arachidonic-acid-omega-9-hydroperoxide and Pain

TRPV1 is a channel expressed highly in small sensory neurons. TRPV1 is a ligand-gated, cation channel that is activated by heat, acid and capsaicin, a principal ingredient in hot peppers. Because of its possible role as a polymodal molecular detector, TRPV1 is studied most extensively. In mice lacking TRPV1, thermal hyperalgesia induced by inflammation is reduced, suggesting a role for mediating inflammatory pain. Activity of TRPV1 is modulated by actions of various kinases such as protein kinase A and C. Furthermore, phosphorylation by Ca(2+)-calmodulin-dependent kinase II is required for its ligand binding. TRPV1 is activated by various endogenous lipids, such as anandamide, N-arachidonoyl-dopamine, and various metabolic products of lipoxygenases. 12-hydroperoxyeicosatetraenoic acid, an immediate metabolic product of 12-lipoxygenase, activates TRPV1 and shares 3-dimensional structural similarity with capsaicin. Because lipoxygenase products can activate TRPV1 in sensory neurons, upstream signals to lipoxygenase/TRPV1 pathway have been questioned. Indeed, bradykinin, a potent pain-causing substance, is now known to activate TRPV1 via lipoxygenase pathway. However, we cannot overlook the sensitizing effect of bradykinin via the phospholipase C or protein kinase C pathway. Interestingly, histamine, a pruritogenic substance, also appears to use the lipoxygenase/TRPV1 pathway in order to excite sensory neurons. Because of its role in the mediation of nociception, antagonists of TRPV1 are targeted for development of potential analgesics. In the present review, theoretical background of organic synthesis of SC0030, a potent antagonist of TRPV1 is presented.

Topics: Analgesics; Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases; Humans; Ion Channels; Leukotrienes; Models, Molecular; Neurons, Afferent; Pain; Phosphorylation; TRPV Cation Channels

This study investigated role of spinal lipoxygenase metabolites in induction of hyperalgesia and development of opioid analgesic tolerance. In the rat, nociception was measured using formalin and tail-flick tests. Intrathecal administration of leukotriene receptor agonist (LTB4) augmented the second phase of the formalin response and marginally increased sensitivity to acute thermal stimulation in the tail-flick test, responses suppressed by 6-(6-(3R-hydroxy-1E,5Z-undecadien-1-yl)-2-pyridinyl)-1,5S-hexanediol (U75302), a leukotriene BLT receptor antagonist. Treatment with 15-hydroxyperoxyeicosatetranoic acid (HPETE) increased phase II formalin activity, but had no effect on tail-flick responses. 12-HPETE failed to produce an effect in either nociceptive test. In the second part of this study, chronic spinal morphine for 5 days produced progressive decline in morphine antinociception and loss in analgesic potency. These effects were attenuated by co-administration of morphine with selective and nonselective lipoxygenase inhibitors. These results suggest involvement of lipoxygenase metabolites in both pain modulation and induction of opioid tolerance at the spinal level.

Topics: Analgesics, Opioid; Animals; Benzoquinones; Dose-Response Relationship, Drug; Drug Tolerance; Flavanones; Formaldehyde; Hindlimb; Hyperalgesia; Injections, Spinal; Leukotriene B4; Leukotrienes; Lipid Peroxides; Lipoxygenase; Lipoxygenase Inhibitors; Male; Masoprocol; Morphine; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Spinal Cord; Time Factors

The capsaicin-sensitive vanilloid receptor (VR1) was recently shown to play an important role in inflammatory pain (hyperalgesia), but the underlying mechanism is unknown. We hypothesized that pain-producing inflammatory mediators activate capsaicin receptors by inducing the production of fatty acid agonists of VR1. This study demonstrates that bradykinin, acting at B2 bradykinin receptors, excites sensory nerve endings by activating capsaicin receptors via production of 12-lipoxygenase metabolites of arachidonic acid. This finding identifies a mechanism that might be targeted in the development of new therapeutic strategies for the treatment of inflammatory pain.

Topics: Animals; Animals, Newborn; Arachidonate 12-Lipoxygenase; Bradykinin; Cell Line; Cells, Cultured; Diterpenes; Ganglia, Spinal; Humans; Hyperalgesia; Inflammation; Leukotrienes; Neurons; Neurons, Afferent; Neurotoxins; Pain; Rats; Receptors, Bradykinin; Receptors, Drug; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Transfection