olvanil and Pain

Capsaicin produces pain by selectively activating polymodal nociceptive neurons. This involves a membrane depolarization and the opening of a unique, cation-selective, ion channel which can be blocked by ruthenium red. The capsaicin-induced activation is mediated by a specific membrane receptor which can be selectively and competitively antagonised by capsazepine. Repetitive administrations of capsaicin produces a desensitization and an inactivation of sensory neurons. Several mechanisms are involved. These include receptor inactivation, block of voltage activated calcium channels, intracellular accumulation of ions leading to osmotic changes and activation of proteolytic enzyme processes. Systemic and topical capsaicin produces a reversible antinociceptive and antiinflammatory action after an initial undesirable algesic effect. Capsaicin analogues, such as olvanil, have similar properties with minimal initial pungency. Systemic capsaicin produces antinociception by activating capsaicin receptors on afferent nerve terminals in the spinal cord. Spinal neurotransmission is subsequently blocked by a prolonged inactivation of sensory neurotransmitter release. Local or topical application of capsaicin blocks C-fibre conduction and inactivates neuropeptide release from peripheral nerve endings. These mechanisms account for localized antinociception and the reduction of neurogenic inflammation respectively.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcium Channels; Capsaicin; Cell Membrane; Humans; Neurons, Afferent; Nociceptors; Pain; Pain Threshold; Receptors, Drug

Nasal transient receptor potential vanilloid 1 (TRPV1) stimulation with capsaicin produces serous and mucinous secretion in the human nasal airway. The primary aim of this study was to examine topical effects of various TRP ion channel agonists on symptoms and secretion of specific mucins: mucin 5 subtype AC (MUC5AC) and B (MUC5B).. Healthy individuals were subjected to nasal challenges with TRPV1 agonists (capsaicin, olvanil and anandamide), TRP ankyrin 1 (TRPA1) agonists (cinnamaldehyde and mustard oil) and a TRP melastatin 8 (TRPM8) agonist (menthol). Symptoms were monitored, and nasal lavages were analysed for MUC5AC and MUC5B, i.e. specific mucins associated with airway diseases. In separate groups of healthy subjects, nasal biopsies and brush samples were analysed for TRPV1 and MUC5B, using immunohistochemistry and RT-qPCR. Finally, calcium responses and ciliary beat frequency were measured on isolated ciliated epithelial cells.. All TRP agonists induced nasal pain or smart. Capsaicin, olvanil and mustard oil also produced rhinorrhea. Lavage fluids obtained after challenge with capsaicin and mustard oil indicated increased levels of MUC5B, whereas MUC5AC was unaffected. MUC5B and TRPV1 immunoreactivities were primarily localized to submucosal glands and peptidergic nerve fibres, respectively. Although trpv1 transcripts were detected in nasal brush samples, functional responses to capsaicin could not be induced in isolated ciliated epithelial cells.. Agonists of TRPV1 and TRPA1 induced MUC5B release in the human nasal airways in vivo. These findings may be of relevance with regard to the regulation of mucin production under physiological and pathophysiological conditions.

Topics: Acrolein; Administration, Intranasal; Adult; Aged; Arachidonic Acids; Biopsy; Calcium; Calcium Channels; Capsaicin; Cilia; Cross-Over Studies; Double-Blind Method; Endocannabinoids; Humans; Immunohistochemistry; Methanol; Middle Aged; Movement; Mucin 5AC; Mucin-5B; Mustard Plant; Nasal Lavage; Nasal Mucosa; Nerve Tissue Proteins; Pain; Pain Measurement; Plant Oils; Polyunsaturated Alkamides; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Sensory System Agents; Sweden; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPM Cation Channels; TRPV Cation Channels; Young Adult

Inactivation of sensory neurons expressing transient receptor potential vanilloid 1 (TRPV1) enhances breast cancer metastasis. Sensory neurons have profound effects on immune response to a wide range of diseases including cancer. Hence, activation of sensory nerves using feasible approaches such as specific TRPV1 agonists may inhibit breast cancer metastasis through neuroimmune pathways. TRPV1 agonists are considered for the treatment of pain and inflammatory diseases.. We here first determined the effects of four different TRPV1 agonists on proliferation of three different metastatic breast carcinoma cells since TRPV1 is also expressed in cancer cells. Based on the results obtained under in-vitro conditions, brain metastatic breast carcinoma cells (4TBM) implanted orthotopically into the mammary-pad of Balb-c mice followed by olvanil treatment (i.p.). Changes in tumor growth, metastasis and immune response to cancer cells were determined.. Olvanil dose-dependently activated sensory nerve fibers and markedly suppressed lung and liver metastasis without altering the growth of primary tumors. Olvanil (5 mg/kg) systemically increased T cell count, enhanced intra-tumoral recruitment of CD8+ T cells and increased IFN-γ response to irradiated cancer cells and Con-A. Anti-inflammatory changes such as increased IL-10 and decrease IL-6 as well as S100A8+ cells were observed following olvanil treatment.. Our results show that anti-metastatic effects of olvanil is mainly due to activation of neuro-immune pathways since olvanil dose used here is not high enough to directly activate immune cells. Furthermore, olvanil effectively depletes sensory neuropeptides; hence, olvanil is a good non-pungent alternative to capsaicin.

