ABSTRACT
Neurogenic inflammation, an important component of many disease states, is mediated by the release of neuropeptides from sensory nerves. To date, it has been possible to inhibit neurogenic inflammation using neuropeptide receptor blockers or by prevention of neuropeptide release. In the current edition of the British Journal of Pharmacology, Cattaruzza and co-workers discuss a novel way of blocking the action of neuropeptides. They have shown that the re-sensitization of the substance P neurokinin-1 receptor and the substance P-induced pro-inflammatory effects are mediated by the enzyme, endothelin-converting enzyme 1 (ECE-1). Therein, they showed that ECE-1 inhibition could prevent the re-sensitization process. This is exciting progress in our understanding of neurogenic inflammation, but it remains to be seen how inhibition of receptor recycling via ECE-1 blockade will affect other inflammatory pathways.
Subject(s)
Aspartic Acid Endopeptidases/physiology , Metalloendopeptidases/physiology , Neurogenic Inflammation/metabolism , Receptors, Neurokinin-1/physiology , Animals , Aspartic Acid Endopeptidases/biosynthesis , Calcium Signaling , Capillary Permeability , Endocytosis , Endosomes/metabolism , Endothelial Cells/metabolism , Endothelin-Converting Enzymes , Endothelium, Vascular/cytology , Metalloendopeptidases/biosynthesis , Microvessels/cytology , Rats , Receptors, Neurokinin-1/biosynthesis , Substance P/metabolismABSTRACT
Inflammatory diseases associated with pain are often difficult to treat in the clinic due to insufficient understanding of the nociceptive pathways involved. Recently, there has been considerable interest in the role of reactive oxygen species (ROS) in inflammatory disease, but little is known of the role of hydrogen peroxide (H(2)O(2)) in hyperalgesia. In the present study, intraplantar injection of H(2)O(2)-induced a significant dose- and time-dependent mechanical and thermal hyperalgesia in the mouse hind paw, with increased c-fos activity observed in the dorsal horn of the spinal cord. H(2)O(2) also induced significant nociceptive behavior such as increased paw licking and decreased body liftings. H(2)O(2) levels were significantly raised in the carrageenan-induced hind paw inflammation model, showing that this ROS is produced endogenously in a model of inflammation. Moreover, superoxide dismutase and catalase significantly reduced carrageenan-induced mechanical and thermal hyperalgesia, providing evidence of a functionally significant endogenous role. Thermal, but not mechanical, hyperalgesia in response to H(2)O(2) (i.pl.) was longer lasting in TRPV1 wild type mice compared to TRPV1 knockouts. It is unlikely that downstream lipid peroxidation was increased by H(2)O(2). In conclusion, we demonstrate a notable effect of H(2)O(2) in mediating inflammatory hyperalgesia, thus highlighting H(2)O(2) removal as a novel therapeutic target for anti-hyperalgesic drugs in the clinic.
Subject(s)
Hydrogen Peroxide/metabolism , Hyperalgesia/drug therapy , Inflammation/complications , Oxidants/metabolism , Pain Threshold/drug effects , Pain Threshold/physiology , TRPV Cation Channels/metabolism , Analysis of Variance , Animals , Carrageenan , Disease Models, Animal , Edema/etiology , Edema/pathology , Female , Hydrogen Peroxide/adverse effects , Hyperalgesia/etiology , Hyperalgesia/genetics , Hyperalgesia/pathology , Inflammation/chemically induced , Inflammation/genetics , Lipid Peroxidation/drug effects , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neutrophils/drug effects , Neutrophils/physiology , Oxidants/adverse effects , Pain Measurement/methods , Proto-Oncogene Proteins c-fos/metabolism , Reaction Time/drug effects , Spinal Cord/metabolism , TRPV Cation Channels/deficiency , Thiobarbituric Acid Reactive Substances/metabolism , Time FactorsABSTRACT
Capsaicin is the pungent component of chilli peppers that concomitantly activates and desensitizes C-fibre and Adelta sensory nerve fibres. Stimulation causes an acute neurogenic response including vasodilation, plasma extravasation and hypersensitivity. However, in the present study we have shown that capsaicin produces a dose-dependent vasoconstrictor effect in the mouse knee joint via Transient Receptor Potential Vanilloid 1 (TRPV1) receptor activation. A (125)I-albumin accumulation technique showed that the intravascular volume of capsaicin-treated joints in wild type (WT) mice was significantly reduced compared to TRPV1 knockout mice (p<0.01). Similarly, a laser Doppler technique showed significantly reduced blood flow in the capsaicin-treated joints of WT compared to TRPV1 knockout mice (p<0.001). Pretreatment with guanethinidine (50 mg kg(-1), i.p.) had no effect on the vasoconstriction. These data are important considering the involvement of TRPV1 receptors in joint disease. The mechanisms underlying the vasoconstriction therefore require further investigation.
