Reorganization of the spinal dorsal horn in models of chronic pain: correlation with behaviour.

摘要

Central reorganization is known to occur in chronic pain models resulting from peripheral injury. Systematic analysis of anatomical and behavioural changes and a comparison of these changes between different models over an extended time course has not been reported. We address this issue by quantifying alterations in markers known to be associated with central reorganization in three models of peripheral injury: complete Freund's adjuvant induced inflammation of the hindpaw, chronic constriction of the sciatic nerve, and tight ligation of the sciatic nerve. Hyperalgesic behaviour to thermal and mechanical stimuli was quantified at four, seven, 14, 28 days post-injury. Distribution and immunodensity changes of the mu-opioid receptor, the neurokinin-1 receptor, and brain nitric oxide synthase distribution were assessed in the superficial dorsal horn, laminae I-II, of the lumbar spinal cord of the rat. Reorganization and behavioural changes were quantified as a per cent change (ipsilateral versus contralateral) and examined together over the duration of the experiment. Chronic constriction injury and inflammation both produced hyperalgesic behaviour in the hindpaw ipsilateral to injury. Decreases in thermal and mechanical withdrawal latencies were maximal at day 4. Complete Freund's adjuvant-treated animals displayed a 25.5%+/-3.8% decline in thermal withdrawal latency and 84.1%+/-8.0% decline in mechanical withdrawal latency. Chronic constriction of the sciatic nerve resulted in an decrease in thermal and mechanical withdrawal latencies, 27.9%+/-3.3%, 90.5%+/-4.4%, respectively. Tight ligation of the sciatic nerve resulted in early increases in the latency of withdrawal that were maximal at seven days 40.7%+/-8.4% for thermal stimulus and at four days 417%+/-5.8% for mechanical stimulus, consistent with deafferentation. The greatest changes in immunolabelling were always found at L4-L5 spinal level, corresponding to the entry zone of sciatic afferents. Mu-opioid receptor immunodensities increased in the dorsal horn ipsilateral to the treated side up to a maximum of 38.3%+/-5.6% at day 7 with inflammation and up to 26.3%+/-3.2%, at day 14 with chronic constriction injury. Mu-opioid receptor immunodensities decreased maximally by 20.0%+/-2.1% at day 4 in the tight ligature model. Significant differences in mu-opioid receptor immunolabelling persisted at day 28 for neuropathic models, at which time there was an absence of significant hyperalgesic behaviour in any group. The number of brain nitric oxide synthase-positive cells decreased at seven days by a maximum of 45.3%+/-5.1% and 59.0%+/-5.2%, respectively, in animals with chronic constriction injury or tight ligature. This decline in immunolabelled brain nitric oxide synthase cells in the dorsal horn ipsilateral to injury persisted at day 28. No significant alteration in brain nitric oxide synthase immunolabelling was found in association with inflammation of the hindpaw. Inducible nitric oxide synthase was not detected in the dorsal horn at any time during the experiment in either tissue of treated or control rats. Neurokinin-1 receptor immunodensity consistently increased ipsilateral to injury irrespective of the type of injury, and, of the three markers, paralleled behaviour most closely. Changes were maximal for inflammation at four days (75.2%+/-9.3%), for chronic constriction injury at four days (85.1%+/-14.6%) and for tight ligature at 14 days (85.7%+/-11.4%). Comparison of behavioural and anatomical data demonstrates that the peak hyperalgesia is concomitant with the greatest increase in neurokinin-1 receptor immunodensity ipsilateral to the injury. The increase in mu-opioid receptor immunodensity parallels behaviour but with a delayed time course, peaking as hyperalgesia abates, except in the case of tight ligature animals where the decrease in immunolabelling appears permanent. (ABSTRACT TRUNCATED)