Metabotropic glutamate mGlu1 receptor mRNA expression in dorsal root ganglia of rats after peripheral nerve injury.

Although cerebral and spinal metabotropic glutamate mGlu(1) receptors are thought to be involved in nociception and in the development/maintenance of chronic pain, it is still unclear to what extent mGlu(1) receptors are present in the dorsal root ganglia of peripheral sensory afferents, and whether their expression is affected during development of chronic pain. It was found in the present study that mGlu(1) receptor messenger RNA (mRNA) is present in rat L5 dorsal root ganglia and that it is strongly downregulated after unilateral axotomy of the tibial branch of the sciatic nerve, a model of chronic neuropathic pain. However, as sham-operated animals showed a similar downregulation, it is suggested that peripheral tissue damage is sufficient to result in a reduction of peripheral mGlu(1) receptor expression.

Pathogenic function of IL-1 beta in psoriasiform skin lesions of flaky skin (fsn/fsn) mice.

IL-1 acts on many cells as an inflammatory mediator. Its two forms, IL-1 alpha and IL-1 beta, are regulated differentially within hyperproliferative inflammatory skin conditions, such as psoriasis. While IL-1 alpha is down-regulated within psoriatic lesions, the levels of IL-1 beta are increased. However, some investigators have described an inactive form of IL-1 beta in psoriasis, while others have detected increased IL-1 beta activity within these lesions. Thus, its in vivo role remains unclear. We have assessed expression and function of IL-1 beta within psoriasiform skin lesions of the spontaneous mouse mutation flaky skin (fsn/fsn ). It was found that IL-1 beta was increased by 357% within psoriasiform lesions of fsn/fsn mice compared with their wild-type or heterozygous (+/?) littermates (P < 0.00001). When the IL-1 beta function was inhibited by i.p. injection with a neutralizing MoAb, no effects were seen in +/? mice. In contrast, psoriasiform features in fsn/fsn mice were alleviated dramatically, as demonstrated by a 40% decrease of the epidermal thickness and a diminished number of intra-epidermal microabscesses. In addition, infiltrating epidermal CD4(+) and CD8(+) T cells were decreased by 68% and 81%, respectively (P < 0.05), and epidermal Langerhans cells also were reduced by 36% (P < 0.005). In contrast, mast cells were not affected, suggesting differential responses of various cutaneous cell types. Our results demonstrate an important in vivo role of IL-1 beta for the generation of hyperproliferative inflammatory skin lesions in the fsn/fsn model.

Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain.

Although cannabinoids are known to be more effective analgesics against chronic rather than acute pain, the mechanism underlying this phenomenon is still unclear. We report now that contralateral thalamic cannabinoid CB(1) receptors are upregulated after unilateral axotomy of the tibial branch of the sciatic nerve, a rat model of chronic neuropathic pain, and hypothesize that cannabinoid CB(1) receptor upregulation contributes to the increased analgesic efficacy of cannabinoids in chronic pain conditions.

Critical role of neutrophils for the generation of psoriasiform skin lesions in flaky skin mice.

Although T cell dysregulation is thought to underlie the pathogenesis of psoriasis, prominent infiltration and microabscess formation by neutrophils is a distinctive hallmark feature of this common disorder. The exact role of neutrophils in the pathogenesis of psoriasiform alterations in vivo, however, is unknown. Similar to human psoriasis, flaky skin mice (fsn/fsn) revealed a prominent infiltrate of neutrophils, and microabscesses within the hyperproliferative epidermis were associated with de novo expression of intercellular adhesion molecule-1. Intraperitoneal injection with the neutrophil-depleting RB6-8C5 monoclonal antibody (anti-Ly-6G) resulted in a dramatic reduction of the epidermal thickness by 58% compared with isotype-treated animals (p < 0.001). In addition, epidermal microabscesses were conspicuously absent (p < 0.001), and cutaneous neutrophils and T cells, but not mast cells or dendritic cells, were markedly reduced in anti-Ly-6G-treated mice. Proinflammatory cytokines, including tumor necrosis factor alpha and interleukin-1, were also downregulated. Therapeutic effects occurred as early as 4 d after beginning of treatment. Wildtype skin was not affected. When the integrin alphaMbeta2 (CD11b/CD18), which mediates neutrophil localization through binding to intercellular adhesion molecule-1, was blocked in vivo with the M1/70 monoclonal antibody, the epidermal thickness was reduced by 31% (p < 0.002), and neutrophil and T cell accumulation was diminished compared with control animals. Likewise, treatment of fsn/fsn mice with the MP1-22E9 monoclonal antibody neutralizing granulocyte macrophage-colony stimulating factor, a cytokine stimulating neutrophils by upregulating alphaMbeta2, resulted in significant reduction of inflammation and acanthosis by 30% (p < 0.003). These results demonstrate a critical pathogenic role of neutrophils for hyperproliferative inflammatory lesions in fsn/fsn mice, suggesting that blocking neutrophil function may have therapeutic benefit in some human skin disorders.

Elevation of circulating NO: its effects on hemodynamics and vascular smooth muscle cell proliferation in rats.

Object of our study was to characterize the effects of elevated circulating NO on hemodynamics and vascular smooth muscle cell proliferation in rats. Administration of molsidomine (10, 25, 50 mg/kg, bid p.o.) was followed by pharmacodynamic effects: elevation of plasma nitrite/nitrate levels and reduction of blood pressure (25 and 50 mg/kg, bid p.o.). Under these conditions no antiproliferative activity occurred in a model of "air dried" carotid artery injury. From these results we conclude that NO does not act as an antiproliferative agent under conditions where smooth muscle cell injury predominates.

Stress induced biosynthesis of a 31 kd-glycoprotein in goldfish brain.

The de novo protein synthesis in goldfish brain has been studied under defined stress conditions and after training in an active swimming task. One- and two-dimensional gel electrophoresis of the brain proteins previously labelled in vivo with 35S-methionine indicated that the synthesis of one distinct protein increases after stress but not after successful training. This protein is a glycoprotein with an apparent molecular weight of 31 kd and an isoelectric point of pH 5. It is discussed that the protein may be the ACTH precursor "pro-opiomelanocortin".

Influence of isolation stress and inhibited protein biosynthesis on learning and memory in goldfish.

Goldfish, Carassius auratus auratus L. (Pisces, Cyprinidae), were trained by different kinds of training procedures under the influence of cycloheximide or puromycin, two inhibitors of the protein biosynthesis. After active avoidance training in a shuttle box an apparent amnesia was found only when the fish were exposed to a one day lasting isolation stress prior to training. If the animals were accustomed to isolation over a period of 20 days the inhibitors did not affect memory formation. After learning by positive reinforcement (food rewarded color discrimination) in groups under stress-free conditions, neither learning nor memory formation were impaired in spite of the presence of cycloheximide. It is suggested that the amnestic effect of the inhibitors is caused by isolation treatment. Lack of the additional stress, however, leads to memory formation.