Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) - Volume 10, Issue 1, 2011

Capsaicin and its analogs induce anti-inflammatory and anti-allergic functions as well as causing inflammation and allergy, principally acting on the small primary sensory neurons. This special issue is focused on capsaicin-sensitive (chemo-sensitive) somatic and visceral C-fibers responsible for inflammation and allergy, resulting in the trigger of hyperalgesia, headache, airway sensitivity (cough and hypersensitivity), and itching sensation. Especially, non Ca++-selective, a molecular integrator of nociception, TRPV1 and TRPA1 receptors are highlighted to explain the relationships between inflammatory diseases and efferent functions of chemo-sensitive C fiber terminals. Furthermore, causal interactions (autocrine and paracrine functions) in milieu of C fiber terminals and mast cells are considered for inflammation and allergy in the itch. The direct or indirect mediators participating in inflammation and allergy, such as neuropeptids (especially, calcitonin gene-related peptide), decomposed neuropeptids by protease (their protease-activated receptors as well), prostaglandins, histamine, growth factors, nuclear factor-kappa B (NF-κB) and some cytokines are brought up for discussion of the complicated vital phenomenon. Vanilloid agonists, exerting anti-nociceptive, anti-allergic and anti-inflammatory agents, are surveyed from experimental studies of the topical, perineural and subarachnoidal applications for their available therapeutic use.

Capsaicin and its analogs induce anti-inflammatory and anti-allergic functions as well as causing inflammation and allergy, principally acting on the small primary sensory neurons. This special issue is focused on capsaicin-sensitive (chemo-sensitive) somatic and visceral C-fibers responsible for inflammation and allergy, resulting in the trigger of hyperalgesia, headache, airway sensitivity (cough and hypersensitivity), and itching sensation. Especially, non Ca++-selective, a molecular integrator of nociception, TRPV1 and TRPA1 receptors are highlighted to explain the relationships between inflammatory diseases and efferent functions of chemo-sensitive C fiber terminals. Furthermore, causal interactions (autocrine and paracrine functions) in milieu of C fiber terminals and mast cells are considered for inflammation and allergy in the itch. The direct or indirect mediators participating in inflammation and allergy, such as neuropeptids (especially, calcitonin gene-related peptide), decomposed neuropeptids by protease (their protease-activated receptors as well), prostaglandins, histamine, growth factors, nuclear factor-kappa B (NF-κB) and some cytokines are brought up for discussion of the complicated vital phenomenon. Vanilloid agonists, exerting anti-nociceptive, anti-allergic and anti-inflammatory agents, are surveyed from experimental studies of the topical, perineural and subarachnoidal applications for their available therapeutic use.

The specific actions of capsaicin on the small primary afferent neurons with regard to neurogenic inflammation and plasma extravasation are examined in this review. First, a short history of the study of capsaicin is introduced from the viewpoint of the efferent function of capsaicin-sensitive nerve fibers. Agonist (resiniferatoxin) and antagonists (capsazepine and ruthenium red) of capsaicin are referred, to better understand the action of the drug. The significance of the discovery of capsaicin receptor, TRPV1, and its characteristic features (polymodal receptor) are discussed based on recent reports, although the sensitization or desensitization mechanisms are not yet resolved. This review also briefly deals with the therapeutic use of capsaicin and its agonist and antagonist for relief pain. Whether or not capsaicin-sensitive nerve fibers are involved in itching is examined by a recent literature survey. TRPV1- expressing nerve fibers were recently reported to be responsible for the itching sensation. Three possible itching pathways were raised. The participation of pure sensory nerve fibers which exclusively transmit itchiness has not been found, as yet.

The specific actions of capsaicin on the small primary afferent neurons with regard to neurogenic inflammation and plasma extravasation are examined in this review. First, a short history of the study of capsaicin is introduced from the viewpoint of the efferent function of capsaicin-sensitive nerve fibers. Agonist (resiniferatoxin) and antagonists (capsazepine and ruthenium red) of capsaicin are referred, to better understand the action of the drug. The significance of the discovery of capsaicin receptor, TRPV1, and its characteristic features (polymodal receptor) are discussed based on recent reports, although the sensitization or desensitization mechanisms are not yet resolved. This review also briefly deals with the therapeutic use of capsaicin and its agonist and antagonist for relief pain. Whether or not capsaicin-sensitive nerve fibers are involved in itching is examined by a recent literature survey. TRPV1- expressing nerve fibers were recently reported to be responsible for the itching sensation. Three possible itching pathways were raised. The participation of pure sensory nerve fibers which exclusively transmit itchiness has not been found, as yet.