Topics: Animals; Breast Neoplasms; Capsaicin; Cell Line, Tumor; Cell Proliferation; Female; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Nerve Fibers; Pain; Sensory Receptor Cells; TRPV Cation Channels

The pharmacological inhibition of anandamide (AEA) hydrolysis by fatty acid amide hydrolase (FAAH) attenuates pain in animal models of osteoarthritis (OA) but has failed in clinical trials. This may have occurred because AEA also activates transient receptor potential vanilloid type 1 (TRPV1), which contributes to pain development. Therefore, we investigated the effectiveness of the dual FAAH-TRPV1 blocker OMDM-198 in an MIA-model of osteoarthritic pain. We first investigated the MIA-induced model of OA by (1) characterizing the pain phenotype and degenerative changes within the joint using X-ray microtomography and (2) evaluating nerve injury and inflammation marker (ATF-3 and IL-6) expression in the lumbar dorsal root ganglia of osteoarthritic rats and differences in gene and protein expression of the cannabinoid CB1 receptors FAAH and TRPV1. Furthermore, we compared OMDM-198 with compounds acting exclusively on FAAH or TRPV1. Osteoarthritis was accompanied by the fragmentation of bone microstructure and destroyed cartilage. An increase of the mRNA levels of ATF3 and IL-6 and an upregulation of AEA receptors and FAAH in the dorsal root ganglia were observed. OMDM-198 showed antihyperalgesic effects in the OA model, which were comparable with those of a selective TRPV1 antagonist, SB-366,791, and a selective FAAH inhibitor, URB-597. The effect of OMDM-198 was attenuated by the CB1 receptor antagonist, AM-251, and by the nonpungent TRPV1 agonist, olvanil, suggesting its action as an "indirect" CB1 agonist and TRPV1 antagonist. These results suggest an innovative strategy for the treatment of OA, which may yield more satisfactory results than those obtained so far with selective FAAH inhibitors in human OA.

Topics: Activating Transcription Factor 3; Amidohydrolases; Anilides; Animals; Arachidonic Acids; Benzamides; Capsaicin; Carbamates; Cinnamates; Disease Models, Animal; Endocannabinoids; Ganglia, Spinal; Gene Expression; Hyperalgesia; Inflammation; Interleukin-6; Lumbar Vertebrae; Male; Osteoarthritis; Pain; Pain Management; Pain Measurement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; TRPV Cation Channels

TRPV1 (transient receptor potential vanilloid 1) is a ligand-gated ion channel expressed predominantly in nociceptive primary afferents that plays a key role in pain processing. In vivo activation of TRPV1 receptors by natural agonists like capsaicin is associated with a sharp and burning pain, frequently described as pungency. To elucidate the mechanisms underlying pungency we investigated a series of TRPV1 agonists that included both pungent and non-pungent compounds covering a large range of potencies. Pungency of capsaicin, piperine, arvanil, olvanil, RTX (resiniferatoxin) and SDZ-249665 was evaluated in vivo, by determining the increase in the number of eye wipes caused by direct instillation of agonist solutions into the eye. Agonist-induced calcium fluxes were recorded using the FLIPR technique in a recombinant, TRPV1-expressing cell line. Current-clamp recordings were performed in rat DRG (dorsal root ganglia) neurons in order to assess the consequences of TRPV1 activation on neuronal excitability. Using the eye wipe assay the following rank of pungency was obtained: capsaicin>piperine>RTX>arvanil>olvanil>SDZ-249665. We found a strong correlation between kinetics of calcium flux, pungency and lipophilicity of TRPV1 agonists. Current-clamp recordings confirmed that the rate of receptor activation translates in the ability of agonists to generate action potentials in sensory neurons. We have demonstrated that the lipophilicity of the compounds is directly related to the kinetics of TRPV1 activation and that the latter influences their ability to trigger action potentials in sensory neurons and, ultimately, pungency.

