OBJECTIVE:Pain is one of the major public health burdens worldwide, however, conventional analgesics are often ineffective. Capsaicin-the active compound of Capsicum species, being responsible for their pungency-has been part of traditional medicine long ago. Capsaicin is a natural agonist of the Transient Receptor Potential Vanilloid 1 receptor-localized on capsaicin-sensitive sensory neurons and strongly involved in pain transmission-, and has been in focus of analgesic drug research for many years. In this study, we aimed to develop a sustained release transdermal patch (transdermal therapeutic system, TTS) combining the advantages of low-concentration capsaicin and diclofenac embedded in an innovative structure, as well as to perform complex preclinical investigations of its analgesic effect. METHODS:Drug delivery properties of the TTS were investigated with Franz cell and flow-through cell tests. Analgesic effect of the TTS was examined in in vivo models of acute postoperative and inflammatory, chronic neuropathic and osteoarthritic pain. RESULTS:Modified silicone polymer matrix-based TTS containing low-concentration capsaicin and diclofenac has been developed, releasing both compounds according to zero-order kinetics. Moreover, capsaicin and diclofenac facilitated the liberation of each other. Combined TTS significantly reduced acute postoperative and inflammatory pain, as well as chronic neuropathic and osteoarthritic pain. Interestingly, in acute postoperative and chronic osteoarthritic pain, capsaicin prolonged and potentiated the pain-relieving effect of diclofenac. CONCLUSIONS:New generation combined low-concentration capsaicin-diclofenac containing TTS can be an effective therapeutic tool in acute and chronic pain states involving neuropathic and inflammatory components.

Chronic primary pain (CPP) persisting for more than 3 months, associated with significant emotional distress without any known underlying cause, is an unmet medical need. Traditional or adjuvant analgesics do not provide satisfactory pain relief for a great proportion of these patients. Therefore, identifying novel therapeutic targets and determining new treatments is important. In the present systematic review, we provide a comprehensive summary of Phases 1–3 clinical trials conducted between 01 January 2014 and 31 July 2024, available on clinicaltrials.gov , clinicaltrialsregister.eu and PubMed, concerning both original drug development approaches and repurposing for the important widespread and regional musculoskeletal CPP conditions fibromyalgia (FM), complex regional pain syndrome and chronic low back pain. Unfortunately, there has not been a breakthrough in the pharmacotherapy of these conditions. This may be related to (i) the unsuccessful approaches to reveal pathophysiological mechanisms and identifying novel targets, with the lack of appropriate preclinical animal models with translational relevance, and (ii) the heterogeneity of these patient populations with several co‐morbidities. Alongside innovative drug developmental concepts such as TRPA1 and the P2X7 purine receptor inhibition and somatostatin SST 4 receptor activation, most trials have focussed on repurposing antidepressants, antiepileptics, psychedelics, immune modulators, or suppressants. The most promising candidates have targeted cannabinoid, glutamate, GABAergic, neuroinflammatory and immune mechanisms, because several studies were initiated focussing on these pathways and proving their efficacy and safety. Only cannabidiol (CBD) and (es)ketamine have been tested for all three CPPs despite similar etiological factors and mechanisms related to stress‐pain interactions.

Dysfunction of dopamine receptors and interruption of normal dopaminergic signaling have been linked to severe neuropsychiatric diseases such as schizophrenia, Parkinson's disease and depression. Although these receptors are among the most drug-targeted families of GPCRs, designing compounds with subtype-specific pharmacological profile remains challenging due to the structural similarities among the subtypes of the family. Considering the structural moieties of cariprazine, a prototypic drug with D3 receptor (D3R) preference, we report a library of bitopic analogues to explore how the orthosteric and secondary binding motifs, coupled with different linkers, affect D2R/D3R selectivity and activity. Compounds with promising dopamine receptor selectivities and binding affinities were further characterized on a GPCR panel and in functional assays. Our efforts resulted in an advanced lead compound (20b) with improved D3R and 5-HT2AR, as well as decreased D2R and 5-HT1AR potencies (EC50) compared to cariprazine. The cleaner receptor profile of this compound retained activities for the most important antidepressant mechanisms that were confirmed by reducing the depression-like behavior in mice.

There is an unmet need for novel therapeutic tools relieving chronic pain. Hydrogen sulfide (H2S) is highly involved in pain processes; however, the development of ideal matrices for sulfide donor compounds remains a great pharmaceutical challenge. We aimed to establish a suitable transdermal therapeutic system (TTS) using the H2S donor diallyl disulfide (DADS) as a model compound. After the preparation of DADS, its solubility was investigated in different liquid excipients (propylene glycol, polyethylene glycol, silicone oil) and its membrane diffusivity was assessed in silicone matrices of different compositions. Drug-releasing properties of DADS-containing patches with different silicone oil contents were determined with Franz and flow-through cells. We found a correlation between the liquid excipient content of the patch and the diffusion rate of DADS. DADS showed the best solubility in dimethyl silicone oil, and the diffusion constant was proportional to the amount of oil above the 3 m/m% threshold value. The 8-day-old patch showed a significantly lower, but better-regulated, drug release over time than the 4-day-old one. In conclusion, the silicone-based polymer matrix developed in this study is suitable for stable storage and optimal release of DADS, providing a good basis for a TTS applied in chronic pain.

