The effect of cyclo (Leu-Gly) on chemical denervation supersensitivity of dopamine receptors induced by intracerebroventricular injection of 6-hydroxydopamine in mice

Chemical denervation supersensitivity of postsynaptic dopamine receptors was induced in mice by intracerebroventricular injection of 6-hydroxydopamine. Fourteen days after the 6-hydroxydopamine injection, mice exhibited greater spontaneous locomotor activity and hypothermic response when challenged intraperitoneally with apomorphine. Whole brain levels of dopamine were reduced by 80%. Daily subcutaneous administration of cyclo (Leu-Gly) (50 μg/mouse/day) for 14 days inhibited the development of dopamine receptor supersensitivity induced by 6-hydroxydopamine as evidenced by the blockade of an apomorphine induced locomotor and hypothermic effect. Cyclo (Leu-Gly) did not alter the depletion of brain dopamine induced by 6-hydroxydopamine. These data suggest that cyclo (Leu-Gly) can block the development of dopamine receptor supersensitivity induced by 6-hydroxydopamine without protecting the neurons from dopamine depletion.     

Interactions between dopamine and melatonin organize circadian rhythmicity in the retina of the green iguana

Circadian physiology in the vertebrate retina is regulated by several neurotransmitters. In the lateral eyes of the green iguana the circadian rhythm of melatonin content peaks during the night while the rhythm of dopamine peaks during the day. In the present work, the authors explore the interaction of these 2 neurotransmitters during the circadian cycle. They depleted retinal dopamine with intravitreal injections of 6-hydroxydopamine (6-OHDA) and measured ocular melatonin content in vivo throughout 1 circadian cycle. The circadian rhythm of ocular melatonin not only persisted but increased 10-fold in amplitude. This increase was substantially reduced by the intraocular administration of dopamine. 6-OHDA-treated retinas, unlike those from untreated animals, did not express a circadian rhythm of melatonin synthesis in vitro. To deplete retinal melatonin, the authors pinealectomized iguanas and blocked retinal melatonin synthesis by depleting serotonin with intraocular injections of 5,6-dihydroxytryptamine. In animals so treated, they found that the circadian rhythm of retinal dopamine content was abolished, the levels of dopamine were lowered, and the levels of dopamine metabolites were greatly increased. The data suggest that in iguanas, the amplitude of the circadian rhythm of melatonin synthesis in the eye is suppressed by dopamine while the rhythm of dopamine depends, at least in part, on the presence of melatonin.     

Regulation of the systemic immune response by visible light and the eye

The injection of certain antigens into the anterior chamber (AC) of the eye results in the induction of antigen-specific suppressor T cells (Ts cells), which inhibit systemic delayed-type hypersensitivity (DTH). We have previously shown that down-regulation by Ts cells after AC injection with 2,4,6-trinitrophenol (TNP)-coupled spleen cells (TNP-Spl) is initiated by the intraocular activation of Ts inducer cells. These cells activate T suppressor-effector cells in the spleen that are responsible for suppressed DTH. With dark- and light-reared mice (Balb/c), we show that visible light has a direct effect on the intraocular T cell reaction that leads to systemic suppression. Our results show that if light is prevented from reaching the eye by dark rearing, by placing light-reared animals in the dark after AC injection, or by closing the eyelids of light-reared animals after AC injection, Ts cells are not activated. We show that light is responsible for establishing conditions in the eye that cause the preferential activation of Ts cells. The intraocular conditions established by light are not developmentally mandated as is visual development, but can be eliminated in adult light-reared animals by placing them in the dark for 18 h after AC injection. These conditions can also be induced in adult dark-reared animals by returning them to the light for just over 24 h before AC injection. These studies have important implications for understanding intraocular immune responses and possibly for the treatment of eye disease.     