Topics: Action Potentials; Alkaloids; Animals; Benzodioxoles; Capsaicin; Diterpenes; Ganglia, Spinal; Kinetics; Lipid Metabolism; Male; Neurons, Afferent; Pain; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Sensory Receptor Cells; Solubility; TRPV Cation Channels; Urea

Desensitization is a process that describes the diminishing effect of a drug upon repeated applications. In regard to capsaicin, the pungent compound in hot pepper, it is well established that removal of extracellular calcium markedly diminishes desensitization. To explore whether this behavior extends to other analogues of capsaicin, we have determined the effect of removing extracellular calcium with capsaicin analogues, zingerone and olvanil, by whole-cell patch clamping cultured rat trigeminal ganglion neurons. Zingerone, like capsaicin, is pungent but has a shorter acyl chain, whereas olvanil is non-pungent and has a longer acyl chain. The currents evoked by 30-s applications of 30 mM zingerone or 1 microM olvanil repeated every 3 min differ in two important ways from the responses evoked by 1 microM capsaicin under these same conditions. In the presence of extracellular calcium, repeated applications of zingerone and olvanil produce nearly complete desensitization. Also in contrast to capsaicin, removing extracellular calcium for these two agonists does not diminish desensitization. These data analyses suggest the existence of calcium-independent pathways that can result in desensitization, and that pungency is not related to the phenomenon of desensitization.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcium; Capsaicin; Extracellular Space; Guaiacol; Neurons, Afferent; Pain; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Stimulation, Chemical; Tachyphylaxis; Taste; Trigeminal Ganglion

Capsaicin, the pungent ingredient in hot pepper, activates and subsequently desensitizes a subset of polymodal nociceptors. Because its initial application to skin produces pain, nonpungent analogs such as olvanil and glyceryl nonivamide (GLNVA) were synthesized to enhance its clinical use. To explore how these nonpungent analogs differ from capsaicin, whole-cell patch-clamp recordings were performed on cultured rat trigeminal ganglion neurons. In neurons held at -60 mV, capsaicin, olvanil, and GLNVA were found to activate one or two kinetically distinct inward currents. Two inward currents were also activated when extracellular Ca2+ was replaced with Ba2+ and also when intracellular chloride was replaced by aspartate. The reversal potentials of the rapidly and slowly activating currents were 15.3 +/- 6 and -4.0 +/- 2.5 mV, respectively. These data provide strong evidence for subtypes of vanilloid receptors. One difference among these agonists is that, on average, the activation kinetics of the currents evoked by 1 microM olvanil and 30 microM GLNVA are considerably slower than those evoked by 1 microM capsaicin. Measurements of the peak current, Ip, versus agonist concentration were fit to the Hill equation to yield values of the half maximal concentrations (K1/2), and the Hill coefficients (n). For capsaicin, olvanil, and GLNVA, K1/2 = 0.68, 0.59, and 27.0 microM and n = 1.38, 1.32, and 1.24, respectively. We propose that olvanil and GLNVA are nonpungent because they activate different subtypes of receptors and/or because of their activation kinetics (compared with capsaicin) are, on average, slower than the rate they inhibit action potentials from polymodal nociceptors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Capsaicin; Cells, Cultured; Dose-Response Relationship, Drug; Glycerol; Neurons; Pain; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, Drug; Tachyphylaxis; Taste; Trigeminal Ganglion

Systemic capsaicin and an analogue, olvanil (NE-19550, 4-hydroxy-3-methoxyphenyl methyl-9Z-octadecenamide), were tested for antinociceptive activity in a model of persistent pain produced by the subcutaneous injection of formalin into the rodent hind paw. Formalin induced a biphasic nociceptive response in mice and rats which was measured (a) by the time spent licking the injected paw in mice and (b) by making electrophysiological recordings of single nociceptive neurone discharges in L1-L3 of the spinal dorsal horn of halothane-anaesthetised rats. In mice the initial phase of the response was reduced by systemic administration of morphine, capsaicin and olvanil but not by indomethacin. The second, more prolonged, inflammatory phase of the response was reduced by each agent. In rats, similar concentrations of capsaicin and olvanil reduced both the first and second components of the formalin response. These data show that capsaicin and a non-pungent analogue, olvanil, are efficacious antinociceptive agents in a model of prolonged chemical nociception induced by formalin. Their activity compares favourably with that of morphine and appears superior to that of indomethacin.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Capsaicin; Electrophysiology; Foot; Formaldehyde; Indomethacin; Inflammation; Mice; Morphine; Neurons; Pain; Spinal Cord