Mast cell and sensory nerve relationships fall into three categories: proximity, communication and a shared fate. Mast cells are found in all tissues of the human body, especially located closely to nerves. Mast-nerve membrane to membrane contact is a highly common configuration. This should be by design rather than by accident since such spatial distributions generally indicate a functional relationship. Mast cells associated to sensory nerves contain abundant neuropeptides and also a range of neuropeptide receptors enabling nerve to mast cell, mast cell to nerve and reciprocal communications which form the basis of neuroimmune interfacing. Wondering about the possible effects of this intimacy and communication potential on several physiological and pathophysiological events, specifically on diseases with low success rates of therapy and mysterious mechanisms, scientists have uncovered many aspects of mast-nerve interactions. In light of these studies, from a focal point between the nervous and immune systems, mast cells highlight the concept of collaboration as an indispensable building block of the neuroimmune system.

Mast cell and sensory nerve relationships fall into three categories: proximity, communication and a shared fate. Mast cells are found in all tissues of the human body, especially located closely to nerves. Mast-nerve membrane to membrane contact is a highly common configuration. This should be by design rather than by accident since such spatial distributions generally indicate a functional relationship. Mast cells associated to sensory nerves contain abundant neuropeptides and also a range of neuropeptide receptors enabling nerve to mast cell, mast cell to nerve and reciprocal communications which form the basis of neuroimmune interfacing. Wondering about the possible effects of this intimacy and communication potential on several physiological and pathophysiological events, specifically on diseases with low success rates of therapy and mysterious mechanisms, scientists have uncovered many aspects of mast-nerve interactions. In light of these studies, from a focal point between the nervous and immune systems, mast cells highlight the concept of collaboration as an indispensable building block of the neuroimmune system.

In the last 15 years, studies of transient receptor potential (TRP) channels have significantly extended our knowledge about the molecular basis of sensory function in pulmonary vagal afferents. In particular, TRPV1 and TRPA1 channels are unique cellular sensors for a wide range of inflammatory mediators and noxious irritants. These channels act as the molecular integrator of multiple nociceptive stimuli and are involved in multiple cellular functions, ranging from transduction of sensory signals to the release of neuropeptides in pulmonary vagal afferents. Increased activity of TRPV1 channels is now recognized as a cause of airway hypersensitivity in inflammatory airway diseases. In this review, we summarize current knowledge about the activation mechanisms of TRPV1 and TRPA1, and discuss the possible functional implications of TRPV1 and TRPA1 in human physiology and pathophysiology, such as the cough reflex and hypersensitivity.

In the last 15 years, studies of transient receptor potential (TRP) channels have significantly extended our knowledge about the molecular basis of sensory function in pulmonary vagal afferents. In particular, TRPV1 and TRPA1 channels are unique cellular sensors for a wide range of inflammatory mediators and noxious irritants. These channels act as the molecular integrator of multiple nociceptive stimuli and are involved in multiple cellular functions, ranging from transduction of sensory signals to the release of neuropeptides in pulmonary vagal afferents. Increased activity of TRPV1 channels is now recognized as a cause of airway hypersensitivity in inflammatory airway diseases. In this review, we summarize current knowledge about the activation mechanisms of TRPV1 and TRPA1, and discuss the possible functional implications of TRPV1 and TRPA1 in human physiology and pathophysiology, such as the cough reflex and hypersensitivity.

This review focuses on the critical pathophysiological significance of capsaicin-sensitive trigeminal primary afferent neurons in the mechanisms of neurovascular responses in animal models of cranial pain and their possible relevance for primary headaches. In the rat dura mater, neurogenic sensory vasodilator responses elicited by activation of the transient receptor potential vanilloid type 1 (TRPV1) receptor are mediated by the release of calcitonin gene-related peptide (CGRP) from sensory nerves, which suggests that similar mechanisms may operate in man during migraine attacks, when an increased concentration of CGRP is measured in the jugular venous blood. Capsaicin-sensitive trigeminal afferent nerves also contribute to the vasodilatory responses induced by the activation of protease-activated receptor 2 (PAR-2), which involves the release of CGRP from capsaicin-sensitive afferent nerves. Importantly, the activation of PAR-2 has been shown to sensitize the TRPV1 receptor. Demonstration of the colocalization of PAR-2 and TRPV1 receptors in the meningeal axons lends further support to this mechanism. Neurogenic vasodilatory responses mediated by capsaicinsensitive afferent nerves may serve a protective function via the elimination of inflammatory mediators from the tissue, a mechanism which may play a role in the resolution of headaches. Pathological conditions such as diabetes mellitus may compromise this protective mechanism through decreases in the expression of TRPV1 and the release of CGRP. These observations indicate an important role of capsaicin-sensitive meningeal afferent nerves in the pathophysiology of headaches and suggest that pharmacological manipulation of the TRPV1 receptor may offer a promising approach to the management of headaches.

