ABSTRACT
A neurogenic contribution to joint inflammation has been demonstrated in rat adjuvant arthritis, however as inflammatory mechanisms vary between species it is unclear whether these observations can be applied more generally. The aim of this study was to assess the neurogenic contribution to cellular infiltration and other outcome measures in a guinea pig model of arthritis. Compared to arthritic controls, animals pre-treated with capsaicin at doses sufficient to reduce sensory activity exhibited a significant attenuation of both mechanical and thermal hyperalgesia. Measures of inflammation, including swelling and radiological scores were also improved. Furthermore, capsaicin selectively reduced synovial T cell infiltration whereas no difference was seen with respect to synovial macrophages. These observations confirm a neurogenic component in guinea pig arthritis and indicate a selective sensory influence on T cell activity within the chronically inflamed joint. As T cells are strongly implicated in the pathogenesis of rheumatic disease, such an influence may serve to explain some of the clinical features observed in these disorders.
Subject(s)
Arthritis, Experimental/physiopathology , Cell Movement/physiology , Leukocytes/immunology , Neurogenic Inflammation/physiopathology , Neurons, Afferent/immunology , Peripheral Nerves/physiopathology , Synovitis/physiopathology , Animals , Arthritis, Experimental/drug therapy , Arthritis, Experimental/immunology , Capsaicin/pharmacology , Cell Movement/drug effects , Disease Models, Animal , Guinea Pigs , Joints/immunology , Joints/innervation , Joints/physiopathology , Leukocytes/drug effects , Macrophages/drug effects , Macrophages/immunology , Male , Neurogenic Inflammation/drug therapy , Neurogenic Inflammation/immunology , Neurons, Afferent/drug effects , Neurons, Afferent/metabolism , Neuropeptides/metabolism , Peripheral Nerves/drug effects , Peripheral Nerves/immunology , Synovitis/drug therapy , Synovitis/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Treatment OutcomeABSTRACT
The precise nature of neurokin receptor involvement in human immune cell chemotaxis is unclear. This study therefore sought to directly compare the chemotactic effects of neurokinins on human T lymphocytes and monocytes. Substance P was found to have a similar dose-dependent chemotactic action on T lymphocyte and monocyte populations. In contrast, T lymphocytes were found to be more responsive than monocytes both to the highly selective NK-1 agonist, [Sar(9)Met O(2)(11)]-substance P, and also to the NK-2 selective agonist, beta-alanine neurokinin A((4-10)). Consistent with these findings, substance P-induced chemotaxis of both T lymphocyte and monocytes was attenuated by the selective NK-1 antagonist LY303870. However, the selective NK-2 antagonist MEN 10,376 was only effective in inhibiting the T lymphocyte response. The study confirms that neurokinins have chemotactic actions on immune cells and indicates important functional differences between human T lymphocyte and monocyte responses. This provides a potential mechanism by which the nervous system can selectively influence cellular recruitment in inflammatory disease.
Subject(s)
Chemotaxis, Leukocyte , Monocytes/metabolism , Receptors, Neurokinin-1/metabolism , T-Lymphocytes/metabolism , Chemotaxis, Leukocyte/drug effects , Dose-Response Relationship, Drug , Humans , Indoles/pharmacology , Inflammation/immunology , Inflammation/pathology , Monocytes/drug effects , Monocytes/immunology , Neurokinin A/analogs & derivatives , Neurokinin A/antagonists & inhibitors , Neurokinin A/pharmacology , Neurokinin-1 Receptor Antagonists , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/pharmacology , Piperidines/pharmacology , Receptors, Neurokinin-1/agonists , Receptors, Neurokinin-2/agonists , Receptors, Neurokinin-2/antagonists & inhibitors , Receptors, Neurokinin-2/metabolism , Substance P/analogs & derivatives , Substance P/antagonists & inhibitors , Substance P/pharmacology , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
1. We have studied the characteristics of the abnormal properties of damaged myelinated fibers (conduction velocity > 2.0 m/ s) after peripheral nerve injury in a novel in vitro model of the rat sciatic nerve/dorsal root ganglion/dorsal root (L4-5) preparation removed from control naíve or sham-operated rats and animals that had received sciatic neurectomy 12-24 days before the in vitro study. A total of 122-245 filaments were recorded in each dorsal root. The proportion of A alpha, beta and A delta fibers were not significantly different between control, sham-operated, and axotomized nerves. Spontaneous activity was recorded in 3.4% (A alpha, beta) and 4.6% (A delta) of fibers in comparison with 0.4% (A alpha, beta) and 0.3% (A delta) in naíve controls. 2. A sporadic, irregular, low-frequency (< 1 Hz) firing was seen in 26% of the fibers with spontaneous activity. Periodical (irregular) bursting pattern was observed in 43% of spontaneously active fibers, whereas a relatively stable, ongoing firing pattern (median frequency: 7.1 Hz) was displayed by 31% of active fibers. 3. Mechanosensitivity of the neuroma/peripheral nerve was displayed in preparations from lesioned [axotomized: 18.2% (A alpha, beta) and 14.1% (A delta), sham operated: 2% (A alpha, beta) and 0% (A delta)], but not control naíve animals. There was no correlation between the presence of spontaneous activity and mechanosensitivity in single fibers. 4. The principal site of spontaneous activity generation was the dorsal root ganglion. Transection of the peripheral nerve (or removal of the neuroma), while recording from dorsal root filaments, produced a cessation of firing in 21% of fibers firing with ongoing discharge. The remaining active fibers continued firing until the DRG was removed. A sustained injury discharge was observed in damaged fibers but not control, undamaged fibers from naíve animals after acute peripheral nerve transection. 5. We present an in vitro model for the study of abnormal primary sensory activity in peripheral neuropathy. Although our data are consistent with in vivo electrophysiological findings in published reports, the proportion of damaged afferent fibers displaying spontaneous activity was significantly lower under in vitro conditions. This model may serve as a valuable tool for further physiological and pharmacological studies of peripheral neuropathy.