Dissociate destruction of noradrenaline and dopamine descending projections in the thoracic spinal cord of the rat

Intracisternal administration of 6-hydroxydopamine to male Wistar rats produced a near complete depletion of noradrenaline levels, as measured by a radioenzymatic assay in micropunches sampled from the dorsal, lateral and ventral horns of the thoracic spinal cord. This drastic effect was reversed by pretreatment with desipramine, a pharmacological inhibitor of noradrenergic neuron uptake. Surprisingly, dopamine content was not significantly reduced. The question as to whether such a lack of concomitant dopamine decrease might be inherent to the dopamine assay itself could be answered by the results obtained with both pharmacological (reserpine) treatments and interference determinations in the dopamine assay. The relative potency of 6-hydroxydopamine to destroy noradrenergic and dopaminergic neurons might account for their differential behavior. Conversely, a large midbrain section performed by knife cut could decrease both dopamine and DOPAC (one of its major acid metabolites) in the thoracic lateral horn and partly in the ventral one. The noradrenaline content was not reduced. Results are discussed in light of recently reported data on dopaminergic descending projections to the spinal cord. The lesion procedures presented here seem to provide valuable tools to dissociate noradrenergic from dopaminergic spinal projections, which is necessary for further anatomical and functional studies on these systems.     

Effects of Dopaminergic Transmission Interruption on the D2 Receptor Isoforms in Various Cerebral Tissues

We examined the effects of an interruption of dopamine neurotransmission, by either dopamine receptor blockade or degeneration of dopamine neurons by 6-hydroxydopamine, on the levels of D2 receptor mRNAs. In addition, we evaluated by the polymerase chain reaction (PCR) the relative abundance of the two D2 receptor isoform mRNAs generated by alternative splicing. Daily injections of 4 mg/kg of haloperidol to rats elicited in striatum a rapid and progressive increase in D2 receptor mRNA levels, which reached 70% after a 15-day treatment. By contrast, there was no apparent change in D2 receptor mRNA levels in cerebral cortex and pons-medulla, in spite of an increased density of D2 receptor in the former tissue. Using the PCR with primers flanking the alternative exon, we observed that the relative proportion of the shorter receptor isoform (D2S) mRNA was slightly but significantly enhanced in cerebral cortex (17%) and pons-medulla (18%) after a 15-day haloperidol treatment. Unilateral degeneration of dopamine neurons induced by local injection of 6-hydroxydopamine resulted in a marked decrease in levels of total D2 receptor mRNAs in substantia nigra (-79%) and ventral tegmental (-63%) area, two cell body areas. In the substantia nigra, the longer isoform (D2L) mRNA was significantly more decreased in content than the D2S isoform mRNA, so that there was a large enhancement in the relative abundance of the latter (81%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Functional Activity of Substantia Nigra Grafts Reinnervating the Striatum: Neurotransmitter Metabolism and [14C]2-Deoxy-d-glucose Autoradiography

Dopaminergic innervation of the caudate nucleus in adult rats can be partially restored by the grafting of embryonic substantia nigra into the overlying parietal cortex with concomitant compensation of certain behavioral abnormalities. In this study the function of such grafts was investigated neurochemically by quantification of transmitter metabolism and glucose utilization in the reinnervated target. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle received a single graft to the dorsal caudate-putamen and were screened for rotational behavior following 5 mg/kg methamphetamine. The grafts restored dopamine concentrations in the caudate-putamen from initially less than 0.5% to an average of 13.6% of normal in rats with behavioral compensation. The ratio of 3,4-dihydroxyphenylacetic acid to dopamine, which is a measure of the rate of transmitter turnover, were equivalent in transplanted and normal control rats. Moreover, measurements of DOPA accumulation for a 30-min period after DOPA decarboxylase inhibition indicated similar fractional dopamine turnover rates in normal and transplant-reinnervated tissues. Correlations between rotational behavior and dopamine concentrations showed that reinnervation to only 3% of normal was sufficient to counterbalance the motor asymmetry. Measurements of glucose utilization by [14C]deoxyglucose autoradiography indicated equivalent metabolic rates for the grafted tissue and the intact substantia nigra. 6-Hydroxydopamine denervation of the caudate-putamen had no significant effect on neuronal metabolism in that region, nor did subsequent reinnervation from a graft. Grafts, however, were associated with a 16% reduction of glucose uptake in the ipsilateral globus pallidus, indicating a significant transsynaptic influence of the nigral transplants on neuronal metabolism in the host brain. Overall the results indicate that behaviorally functional neuronal grafts spontaneously metabolize dopamine and utilize glucose at rates characteristic of the intact nigrostriatal system. This provides further evidence that ectopic intracortical nigral transplants can reinstate dopaminergic neurotransmission in regions of the host brain initially denervated by the 6-hydroxydopamine lesion.     

