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      New topical treatment of vulvodynia based on the pathogenetic role of cross talk between nociceptors, immunocompetent cells, and epithelial cells

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          Abstract

          Topical treatments of localized neuropathic pain syndromes in general are mostly neglected, mainly due to the fact that most pain physicians expect that a topical formulation needs to result in a transdermal delivery of the active compounds. On the basis of the practical experience, this study brings forth a new, somewhat neglected element of the vulvodynia pathogenesis: the cross talk between the nerve endings of nociceptors, the adjacent immunocompetent cells, and vaginal epithelial cells. Insight into this cross talk during a pathogenic condition supports the treatment of vulvodynia with topical (compounded) creams. Vulvodynia was successfully treated with an analgesic cream consisting of baclofen 5% together with the autacoid palmitoylethanolamide 1%, an endogenous anti-inflammatory compound. In this review, data is presented to substantiate the rationale behind developing and prescribing topical products for localized pain states such as vulvodynia. Most chronic inflammatory disorders are based on a network pathogenesis, and monotherapeutic inroads into the treatment of such disorders are obsolete.

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          Most cited references 46

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          Nerve growth factor: from neurotrophin to neurokine.

          Nerve growth factor (NGF) is largely known as a target-derived factor responsible for the survival and maintenance of the phenotype of specific subsets of peripheral neurones and basal forebrain cholinergic nuclei during development and maturation. However, NGF also exerts a modulatory role on sensory, nociceptive nerve physiology during adulthood that appears to correlate with hyperalgesic phenomena occurring in tissue inflammation. Other NGF-responsive cells are now recognized as belonging to the haemopoietic-immune system and to populations in the brain involved in neuroendocrine functions. The concentration of NGF is elevated in a number of inflammatory and autoimmune states in conjunction with an increased accumulation of mast cells. Mast cells and NGF appear to be involved in neuroimmune interactions and tissue inflammation, with NGF acting as a general 'alert' molecule capable of recruiting and priming tissue defence processes following insult as well as systemic defensive mechanisms. Moreover, mast cells themselves produce NGF, suggesting that alterations in normal mast cell behaviours can provoke maladaptive neuroimmune tissue responses whose consequences could have profound implications in inflammatory disease states. This review discusses recent discoveries involving novel and diverse biological activities of this fascinating molecule.
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            Cell damage excites nociceptors through release of cytosolic ATP.

            The release of cytosol from damaged cells has been proposed to be a chemical trigger for nociception. K(+), H(+), adenosine triphosphate (ATP), and glutamate are algogenic agents within cytosol that might contribute to such an effect. To examine which, if any, compounds in cytosol activate ion channels on nociceptors, we recorded currents in dissociated nociceptors when nearby skin cells were damaged. Skin cell damage caused action potential firing and inward currents in nociceptors. Extracts of fibroblast cytosol did the same. Virtually all response to extract and cell killing was eliminated by enzymatic degradation of ATP or desensitization or blockade of P2X receptors, ion channels that are activated by extracellular ATP. Thus, if cytosol provides a rapid nociceptive signal from damaged tissue, then ATP is a critical messenger and P2X receptors are its sensor.
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              Selective keratinocyte stimulation is sufficient to evoke nociception in mice.

              The skin epidermis is densely innervated by peripheral sensory nerve endings. Nociceptive neurons, whose terminals are in close contact with epidermal keratinocytes, can be activated directly by noxious physical and chemical stimuli to trigger pain. However, whether keratinocytes can signal acutely to sensory nerve terminals to initiate pain in vivo remains unclear. Here, using the keratin 5 promoter to selectively express the capsaicin receptor TRPV1 in keratinocytes of TRPV1-knockout mice, we achieved specific stimulation of keratinocytes with capsaicin. Using this approach, we found that keratinocyte stimulation was sufficient to induce strong expression of the neuronal activation marker, c-fos, in laminae I and II of the ipsilateral spinal cord dorsal horn and to evoke acute paw-licking nocifensive behavior and conditioned place aversion. These data provide direct evidence that keratinocyte stimulation is sufficient to evoke acute nociception-related responses.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2016
                03 October 2016
                : 9
                : 757-762
                Affiliations
                [1 ]Institute for Neuropathic Pain, Bosch en Duin
                [2 ]Institute for Neuropathic Pain, Amsterdam, The Netherlands
                [3 ]Scripps Memorial Hospital La Jolla, La Jolla, CA, USA
                Author notes
                Correspondence: J M Keppel Hesselink, Institute for Neuropathic Pain, Spoorlaan 37a, 3735 MV, Bosch en Duin, The Netherlands, Tel +31 6 5170 0527, Email jan@ 123456neuropathie.nu
                Article
                jpr-9-757
                10.2147/JPR.S115407
                5055105
                © 2016 Keppel Hesselink et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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