Nitric oxide signaling contributes to ectopic orofacial neuropathic pain.

Inferior alveolar nerve (IAN) injury induces persistent ectopic pain which spreads to a wide area in the orofacial region. Its exact mechanism remains unclear. We investigated the involvement of nitric oxide (NO) in relation to ectopic orofacial pain caused by IAN transection (IANX). We assessed the changes in mechanical sensitivity of the whisker pad skin following IANX, neuronal nitric oxide synthase (nNOS) expression in the trigeminal ganglion (TG), and the functional significance of NO in relation to the mechanical allodynia following intra-TG administration of a chemical precursor to NO and selective nNOS inhibitors. IANX induced mechanical allodynia, which was diminished by intra-TG administration of selective nNOS inhibitors. NO metabolites and nNOS immunoreactive neurons innervating the lower lip were also increased in the TG. Intra-TG administration of nNOS substrate induced the mechanical allodynia. The present findings suggest that NO released from TG neurons regulates the excitability of TG neurons innervating the whisker pad skin, and the enhancement of TG neuronal excitability may underlie ectopic mechanical allodynia.

Memory phenotype CD8(+) T cells in IL-15 transgenic mice are involved in early protection against a primary infection with Listeria monocytogenes.

We recently constructed IL-15 transgenic (Tg) mice using cDNA encoding a secretable isoform of the IL-15 precursor protein under the control of an MHC class I promoter. The IL-15 Tg mice exhibited resistance against a primary infection with Listeria monocytogenes. The numbers of memory CD8(+) T cells were markedly increased in the IL-15 Tg mice following Listeria infection accompanied by sustained IL-15 production. The increased CD44(+)CD8(+) T cells in the infected IL-15 Tg mice were not specialized to recognize Listeria-specific antigen but produced a large amount of IFN-gamma in response to bystander stimulation exogenous IL-15 in combination with IL-12. Furthermore, Listeria-specific Th1 response by CD4(+) T cells was significantly augmented in the IL-15 Tg mice compared with control mice following Listeria infection. In vivo depletion of the CD8(+) T cells by anti-CD8 monoclonal antibody and adoptive transfer of the T cells from naive IL-15 Tg mice indicated that the CD8(+) T cells functioned not only to eliminate bacteria at the early stage of infection but also to promote Th1 response to L. monocytogenes. Overexpression of IL-15 shed light on a novel role of memory CD8(+) T cells in early protection and promotion of Th1 response against a primary infection with L. monocytogenes.

Overexpression of IL-15 in vivo enhances Tc1 response, which inhibits allergic inflammation in a murine model of asthma.

IL-15, a pleiotropic cytokine, is involved in the inflammatory responses in various infectious and autoimmune diseases. We have recently constructed IL-15-transgenic (Tg) mice, which have an increased number of memory-type CD8+ T cells in the peripheral lymphoid tissues. In the present study, we found that eosinophilia and Th2-type cytokine production in the airway were severely attenuated in OVA-sensitized IL-15-Tg mice following OVA inhalation. IL-15-Tg mice preferentially developed Tc1 responses mediated by CD8+ T cells after OVA sensitization, and in vivo depletion of CD8+ T cells by anti-CD8 mAb aggravated the allergic airway inflammation in IL-15-Tg mice following OVA inhalation. Adoptive transfer of CD8+ T cells from OVA-sensitized IL-15-Tg mice into normal mice before OVA sensitization suppressed Th2 response to OVA in the normal mice. These results suggest that overexpression of IL-15 in vivo suppresses Th2-mediated-allergic airway response via induction of CD8+ T cell-mediated Tc1 response.

The role of leukotriene D4 in allergic rhinitis.

We investigated the clinical significance of leukotriene D4 (LTD4) in nasal symptoms of allergy and compared this with antigen and histamine. Nasal provocations were carried out in patients with allergic rhinitis using serially increasing doses of LTD4, histamine, or antigen. The nasal responses induced were evaluated by counting the number of sneezes, the quantity of nasal secretion, and of nasal airway resistance. When the effects of topical provoking agents were compared at the threshold concentration, LTD4 produced no sneezing--unlike antigen and histamine--increased nasal secretion to a lesser degree than antigen and histamine (P less than .001), and increased nasal airway resistance similar to histamine but less than antigen (P less than .1) and longer than histamine, and similar to antigen in duration. LTD4 was approximately 5,000 times stronger than histamine in threshold concentration for nasal response. In conclusion, LTD4 plays an important role in nasal allergy presumably through long lasting and strong nasal blockage effects.

The effects of autonomotropic drugs on allergic nasal mucosa.

The purpose of the present study was to elucidate the effects of different kinds of autonomotropic drugs on the nasal mucosa as well as on the nasal reaction to specific allergens in patients with nasal allergy. First, phenylephrine (alpha-agonist), phentolamine (alpha-antagonist), isoproterenol (beta-agonist), propranolol (beta-antagonist), methacholine (choline agonist), or ipratropium (choline antagonist) was applied to the nasal mucosa with an atomizer using saline as control. Definitive effects appeared at the spray of alpha-agonist or choline agonist. Phenylephrine reduced nasal airway resistance, and methacholine increased nasal secretion. Secondly, after treatment with the drugs, nasal provocations were performed. The statistically significant effects were noted as follows: phenylephrine spray inhibited the increase of nasal airway resistance, while phentolamine or isoproterenol enhanced it. Methacholine enhanced nasal secretion, while ipratropium inhibited it. None of the drugs, however, affected the number of sneezes. The present results suggest that adrenergic receptors are mainly distributed on the walls of vessels and cholinergic receptors mainly on the secretory glands. Pharmacological conditions of the local autonomic nervous system would affect the nasal response in allergy in different ways according to different conditions.

Nasal histamine sensitivity in allergic rhinitis.

Our recent studies of nasal histamine sensitivity in nasal allergy are presented. The sensitivity differed according to the site and size of the nasal mucosa and was correlated with the degree of provocation reaction to antigen. This sensitivity appears to be established in childhood and strongly correlated with the increased sensitivity of histamine receptors as well as the autonomic nervous system dysfunction of the nose.