Noradrenaline and selective attention

Rats depleted of forebrain noradrenaline by intracerebral injection of four micrograms of 6-hydroxydopamine into the dorsal noradrenergic bundle were examined on their ability to ignore irrelevant stimuli. In the latent inhibition paradigm normal rats were pre-exposed to visual and auditory stimuli in the absence of reward and such pre-exposure was found to slow subsequent learning of a successive discrimination task using these stimuli. Noradrenaline depletion blocked the usual latent inhibition effect, thus suggesting that the lesioned animals were impaired in ignoring irrelevant stimuli. A second paradigm, a nonreversal shift, involved training rats on a two-dimension discrimination task with one dimension relevant and the other irrelevant. Nonreversal shift (in which the initially irrelevant dimension became the sole relevant one) was significantly improved by 6-hydroxydopamine lesion. It is thus concluded that strong evidence has been presented in favour of a role for the dorsal noradrenergic bundle in attentional filtering processes.     

NORADRENALINE NERVE TERMINALS IN THE CEREBRAL CORTEX: EFFECTS ON NORADRENALINE UPTAKE AND STORAGE FOLLOWING AXONAL LESION WITH 6-HYDROXYDOPAMINE

The ascending noradrenaline-containing neuronal system from the locus coeruleus to the cerebral cortex was unilaterally lesioned by an intracerebral injection of 8 μg 6-hydroxydopamine in the dorsomedial reticular formation in the caudal mesencephalon. The 6-hydroxydopamine caused injury to axons of the dorsal catecholamine bundle associated with its specific neurotoxic action, while very limited unspecific tissue necrosis was observed. Following this treatment the endogenous noradrenaline in the ipsilateral cerebral cortex (neocortex) increased acutely (up to 2 days), as observed both with noradrenaline assay and fluorescence histochemistry. The noradrenaline concentration then gradually decreased to 15 per cent of the contralateral side 15 days after the lesion. At this time interval and up to at least 90 days no fluorescent catecholamine nerve terminals could be detected. The acute noradrenaline increase could be blocked partially by tyrosine hydroxylase inhibition produced by α-methyl-p-tyrosine. The disappearance of endogenous noradrenaline following tyrosine hydroxylase inhibition was also reduced after the 6-hydroxydopamine lesion. Studies on the in vitro uptake of [³H]noradrenaline (0.1 μM for 5 min) in slices from the neocortex after the 6-hydroxydopamine lesion showed a gradual decline in uptake reaching maximal reduction (35-40 per cent of the contralateral side) after 15 days. No recovery of [³H]noradrenaline uptake was seen up to 90 days after the lesion. The formation of [³H]noradrenaline from [³H]dopamine in vitro was reduced to 15 per cent of the contralateral side after a chronic lesion. The present results indicate that the disappearance of noradrenaline uptake-storage mechanisms in the neocortex is due to an anterograde degeneration of axons and nerve terminals of the dorsal catecholamine bundle. The data on endogenous noradrenaline and noradrenaline synthesis suggest that approx. 15 per cent of the noradrenaline nerve terminals in the neocortex remain intact following the lesion, while the [³H]noradrenaline uptake data reflect uptake in other tissue structures in addition to noradrenaline nerve terminals, e.g. dopamine nerve terminals, pericytes and/or glial cells.     

Dose-dependent protective effect of selenium in rat model of Parkinson's disease: neurobehavioral and neurochemical evidences

Normal cellular metabolism produces oxidants that are neutralized within cells by antioxidant enzymes and other antioxidants. An imbalance between oxidant and antioxidant has been postulated to lead the degeneration of dopaminergic neurons in Parkinson's disease. In this study, we examined whether selenium, an antioxidant, can prevent or slowdown neuronal injury in a 6-hydroxydopamine (6-OHDA) model of Parkinsonism. Rats were pre-treated with sodium selenite (0.1, 0.2 and 0.3 mg/kg body weight) for 7 days. On day 8, 2 micro L 6-OHDA (12.5 micro g in 0.2% ascorbic acid in normal saline) was infused in the right striatum. Two weeks after 6-OHDA infusion, rats were tested for neurobehavioral activity, and were killed after 3 weeks of 6-OHDA infusion for the estimation of glutathione peroxidase, glutathione-S-transferase, glutathione reductase, glutathione content, lipid peroxidation, and dopamine and its metabolites. Selenium was found to be successful in upregulating the antioxidant status and lowering the dopamine loss, and functional recovery returned close to the baseline dose-dependently. This study revealed that selenium, which is an essential part of our diet, may be helpful in slowing down the progression of neurodegeneration in parkinsonism.     

