Kinin receptors in pain and inflammation.

Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes. These short-lived peptides, including bradykinin, kallidin and T-kinin, are generated during tissue injury and noxious stimulation. However, emerging evidence also suggests that kinins are stored in neuronal elements of the central nervous system (CNS) where they are thought to play a role as neuromediators in various cerebral functions, particularly in the control of nociceptive information. Kinins exert their biological effects through the activation of two transmembrane G-protein-coupled receptors, denoted bradykinin B(1) and B(2). Whereas the B(2) receptor is constitutive and activated by the parent molecules, the B(1) receptor is generally underexpressed in normal tissues and is activated by kinins deprived of the C-terminal Arg (des-Arg(9)-kinins). The induction and increased expression of B(1) receptor occur following tissue injury or after treatment with bacterial endotoxins or cytokines such as interleukin-1 beta and tumor necrosis factor-alpha. This review summarizes the most recent data from various animal models which convey support for a role of B(2) receptors in the acute phase of the inflammatory and pain response, and for a role of B(1) receptors in the chronic phase of the response. The B(1) receptor may exert a strategic role in inflammatory diseases with an immune component (diabetes, asthma, rheumatoid arthritis and multiple sclerosis). New information is provided regarding the role of sensory mechanisms subserving spinal hyperalgesia and intrapleural neutrophil migration that occur upon B(1) receptor activation in streptozotocin-treated rats, a model of insulin-dependent diabetes mellitus in which the B(1) receptor seems to be rapidly overexpressed. Although it is widely accepted that the blockade of kinin receptors with specific antagonists could be of benefit in the treatment of somatic and visceral inflammation and pain, recent molecular and functional evidence suggests that the activation of B(1) receptors with an agonist may afford a novel therapeutic approach in the CNS inflammatory demyelinating disorder encountered in multiple sclerosis by reducing immune cell infiltration (T-lymphocytes) into the brain. Hence, the B(1) receptor may exert either a protective or detrimental effect depending on the inflammatory disease. This dual function of the B(1) receptor deserves to be investigated further.

Distribution of proteasomes and of the five proteolytic activities in rat tissues.

Five peptidase activities (ChT-L, T-L, PGPH, BrAAP, and SNAAP) of the proteasome, and its caseinolytic activity, were measured in crude extracts of 10 rat tissues under experimental conditions simulating those found in vivo, thereby eliminating the alterations observed with the purified enzyme. The total and individual peptidase activities varied considerably from one tissue to another, whereas the proteolytic activity measured with [(14)C]methylcasein varied no more than twofold. The tissue-specific variations in individual peptidase activities may reflect tissue-specific differences in proteasome subunit composition, or the presence of regulators. Immunological assay using an antibody directed against the iota (alpha1) subunit showed that there was no correlation between protein abundance and peptidase activity. The results also show that the different peptidase activities are not representative of proteasome distribution in the different tissues.

Differences between the tactile sensitivity on the anterior torso of normal individuals and those having suffered complete transection of the spinal cord.

Using the method of limits and a magnitude estimation procedure, the sense of touch was examined at multiple sites on the anterior torso of normal subjects. Their performance was compared with the performance of individuals having experienced a functionally complete spinal cord transection more than 6 months prior to the tests. Near the insentient regions of the spinal cord-injured patients there was a zone wherein the threshold for light touch was elevated and variable. Within this same transition zone, estimates of the magnitude of a brushing stimulus increased as a linear function of distance from the border for approximately 12 cm away from insentient skin. Throughout the rest of the thorax, spinal cord-injured patients displayed touch thresholds 67% higher than normals and, at the same test sites, spinal cord-injured patients offered estimates of the intensity of the brushing stimulus that averaged 62% higher than normal subjects. The greater intensity of the sensations experienced by spinal cord-injured patients with even very weak stimuli and the smaller range within which they were able to scale stimulus intensity, produced a situation wherein the patients made frequent errors of judgement even on skin regions far from the body parts affected by the lesion. These observations support the hypothesis that spinal cord lesions interrupt tonic modulatory mechanisms having global influences on the sense of touch. This loss produces an elevation of the touch threshold and a reduction of the normal dynamic range of tactile sensory perception for all skin surfaces on the anterior torso.