The cold plate as a test of nociceptive behaviors: description and application to the study of chronic neuropathic and inflammatory pain models.

A cold plate apparatus was designed to test the responses of unrestrained rats to low temperature stimulation of the plantar aspect of the paw. At plate temperatures of 10 degrees C and 5 degrees C, rats with either chronic constriction injury (CCI) of the sciatic nerve or complete Freund's adjuvant (CFA) induced inflammation of the hindpaw displayed a stereotyped behavior. Brisk lifts of the treated hindpaw were recorded, while no evidence of other nociceptive behaviors could be discerned. The most consistent responses were obtained with a plate temperature of 5 degrees C in three 5-min testing periods, separated by 10-min intervals during which the animals were returned to a normal environment. Concomitantly to cold testing, the rats were evaluated for their response to heat (plantar test) and mechanical (von Frey hairs) stimuli. In both injury models, while responses to heat stimuli had normalized at 60 days post-injury, a clear lateralization of responses to cold was observed throughout the entire study period. Systemic lidocaine, clonidine, and morphine suppressed responses to cold in a dose-related fashion. At doses that did not affect motor or sensory behavior, both lidocaine and its quaternary derivative QX-314 similarly reduced paw lifts, suggesting that cold hyperalgesia is in part due to peripheral altered nociceptive processing. Clonidine was more potent in CCI then in CFA rats in reducing the response to cold. Paradoxically, clonidine increased the withdrawal latencies to heat in the CCI hindpaw at 40 days and thereafter, at a time when both hindpaws had the same withdrawal latencies in control animals. Morphine was also more potent on CCI than CFA cold responses, indicating that, chronically, CFA-induced hyperalgesia might be opiate resistant. Evidence for tonic endogenous inhibition of cold hyperalgesia was obtained for CFA rats, when systemic naltrexone significantly increased the number of paw lifts; this was not found in rats with CCI. At 60 days, neither morphine nor naltrexone affected cold-induced paw lifting in CFA rats, suggesting that the neuronal circuit mediating cold hyperalgesia in these animals had become opiate insensitive. In conclusion, the cold plate was found to be a reliable method for detecting abnormal nociceptive behavior even at long intervals after nerve or inflammatory injuries, when responses to other nociceptive stimuli have returned to near normal. The results of pharmacological studies suggest that cold hyperalgesia is in part a consequence of altered sensory processing in the periphery, and that it can be independently modulated by opiate and adrenergic systems.

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

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)

Experimental realization of a multiproduct photorefractive correlation system for temporal signals.

The design and operation of a multidimensional photorefractive correlator is described. With a photorefractive medium as the integrator, this system effects the correlation of up to four time-evolving signals. The holographic correlation volume is viewed by projection onto a two-dimensional detector. The correlator is designed for use with binary-phase signals, especially pseudorandom noise sequences.

Progression of methotrexate-induced leukoencephalopathy in children with leukemia.

From 1972-1974, 228 children began treatment for acute lymphocytic leukemia and were prospectively assessed for neurologic complications. After CNS irradiation (2,400 rad) and intrathecal methotrexate (MTX), they received weekly intravenous maintenance therapy with MTX alone (40-60 mg/m2; 20 patients) or MTX (10-30 mg/m2) with other drugs (208 patients). Signs of leukoencephalopathy appeared in 11 children (nine without CNS leukemia) after 4-15 months of IV MTX alone, and included lethargy, seizures, spasticity, paresis, drooling, and dementia. Before or during the clinical onset, EEG frequencies slowed (all ten patients tested). Radionuclide scans showed periventricular accumulation of 99mTc (9/11 patients) and remained abnormal for greater than or equal to six months in eight patients. Cranial computed tomograms or neuropathology findings (five patients each) demonstrated leukoencephalopathy (nine patients) and radiation-related microangiopathy (ten patients). Severe neurologic and neuropsychologic dysfunctions were present in four long-term survivors.

Distractibility and memory deficits in long-term survivors of acute lymphoblastic leukemia.

A comprehensive neuropsychological test battery was administered to 37 long-term survivors of acute lymphoblastic leukemia and 18 newly diagnosed acute lymphoblastic leukemia patients in an attempt to identify patterns of neuropsychological performance. Newly diagnosed patients between 7 and 15 years of age generally obtained scores within normal limits. On most measures of intelligence long-term survivors within the same age range obtained mean test scores approximately 1 standard deviation below the population mean. Fourteen of 30 long-term survivors under 16 years of age exhibited a pattern of test scores suggestive of memory deficits and distractibility which may have interfered with academic achievement. Only one patient over 8 years of age at diagnosis produced a similar pattern of scores. We conclude that young children treated for acute lymphoblastic leukemia are at risk for the development of neuropsychological dysfunction and that appropriate programs for identification and academic remediation should be instituted.

Efficacy of transfusion therapy for one to two years in patients with sickle cell disease and cerebrovascular accidents.

Since 1974 we have entered 12 children with sickle cell disease and strokes on a transfusion protocol to maintain hemoglobin S less than 20%. Serial arteriography, EEGs, brain or CT scans, and neuropsychologic testing were also obtained. Transfusion has been stopped in ten patients after one to two years. Seven of these ten patients have had second strokes five weeks to 11 months after cessation of transfusion (median three months). Arteriography was normal at the time of the initial stroke in two patients; one of these had a second stroke. Arteriograms did not improve during transfusion therapy. EEGs and brain and CT scans were occasionally useful at the time of the initial stroke but were of little value in following these patients. Neuropsychologic testing indicated severe impairment of sensory-motor and cognitive processes at the time of the initial stroke and was useful in following improvement or deterioration and in designing remedial education programs. We conclude that short-term transfusion therapy will not prevent second strokes once transfusion is stopped and that arteriography is of limited value in these patients.

Emotional reactions of children to isolation in a cancer hospital.

Emotional reactions of 123 hospitalized children and their mothers were evaluated during standard isolation with limited visitation and during peninsula isolation with visitation only through glass partitions. Self-report surveys and behavioral observations by nurses indicated that (1) patients and parents in both isolation facilities had overall high levels of hospital-related anxiety and depression which varied with the patient's chronologic age; and (2) parents of preschool children had more negative opinions toward peninsula isolation than did parents of older children. These results confirm the need for psychologically supportive programs for the families of children being treated for catastrophic diseases.