neurokinin-a and Arthritis

In spinal cord neurons in anesthetized rats, the role on neurokinin A and neurokinin-2 receptors in the processing of nociceptive information from the knee joint was studied. The specific non-peptide antagonist at the neurokinin-2 receptor, SR48968, its inactive R-enantiomer, SR48965, neurokinin A, substance P and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), were administered ionophoretically close to neurons with input from the knee joint. SR48968 reduced the effects of exogenous neurokinin A, but not those of exogenous substance P and AMPA, indicating selective blockade of neurokinin-2 receptors. In most neurons with input from the normal knee joint, SR48968 reduced dose-dependently the responses to noxious pressure with applied to the knee, and in approximately 50% of the neurons the responses to innocuous pressure. The administration of SR48968 during the induction of an experimental joint inflammation markedly attenuated the development of inflammation-evoked hyperexcitability. In hyperexcitable neurons with input from the inflamed joint, SR48968 reduced the responses to noxious and innocuous pressure. The relative reduction of the responses was more pronounced than in neurons with input from the normal joint. None of the effects of SR48968 was mimicked by SR48965. These data show that neurokinin-2 receptors are involved in the spinal processing of nociceptive information from the normal joint. Furthermore, neurokinin-2 receptors must be coactivated at an early stage of inflammation, to allow the generation of hyperexcitability. Finally, neurokinin-2 receptors are involved in maintenance of hyperexcitability during inflammation. In summary, spinal neurokinin-2 receptors are important in the generation of pain in the normal and inflamed joint.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Arthritis; Benzamides; Carrageenan; Hyperalgesia; Iontophoresis; Kaolin; Knee Joint; Male; Neurokinin A; Nociceptors; Pain; Piperidines; Pressure; Rats; Rats, Wistar; Receptors, Neurokinin-2; Spinal Cord; Substance P

To study the interaction between human recombinant interleukin-1 alpha and the nervous system, substance P-, neurokinin A-, calcitonin gene-related peptide-, and neuropeptide Y-like immunoreactivity in the cerebrospinal fluid, plasma, and temporomandibular joint (TMJ) perfusates of rats during acute experimental monarthritis were examined. The right TMJs of the experimental rats were injected with 0.01 mL of human recombinant interleukin-1 alpha. The right TMJs of control rats were injected with 0.01 mL of saline. Cerebrospinal fluid, plasma, and perfusates from the right TMJs were obtained at 2, 6, and 24 hours following injection, and neuropeptide-like immunoreactivity was analyzed by specific radioimmunoassays. Values of neuropeptide-like immunoreactivity for the experimental rats were compared with those of the control rats. In the experimental group, substance P-, neurokinin A-, and calcitonin gene-related peptide-like immunoreactivities were increased in cerebrospinal fluid compared to those of the control group. In plasma, no changes in neuropeptide-like immunoreactivities rose significantly in the TMJ perfusates. Most pronounced changes in neuropeptide Y-like immunoreactivity occurred intra-articularly in the TMJ perfusates. The results indicate that the contribution of the nervous system to human recombinant interleukin-1 alpha-induced monarthritis is most pronounced in the affected joint.

Topics: Animals; Arthritis; Calcitonin Gene-Related Peptide; Humans; Interleukin-1; Male; Neuroimmunomodulation; Neurokinin A; Neuropeptide Y; Neuropeptides; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Substance P; Synovial Fluid; Temporomandibular Joint; Temporomandibular Joint Disorders

