neurokinin-a and Acute-Disease

To address the neurochemistry of the mechanisms that underlie the development of acute and persistent pain, our laboratory has been studying mice with deletions of gene products that have been implicated in nociceptive processing. We have recently raised mice with a deletion of the preprotachykinin-A gene, which encodes the peptides substance P (SP) and neurokinin A (NKA). These studies have identified a specific behavioral phenotype in which the animals do not detect a window of "pain" intensities; this window cuts across thermal, mechanical, and chemical modalities. The lowered thermal and mechanical withdrawal thresholds that are produced by tissue or nerve injury, however, were still present in the mutant mice. Thus, the behavioral manifestations of threshold changes in nociceptive processing in the setting of injury do not appear to require SP or NKA. To identify relevant neurochemical factors downstream of the primary afferent, we are also studying the dorsal horn second messenger systems that underlie the development of tissue and nerve injury-induced persistent pain states. We have recently implicated the gamma isoform of protein kinase C (PKCgamma) in the development of nerve injury-induced neuropathic pain. Acute pain processing, by contrast, is intact in the PKCgamma-null mice. Taken together, these studies emphasize that there is a distinct neurochemistry of acute and persistent pain. Persistent pain should be considered a disease state of the nervous system, not merely a prolonged acute pain symptom of some other disease conditions.

Topics: Acute Disease; Animals; Chronic Disease; Humans; Isoenzymes; Mice; Mice, Knockout; Neurochemistry; Neurokinin A; Pain; Protein Kinase C; Protein Precursors; Substance P; Tachykinins

The localization of neurokinin A (NK-A) in the normal ankle joint of rats was investigated by an immunoelectron microscopic technique with specific antisera to NK-A. Immunoreactivity was detected in bone matrix, myelinated nerve fiber in the periosteum, and bone marrow and synovial cells. No immunoreactivity was observed in osteoblasts, osteocytes, and osteoclasts. Using radioimmunoassay (RIA), a detectable concentration of NK-A was observed in the bone marrow, periosteum, cortical bone, and ankle of normal rats. In rats with chronic adjuvant arthritis, induced by intradermal injection of mycobacterium butyricum in paraffin oil into the base of the tail, the concentrations of NK-A using RIA in ankles and spinal cords were found to be significantly increased compared with acute or control rats. There were no significant differences between the latter two. Similarly, increased NK-A labeling was observed using immunoelectron microscopy in bone matrix and bone marrow monocyte cells of the chronic arthritic rats. These findings indicate the existence of as well as a biological role of NK-A in bone and joint tissues.

Topics: Acute Disease; Animals; Ankle Joint; Arthritis, Experimental; Bone and Bones; Chronic Disease; Female; Microscopy, Immunoelectron; Neurokinin A; Radioimmunoassay; Rats; Rats, Inbred Lew

In a recent study we have shown a bilateral release of substance P (SP)-, neurokinin A (NKA)-, calcitonin gene-related peptide (CGRP)- and neuropeptide Y (NPY)-like immunoreactivity (-LI) in rat synovial fluid during acute monoarthritis. In order to elucidate the mechanisms underlying these phenomena, we examined the correlation between neuropeptide-LI in rat cerebrospinal fluid (CSF) and synovial fluid and between plasma and synovial fluid following the intra-articular injection of equal volumes (0.05 ml) of either Freund's adjuvans, carrageenan 2%, substance P 10(-5) M or human recombinant interleukin-1 alpha. Control rats were given saline intra-articularly. CSF, plasma and synovial fluid from the knee joints were obtained at 2, 6 and 24 h after injection and were analysed by specific radioimmunoassays. The intra-articular injection of pro-inflammatory substances induced changes in neuropeptide-LI in synovial fluid, CSF and plasma. However, there was no correlation between neuropeptide-LI in synovial fluid and plasma or between synovial fluid and CSF. The results of the present study does not support the hypothesis that the bilateral changes in neuropeptide-LI in synovial fluid were due to a release of neuropeptides from the inflamed joint into the systemic circulation. However, in carrageenan induced inflammation there was a tendency towards a correlation in SP-LI between CSF and synovial fluid suggesting that central neurogenic mechanisms should be studied in order to explain the bilateral changes seen.

Topics: Acute Disease; Animals; Arthritis; Calcitonin Gene-Related Peptide; Knee Joint; Male; Neurokinin A; Neuropeptide Y; Neuropeptides; Osmolar Concentration; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Substance P; Synovial Fluid

Antibody microprobes were used to study the release of immunoreactive neurokinin A into the spinal cord of anaesthetised cats during and following injection of a knee joint with kaolin and carrageenan. A basal level of immunoreactive neurokinin A was detected prior to any noxious stimuli. Innocuous mechanical joint stimuli (flexion or pressure) did not alter this basal level of release. However, on injection of kaolin and carrageenan into a knee joint, evidence of release into the ipsilateral spinal cord was immediately observed. Initially, immunoreactive neurokinin A was detected in 2 regions: one at the dorsal surface of the spinal cord and the other centred on the superficial dorsal horn. Within 1 h of joint injection, however, immunoreactive neurokinin A was detected throughout the dorsal horn and the adjacent white matter. The extensive spread and persistence of immunoreactive neurokinin A in the spinal cord may underlie some of the prolonged excitability changes evoked by brief noxious stimuli and peripheral inflammation reported by other laboratories.

Topics: Acute Disease; Animals; Arthritis; Autoradiography; Carrageenan; Cats; Disease Models, Animal; Kaolin; Molecular Probes; Neurokinin A; Spinal Cord; Stress, Mechanical