mediated autoimmune disease of the peripheral nervous system that serves as an animal model of the acute inflammatory demyelinating polyradiculoneuropathy in Guillain-Barre syndrome (GBS). Although pain is a common symptom of GBS occurring in 55-85% of cases, it is often overlooked and the underlying mechanisms are poorly understood. Here we examined whether animals with EAN exhibit signs of neuropathic pain including hyperalgesia and allodynia, and assessed their peripheral nerve autoimmune inflammation. We immunized Lewis rats with peripheral myelin P2 peptide (amino acids 57-81) emulsified with complete Freund's adjuvant, or with adjuvant only as control. P2-immunized rats developed mild to modest monophasic EAN with disease onset at day 8, peak at days 15-17, and full recovery by day 28 following immunization. Rats with EAN showed a significant decrease in withdrawal latency to thermal stimuli and withdrawal threshold to mechanical stimuli, in both hindpaws and forepaws, during the course of the disease. We observed a significant infiltration of T cells bearing alphabeta receptors, and a significant increase in antigen-presenting cells expressing MHC class II as well as macrophages, in EAN-affected rats. Our results demonstrate that animals with active EAN develop significant thermal hyperalgesia and mechanical allodynia, accompanied by pronounced autoimmune inflammation in peripheral nerves. These findings suggest that EAN is a useful model for the pain seen in many GBS patients, and may facilitate study of neuroimmune mechanisms underlying pain in autoimmune neuropathies.