The Transient Receptor Potential Ankyrin 1 (TRPA1) cation channel expressed on capsaicin-sensitive afferents, immune and endothelial cells is activated by inflammatory mediators and exogenous irritants, e.g., endotoxins, nicotine, crotonaldehyde and acrolein. We investigated its involvement in acute and chronic pulmonary inflammation using Trpa1 gene-deleted (Trpa1−/−) mice. Acute pneumonitis was evoked by intranasal Escherichia coli endotoxin (lipopolysaccharide: LPS) administration, chronic bronchitis by daily cigarette smoke exposure (CSE) for 4 months. Frequency, peak inspiratory/expiratory flows, minute ventilation determined by unrestrained whole-body plethysmography were significantly greater, while tidal volume, inspiratory/expiratory/relaxation times were smaller in Trpa1−/− mice. LPS-induced bronchial hyperreactivity, myeloperoxidase activity, frequency-decrease were significantly greater in Trpa1−/− mice. CSE significantly decreased tidal volume, minute ventilation, peak inspiratory/expiratory flows in wildtypes, but not in Trpa1−/− mice. CSE remarkably increased the mean linear intercept (histopathology), as an emphysema indicator after 2 months in wildtypes, but only after 4 months in Trpa1−/− mice. Semiquantitative histopathological scores were not different between strains in either models. TRPA1 has a complex role in basal airway function regulation and inflammatory mechanisms. It protects against LPS-induced acute pneumonitis and hyperresponsiveness, but is required for CSE-evoked emphysema and respiratory deterioration. Further research is needed to determine TRPA1 as a potential pharmacological target in the lung.

Chronic obstructive pulmonary disease characterized by progressive persistent airway inflammation & airway resistance is caused mainly by cigarette smoke‐triggered inflammatory cascades & tissue damage. The airways are densely innervated by capsaicin‐sensitive sensory nerves expressing Transient Receptor Potential Vanilloid 1 (TRPV1) ion channels, which play an important regulatory role in inflammation through the release of sensory neuropeptides. Pro‐inflammatory peptides, such as tachykinins (substance P, neurokinin A) encoded by the TAC1 gene induce neurogenic inflammation via NK1 & NK2 receptor activation in the innervated area. The overall significance of these mediators depends on the pathophysiological mechanisms involved in certain inflammatory processes. Therefore, we established a predictive mouse model of cigarette smoke‐induced chronic bronchitis & consequent airway hyperresponsiveness to investigate the roles of TRPV1 channel & tachikinins.We exposed TRPV1−/− & TAC1−/− gene‐deleted mice and their C57Bl/6 wildtype counterparts to cigarette smoke in a whole body smoke exposure chamber for 3 months. Bronchial responsiveness & enhanced pause (Penh) correlating with airway resistance to inhalation of 22 mM carbachol were measured with unrestrained whole body plethysmography weekly. At the end of each month inflammatory cell profile and count from the bronchoalveolar lavage fluid (BALF), semiquantitative histopathological scoring of the lung, myeloperoxidase (MPO) activity with spectrophotometry & IL‐1β concentrations with ELISA were performed.In wildtype mice mild bronchial hyperresponsiveness developed in the 1st month, then it decreased & started to increase after 10 weeks. The inflammatory cell peak in BALF was observed in the 2nd month, correlating with the histology. In the 1st month significant perivascular/peribronchial edema, in the 2nd month remarkable inflammatory cell accumulation, then increasing atelectasy, emphysema, mucus production & irregular bronchiolar mucosa were observed. Lung IL‐1β concentration gradually increased, but MPO activity only transiently elevated in the 2nd month. Hyperreactivity occured earlier & increased significantly in TRPV1−/−, but did not change in TAC1−/− mice. Remarkably more severe inflammatory histopathological parameters, higher BALF cell counts, MPO activity a& IL‐1β production were observed in TRPV1‐deficient mice. Meanwhile, some inflammatory alterations in the 1st month, & BALF cell counts in the 2nd month were significantly decreased in the TAC1 gene‐deleted mice.Neurogenic inflammatory mechanisms are not crucial in chronic cigarette smoke‐induced inflammation & hyperresponsiveness. The overall role of TRPV1 receptor is protective in smoking‐induced chronic bronchitis.Support or Funding InformationÚNKP‐18‐3 New National Excellence Program of the Ministry of Human CapacitiesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Tac4 gene-derived hemokinin-1 (HK-1) is present in pain-related regions and activates the tachykinin NK1 receptor, but with binding site and signaling pathways different from Substance P (SP). NK1 receptor is involved in nociception, but our earlier data showed that it has no role in chronic neuropathic hyperalgesia, similarly to SP. Furthermore, NK1 antagonists failed in clinical trials as analgesics due to still unknown reasons. Therefore, we investigated the role of HK-1 in pain conditions of distinct mechanisms using genetically modified mice. Chronic neuropathic mechanical and cold hyperalgesia after partial sciatic nerve ligation (PSL) were determined by dynamic plantar aesthesiometry and withdrawal latency from icy water, motor coordination on the accelerating Rotarod. Peripheral nerve growth factor (NGF) production was measured by ELISA, neuronal and glia cell activation by immunohistochemistry in pain-related regions. Acute somatic and visceral chemonocifensive behaviors were assessed after intraplantar formalin or intraperitoneal acetic-acid injection, respectively. Resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia by aesthesiometry and increasing temperature hot plate. Chronic neuropathic mechanical and cold hypersensitivity were significantly decreased in HK-1 deficient mice. NGF level in the paw homogenates of intact mice were significantly lower in case of HK-1 deletion. However, it significantly increased under neuropathic condition in contrast to wildtype mice, where the higher basal concentration did not show any changes. Microglia, but not astrocyte activation was observed 14 days after PSL in the ipsilateral spinal dorsal horn of wildtype, but not HK-1-deficient mice. However, under neuropathic conditions, the number of GFAP-positive astrocytes was significantly smaller in case of HK-1 deletion. Acute visceral, but not somatic nocifensive behavior, as well as neurogenic inflammatory mechanical and thermal hypersensitivity were significantly reduced by HK-1 deficiency similarly to NK1, but not to SP deletion. We provide evidence for pro-nociceptive role of HK-1, via NK1 receptor activation in acute inflammation models, but differently from SP-mediated actions. Identification of its targets and signaling can open new directions in pain research.