This review focuses on the critical pathophysiological significance of capsaicin-sensitive trigeminal primary afferent neurons in the mechanisms of neurovascular responses in animal models of cranial pain and their possible relevance for primary headaches. In the rat dura mater, neurogenic sensory vasodilator responses elicited by activation of the transient receptor potential vanilloid type 1 (TRPV1) receptor are mediated by the release of calcitonin gene-related peptide (CGRP) from sensory nerves, which suggests that similar mechanisms may operate in man during migraine attacks, when an increased concentration of CGRP is measured in the jugular venous blood. Capsaicin-sensitive trigeminal afferent nerves also contribute to the vasodilatory responses induced by the activation of protease-activated receptor 2 (PAR-2), which involves the release of CGRP from capsaicin-sensitive afferent nerves. Importantly, the activation of PAR-2 has been shown to sensitize the TRPV1 receptor. Demonstration of the colocalization of PAR-2 and TRPV1 receptors in the meningeal axons lends further support to this mechanism. Neurogenic vasodilatory responses mediated by capsaicinsensitive afferent nerves may serve a protective function via the elimination of inflammatory mediators from the tissue, a mechanism which may play a role in the resolution of headaches. Pathological conditions such as diabetes mellitus may compromise this protective mechanism through decreases in the expression of TRPV1 and the release of CGRP. These observations indicate an important role of capsaicin-sensitive meningeal afferent nerves in the pathophysiology of headaches and suggest that pharmacological manipulation of the TRPV1 receptor may offer a promising approach to the management of headaches.

Pain and inflammation are considered strongly associated. The greater pain behavior was demonstrated in animals with greater amount of inflammation. Tissue or nerve injury results in the release of various inflammatory mediators such as prostaglandins, bradykinin, proinflammatory cytokines, chemokines, histamine, serotonin and nerve growth factors from the site of injury. These inflammatory mediators play a critical role in both integrating the inflammatory response and mediating pain hypersensitivity. This review highlights the role of prostaglandins and proinflammatory cytokines in the pain sensitization and its underlying mechanisms, emphasizing the evidence that these molecules are potential targets to develop novel drugs and therapies for the treatment of both inflammation and pain in clinic.

Pain and inflammation are considered strongly associated. The greater pain behavior was demonstrated in animals with greater amount of inflammation. Tissue or nerve injury results in the release of various inflammatory mediators such as prostaglandins, bradykinin, proinflammatory cytokines, chemokines, histamine, serotonin and nerve growth factors from the site of injury. These inflammatory mediators play a critical role in both integrating the inflammatory response and mediating pain hypersensitivity. This review highlights the role of prostaglandins and proinflammatory cytokines in the pain sensitization and its underlying mechanisms, emphasizing the evidence that these molecules are potential targets to develop novel drugs and therapies for the treatment of both inflammation and pain in clinic.

Chemosensitive primary sensory neurones expressing the TRPV1 receptor, a molecular integrator of diverse noxious stimuli, play a fundamental role in the sensation of pain. Capsaicin, the archetypical ligand of the TRPV1 receptor, is one of the most painful chemical irritants, and its acute administration onto the skin and mucous membranes elicits severe pain. However, repeated or high-dose applications of capsaicin, and/or its administration through specific routes dramatically decreases the sensitivity of the innervated tissues to noxious chemical and heat stimuli. This review surveys the mechanisms of the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of vanilloid agonists applied topically, or perineurally, or injected into the subarachnoid space in animal experiments and to put these data into a clinical perspective. The great body of available experimental evidence indicates that vanilloid agonists exert their antinociceptive actions through TRPV1 receptor-mediated selective neurotoxic/neurodegenerative effects directed against somatic and visceral C-fibre nociceptive primary afferent fibres. It is expected that vanilloid agonists will broaden the palette of analgesic drugs which do not cause addiction and tachyphylaxis.