Fluorescent histochemical detection of injected dopamine in lateral hypothalamus after degeneration of catecholaminergic fibres

The fluorescent histochemical technique was used to examine the presence of dopamine 1 h after injection into the lateral hypothalamus which had been depleted of catecholamines by repeated injections of 6-hydroxydopamine. There was considerably more fluorescence at the dopamine injection site which had been previously treated with 6-hydroxydopamine than at the contralateral site treated with saline. These results suggest that the destruction of catecholamine containing nerve fibres from the hypothalamus may impair the ability of brain tissue to remove amines which are produced endogenously during degeneration. This could explain why amine accumulation produced during degeneration of catecholamine-containing neurons can remain for several weeks after the parent cells, hypothesized to have produced the accumulating amine, have died.     

Effect of 6-hydroxydopamine on the electrical characteristics of snail neurons in long-term sensitization

Studies of the influence of neurotoxin 6-hydroxydopamine selectively destroying the catecholamine terminals on long-term sensitization, and the role of dopamine in manifestation of characteristics of a membrane of identified neurons during elaboration of plasticity, were fulfilled. Injection of saline was used as the control. It is shown that preliminary injection of 6-hydroxydopamine reduces duration of long-term sensitization, but does not block it completely. It was shown that injection of 6-hydroxydopamine prevents diminishing of membrane and threshold potentials in withdrawal interneurons during formation of long-term sensitization. The experiments demonstrate that shift of electrical characteristics of withdrawal interneurons caused by injection of neurotoxin 6-hydroxydopamine to both naive snails and sensitized snails, statys during at least 10 days.     

6-羟多巴胺纹状体内注射制作大鼠帕金森病模型的研究

目的 为拓宽6-OHDA损毁多巴胺能神经元所制备大鼠帕金森病模型的应用范围,采用多位点纹状体内注入6-OHDA的途径来制备模型。方法 研究用SD大鼠,两个针道内四点定位注射,每点注射3μg／μ16-OHDA3μl。结果 术后两周出现缓慢旋转,4周旋转行为达到7转／分并保持稳定;形态学染色可见损毁1周后注射侧黑质酪氨酸羟化酶免疫组化阳性细胞减少20％,2周后减少38％,3～4周减少70％以上,6周后损伤趋缓。高效液相-电化学法活体检测纹状体内多巴胺的代谢产物3、4-二羟基苯乙酸(DOPAC)和高香草酸(HVA),发现注射侧和非注射侧相比含量分别下降98．33％和96．05％;组织匀浆检测损毁侧黑质多巴胺含量下降了73％以上,3、4-二羟基苯乙酸(DOPAC)含量下降60％。结论 纹状体内注射6-OHDA能够制备帕金森病大鼠模型。     

Contralateral Retinal Dopamine Decrease and Melatonin Increase in Progression of Hemiparkinsonium Rat

Both dopamine (DA) and melatonin (MLT) are abundant neuromodulators located in vertebrate retina. The retinal DA deficiency and variations in MLT levels have been linked to Parkinson’s disease (PD). No studies have investigated the ipsilateral and contralateral DA and MLT in retina and their relationships in 6-hydroxydopamine (6-OHDA) induced hemiparkinsonian rats. We established PD rat model by unilateral injection of 6-OHDA into the right substantia nigra and the right medial forebrain bundle. Eye tissue was collected and the levels of MLT and DA were measured twice daily at 10:00 and 22:00. The concentrations of DA and its metabolites, 3,4-dihydroxyphenylacetic (DOPAC) and homovanillic acid (HVA), as well as MLT were determined by HPLC. The results show that DA levels in the eye contralateral to the side of a unilateral intracerebral 6-OHDA lesion significantly decreased (P < 0.001). Both the ratios of DOPAC/DA and HVA/DA were increased in comparison with the vehicle groups after 3 weeks post-lesion. The concentrations of MLT at 10:00 and 22:00 in both eyes were distinctly increased compared with the vehicle groups (P < 0.05). The change of DA and its metabolites, as well as MLT appeared to correlate well with the rotation behavior of rats. These findings suggest that rats receive a unilateral intracerebral injection of 6-OHDA that mainly causes the contralateral eye destruction of DA-containing neurons. Increased retinal MLT level probably is associated with the progression of PD.     