Forty-one patients (37 female and four male) with signs and symptoms of temporomandibular joint arthritis, were separated into two diagnostic groups (group I: inflammatory; group II: degenerative/non-specific joint disease). They were examined clinically, fluid was aspirated from the joint with saline and venous blood samples were collected at the same time. The joint fluid and plasma samples were analysed for neuropeptide-like immunoreactivity, i.e. neuropeptide Y (NPY-LI), calcitonin gene-related peptide (CGRP-LI), substance P (SP-LI) and neurokinin A (NKA-LI), using competitive radioimmunoassays. The aim was to investigate any co-variation of the peptides in the joint fluid and plasma. In group I, the median values of peptide concentrations in joint fluid were SP-LI = 129, CGRP-LI = 75, NKA-LI = 36 and NPY-LI = 676 pmol/l and in group II, SP-LI = 52, CGRP-LI = 64, NKA-LI = 45 and NPY-LI = 318 pmol/l. There were no significant differences between the groups for peptide concentrations. In group I, all the neuropeptides were strongly correlated. In group II, SP-LI and NKA-LI were strongly correlated while CGRP-LI was weakly correlated with NPY-LI and NKA-LI. Multiple step-wise regression analysis showed that most of the variation in NPY-LI, CGRP-LI and SP-LI in group I was explained by NKA-LI, but the regression did not reach statistical significance in group II.

Topics: Adult; Aged; Arthritis; Arthritis, Psoriatic; Arthritis, Rheumatoid; Calcitonin Gene-Related Peptide; Female; Humans; Male; Middle Aged; Neurokinin A; Neuropeptide Y; Osteoarthritis; Regression Analysis; Spondylitis, Ankylosing; Substance P; Synovial Fluid; Temporomandibular Joint Disorders

The contribution of the nervous system to the pathophysiology of rheumatoid arthritis has been proposed to be mediated by certain neuropeptides. Neuropeptide Y, calcitonin gene-related peptide, substance P, and neurokinin A are considered modulators of inflammatory joint disease. Parameters of pain, as well as occlusal signs of tissue destruction from the arthritic TMJ and the corresponding neuropeptide concentrations in TMJ synovial fluid, were investigated in patients with various inflammatory joint diseases. The patients with rheumatoid arthritis were also examined in a separate diagnostic group. Visual analog scale, palpatory tenderness, maximal voluntary mouth opening, and anterior open bite were correlated to neuropeptide-like immunoreactivities of the above four neuropeptides. It was found that high concentrations of calcitonin gene-related peptide and neuropeptide Y in TMJ fluid are associated with pain, impairment of mandibular mobility, and occlusal signs of TMJ destruction in patients with rheumatoid arthritis. The results indicated neuropeptide involvement in rheumatoid arthritis, proposing a potentiation of the symptoms and signs by the inflammatory action of calcitonin gene-related peptide and neuropeptide Y.

Topics: Adult; Arthritis; Arthritis, Rheumatoid; Calcitonin Gene-Related Peptide; Female; Humans; Inflammation Mediators; Male; Middle Aged; Neuroimmunomodulation; Neurokinin A; Neuropeptide Y; Neuropeptides; Pain; Pain Measurement; Range of Motion, Articular; Statistics, Nonparametric; Substance P; Synovial Fluid; Temporomandibular Joint Disorders

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

Topics: Amino Acid Sequence; Animals; Arthritis; Cartilage, Articular; Cattle; Collagenases; Dinoprostone; Kinetics; Molecular Sequence Data; Neurokinin A; Neurokinin B; Peptide Fragments; Substance P

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

Near nanomolar concentrations of substance P induce production of IL-1 or an IL-1-like activity in the mouse macrophage cell line P388D1. Moreover, this could be accomplished with the carboxyl-terminal octapeptide substance P4-11, and could be inhibited with the substance P antagonist [D-Pro2, D-Trp7,9]-substance P. Two other mammalian neurokinins, neurokinin A and neurokinin B, were also found to induce secretion of IL-1-like activity in P388D1 cells. These findings suggest that activation of immune cells by neuromodulators can contribute to the maintenance of the chronic inflammatory state and the immunopathology observed in arthritic disease mediated by IL-1. The results also suggest that one approach to the treatment of rheumatoid arthritis might be to attempt to inhibit the local effects of immuno-modulatory neuropeptides, specifically the neurokinins, in affected joints.

Topics: Amino Acid Sequence; Animals; Arthritis; Cell Line; Cell-Free System; Interleukin-1; Leukemia P388; Leukemia, Experimental; Macrophages; Mice; Molecular Sequence Data; Neurokinin A; Peptide Fragments; Substance P