Chemosensitive primary sensory neurones expressing the TRPV1 receptor, a molecular integrator of diverse noxious stimuli, play a fundamental role in the sensation of pain. Capsaicin, the archetypical ligand of the TRPV1 receptor, is one of the most painful chemical irritants, and its acute administration onto the skin and mucous membranes elicits severe pain. However, repeated or high-dose applications of capsaicin, and/or its administration through specific routes dramatically decreases the sensitivity of the innervated tissues to noxious chemical and heat stimuli. This review surveys the mechanisms of the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of vanilloid agonists applied topically, or perineurally, or injected into the subarachnoid space in animal experiments and to put these data into a clinical perspective. The great body of available experimental evidence indicates that vanilloid agonists exert their antinociceptive actions through TRPV1 receptor-mediated selective neurotoxic/neurodegenerative effects directed against somatic and visceral C-fibre nociceptive primary afferent fibres. It is expected that vanilloid agonists will broaden the palette of analgesic drugs which do not cause addiction and tachyphylaxis.

Lipoxins and resolvins are endogenous lipid mediators derived from ω-6 and ω-3 polyunsaturated fatty acids (PUFAs), respectively. Lipoxins, such as lipoxin A4 (LXA4) and lipoxin B4 (LXB4), are known as the first proresolving mediators, and their appearance leads to the resolution of inflammation. In addition, resolvins, such as D series resolvins (RvD) and E series resolvins (RvE), play important roles in the resolution of inflammation. So far, the anti-inflammatory effects of lipoxins and resolvins have been revealed in various experimental models of inflammatory disorders, and much attention has been paid to PUFAs and lipid mediators derived from PUFAs as a therapeutic strategy for inflammatory disorders including inflammatory bowl diseases (IBD). Recent studies using animal experimental models demonstrated that lipoxins; aspirin-triggered lipoxins; and their stable analogues, such as LXA4 and aspirin-triggered 15-epi-LXA4, were able to attenuate colitis. Resolvins, such as RvE1, were also demonstrated to protect against colitis. Moreover, it has been proposed that the biological abilities of endogenous anti-inflammatory lipid mediators are induced via their corresponding receptors, for example, FPR2/ALX for LXA4 and ChemR23 for RvE1, and the expression levels of their receptors were reported to be increased in macrophages and intestinal epithelium stimulated with exogenous antigens such as lipopolysaccaride. In this paper, the anti-inflammatory effects of lipid mediators derived from PUFAs, especially LXA4 and RvE1, are outlined, and the possibility of their use as a therapeutic strategy for IBD is discussed.

Lipoxins and resolvins are endogenous lipid mediators derived from ω-6 and ω-3 polyunsaturated fatty acids (PUFAs), respectively. Lipoxins, such as lipoxin A4 (LXA4) and lipoxin B4 (LXB4), are known as the first proresolving mediators, and their appearance leads to the resolution of inflammation. In addition, resolvins, such as D series resolvins (RvD) and E series resolvins (RvE), play important roles in the resolution of inflammation. So far, the anti-inflammatory effects of lipoxins and resolvins have been revealed in various experimental models of inflammatory disorders, and much attention has been paid to PUFAs and lipid mediators derived from PUFAs as a therapeutic strategy for inflammatory disorders including inflammatory bowl diseases (IBD). Recent studies using animal experimental models demonstrated that lipoxins; aspirin-triggered lipoxins; and their stable analogues, such as LXA4 and aspirin-triggered 15-epi-LXA4, were able to attenuate colitis. Resolvins, such as RvE1, were also demonstrated to protect against colitis. Moreover, it has been proposed that the biological abilities of endogenous anti-inflammatory lipid mediators are induced via their corresponding receptors, for example, FPR2/ALX for LXA4 and ChemR23 for RvE1, and the expression levels of their receptors were reported to be increased in macrophages and intestinal epithelium stimulated with exogenous antigens such as lipopolysaccaride. In this paper, the anti-inflammatory effects of lipid mediators derived from PUFAs, especially LXA4 and RvE1, are outlined, and the possibility of their use as a therapeutic strategy for IBD is discussed.