Selective Depletion of Dopamine, Octopamine, and 5-Hydroxytryptamine in the Nervous Tissue of the Cockroach (Periplaneta americana)

High-performance liquid chromatography with electrochemical detection was used to measure the concentrations of 3,4-dihydroxyphenylethylamine (dopamine), 5-hydroxytryptamine (5-HT), p-hydroxyphenylethanolamine (octopamine), alpha-methyl-p-tyrosine, and tryptophan in the cerebral ganglia of cockroaches (Periplaneta americana) after peripheral administration of alpha-methyl-p-tyrosine and alpha-methyltryptophan. In addition, the levels of dopamine, 5-HT, octopamine, alpha-methyl-p-tyrosine, and tryptophan were determined after injection of alpha-methyl-p-tyrosine, 6-hydroxydopamine, or 5,7-dihydroxytryptamine directly into the cerebral ganglia by means of microinjection needles. Peripheral administration of alpha-methyl-p-tyrosine (400-1,600 micrograms/insect) caused a reduction in dopamine and 5-HT concentrations in cockroach cerebral ganglia, although the reduction in dopamine concentrations was more pronounced. Peripheral injections of alpha-methyl-p-tyrosine also reduced octopamine levels in the cerebral ganglia. Peripheral injection of alpha-methyltryptophan (400-1,600 micrograms/insect) caused a marked reduction in 5-HT and tryptophan concentrations in cockroach cerebral ganglia without altering dopamine or octopamine concentrations. Central injections of alpha-methyl-p-tyrosine (80 micrograms/insect) reduced dopamine concentrations in the cerebral ganglia. However, neither 6-hydroxydopamine (20 micrograms/insect) nor 5,7-dihydroxytryptamine (20 micrograms/insect) caused reductions in amine levels when applied near or directly into the cerebral ganglia. The results suggest that specific lesions of aminergic neurons in insects by either 6-hydroxydopamine or 5,7-dihydroxytryptamine are impractical. The specific, long-lasting depletion of 5-HT by alpha-methyltryptophan suggests that this chemical may be useful in elucidating the functions of 5-HT in insects.     

Studies on axonal transport in dopaminergic neurons: effect of neuropharmacologic lesions

Axonal transport of [³H]protein to the nucleus accumbens, olfactory tubercle, septal region, caudate nucleus, and hypothalamic region was investigated in rats after unilateral injection of [³H]lysine into the substantia nigra. Co-injection of 2 μg of colchicine with the [³H]lysine depressed the recovery of [³H]protein from forebrain structures by over 70 percent without altering incorporation into midbrain protein, whereas 1 or 2 μg of cycloheximide decreased the incorporation of labelled lysine into both midbrain and forebrain protein by 69 to 76 percent. Partial 6-hydroxydopamine (6-OHDA)-induced lesions of the substantia nigra decreased striatal dopamine levels by 78 percent and reduced axonal protein transport by 47 to 82 percent. Injecting the [³H]lysine 2 mm dorsal to the substantia nigra decreased transport by 95 percent. Unilateral kainic acid-induced lesions of the caudate, which decreased striatal glutamic acid decarboxylase activity by 44 percent and spared striatal dopamine content, did not alter the transport of [³H]protein. Thus, axonal transport of protein in dopamine-containing systems is dependent upon the site of injection of labelled precursor and upon the integrity of a 6-OHDA sensitive pathway. Further, transport is sensitive to inhibitors of both microtubule assembly and protein synthesis, and insensitive to intrastriatal kainic acid lesions.     

Protein phosphorylation in rat caudate homogenate: stimulatory effects of dopamine and enhancement of dopamine response following 6-hydroxydopamine treatment.

Dopamine (3-hydroxytyramine) stimulates the incorporation of 32P into proteins endogenous to a homogenate of rat caudate nucleus when 10 microM [gamma-32P]-ATP is used as a substrate following preincubation with 400 microM ATP. The increase in 32P incorporation has pharmacological characteristics similar to caudate tissue. Chronic depletion of striatal dopamine in vivo by stereotaxic injection of 6-hydroxydopamine in the nigrostriatal pathway results in a significant enhancement of the dopamine stimulation of 32 p incorporation in vitro. Cyclic AMP-stimulated phosphorylation of caudate proteins remains unchanged following 6-hydroxydopamine treatment.     

In Vivo Voltammetric Study of 6-Hydroxydopamine-Induced Neuronal Degradation

Freely moving rats were injected intraventricularly with 200 micrograms of 6-hydroxydopamine (6-OHDA) and examined for transport of this substance to the striatum, degradation of dopamine (DA) neurons, and functional recovery through microcomputer-controlled in vivo voltammetry. Approximately 6 min after the injection, 6-OHDA began to appear in the extracellular fluid of the contralateral striatum. It increased linearly and began to decrease exponentially with the termination of the injection. Two hours after the injection with 6-OHDA, a peak began to appear at the same potential as the peak of DA in the differential pulse voltammogram. It persisted for approximately 3 days. When the rats were injected intraperitoneally with L-3,4-dihydroxyphenylalanine (L-Dopa), the conversion of L-Dopa to DA was not found 1 week after the 6-OHDA injection, but was clearly recognized 5 months after the injection. When the rats were examined for behavioral changes arising from the L-Dopa injection, they were found to be clearly less hyperactive 5 months after the 6-OHDA injection than 1 week after.     

CHANGES IN CENTRAL NORADRENALINE NEURONSADMINISTRATION AFTER SYSTEMIC 6-HYDROXYDOPAMINE ADMINISTRATION

—Intravenous injection of a large dose of 6-hydroxydopamine (100 mg/kg) to adult rats caused a significant and long-lasting reduction (about 30 per cent) of the in oirro uptake of [³H]NA in the cerebral cortex and spinal cord, while no changes were seen in the hypothalamus. The endogenous NA in whole brain was similarly reduced (about 20 per cent). Fluorescence histochemistry revealed catecholamine accumulations which are degenerative signs, induced by 6-hydroxydopamine, in axons of the dorsal NA bundle innervating the cerebral cortex. It is concluded that the blood–brain barrier in adult rats is not completely protective with respect to the neurotoxic action of systemically injected 6-hydroxydopamine, which can produce degeneration of a significant number of NA nerve terminals in the cerebral cortex and spinal cord. Previous studies have shown that 6-hydroxydopamine caused a permanent and selective degeneration of a large number of central NA nerve terminals when injected systemically up to 1 week after birth, due to an incompletely developed blood-brain barrier. This barrier for 6-hydroxydopamine develops between the 7th and 9th day after birth (Sachs , 1973). In the present study 6-hydroxydopamine was found to cause a small transient reduction in [³H]NA uptake in cerebral cortex of rats between 9 and 28 days of age, while in older rats the damage produced by 6-hydroxydopamine was long-lasting. Thus, the NA nerves ascending to the cerebral cortex seem to possess a regenerative capacity to a 6-hydroxydopamine-induced degeneration up to about 28 days postnatally, but which later disappears or is markedly retarded.     

甲醛炎性痛对大鼠脊髓HO-1表达的影响

目的:观察足底注射甲醛引起的外周组织炎性疼痛是否可诱导大鼠脊髓血红素氧合酶-1(HO-1)表达发生改变以及变化的时程特征。方法:健康雄性SD大鼠随机分为7组(n=6):对照组(control组)、甲醛6 h组(F6 h组)、甲醛12 h(F12 h组)、甲醛1 d组(F1 d组)、甲醛2 d组(F2 d组)、甲醛3 d组(F3 d组)和甲醛7 d组(F7 d组)。采用足底注射甲醛溶液复制炎性痛模型,采用免疫组织化学方法检测左、右两侧脊髓后角以及中央管周围灰质HO-1蛋白的表达。结果:Control组大鼠HO-1免疫反应阳性细胞在脊髓后角及中央管周围灰质仅有少量分布,且这些细胞染色较浅。足底注射甲醛后6 h,L5节段双侧脊髓后角和中央管周围灰质HO-1免疫反应阳性细胞数目即有所增多,足底注射甲醛后12 h时,双侧脊髓后角和中央管周围灰质HO-1免疫反应阳性细胞数目进一步增多,阳性细胞染色明显加深,1 d时阳性细胞数目和染色深度均达到高峰,7 d时仍高于control组水平。各时间点双侧脊髓后角比较,阳性细胞数目和阳性细胞染色深度均无明显差异。结论:大鼠足底注射甲醛引起的炎性痛可诱导双侧脊髓后角和中央管周围灰质HO-1表达增多,以注射甲醛后1 d时增多最为明显。