It is supposed that TRPA1 receptor can be activated by hydrogen sulphide (H2S). Here, we have investigated the role of TRPA1 receptor in H2S-induced [Ca2+]i increase in trigeminal ganglia (TRG) neurons, and the involvement of capsaicin-sensitive sensory nerves in H2S-evoked cutaneous vasodilatation. [Ca2+]i was measured with ratiometric technique on TRG neurons of TRPA1+/+ and TRPA1−/− mice after NaHS, Na2S, allylisothiocyanate (AITC) or KCl treatment. Microcirculatory changes in the ear were detected by laser Doppler imaging in response to topical NaHS, AITC, NaOH, NaSO3 or NaCl. Mice were either treated with resiniferatoxin (RTX), or CGRP antagonist BIBN4096, or NK1 receptor antagonist CP99994, or K+ ATP channel blocker glibenclamide. Alpha-CGRP−/− and NK1 −/− mice were also investigated. NaHS and Na2S increased [Ca2+]i in TRG neurons derived from TRPA+/+ but not from TRPA1−/− mice. NaHS increased cutaneous blood flow, while NaOH, NaSO3 and NaCl did not cause significant changes. NaHS-induced vasodilatation was reduced in RTX-treated animals, as well as by pre-treatment with BIBN4096 or CP99994 alone or in combination. NaHS-induced vasodilatation was significantly smaller in alpha-CGRP−/− or NK1 −/− mice compared to wild-types. H2S activates capsaicin-sensitive sensory nerves through TRPA1 receptors and the resultant vasodilatation is mediated by the release of vasoactive sensory neuropeptides CGRP and substance P.

The tachykinin NK1 receptor was suggested to be involved in psychiatric disorders, but its antagonists have failed to be effective as antidepressants in clinical trials. Hemokinin-1 (HK-1), the newest tachykinin, is present in several brain regions and activates the NK1 receptor similarly to substance P (SP), but acts also through other mechanisms. Therefore, we investigated the roles of the Tac4 gene-derived HK-1 in comparison with SP and neurokinin A (NKA) encoded by the Tac1 gene, as well as the NK1 receptor in anxiety and depression-like behaviors in mice. Mice lacking SP/NKA, HK-1 or the NK1 receptor (Tac1-/-, Tac4-/-, Tacr1-/-, respectively) compared to C57Bl/6 wildtypes (WT), and treatment with the NK1 antagonist CP99994 were used in the experiments. Anxiety was evaluated in the light-dark box (LDB) and the elevated plus maze (EPM), locomotor activity in the open field (OFT) tests. Hedonic behavior was assessed in the sucrose preference test (SPT), depression-like behavior in the tail suspension (TST) and forced swim (FST) tests. FST-induced neuronal responsiveness was evaluated with Fos immunohistochemistry in several stress-related brain regions. In the LDB, Tac4-/- mice spent significantly less, while Tacr1-/- and CP99994-treated mice spent significantly more time in the lit compartment. In the EPM only Tac4-/- showed reduced time in the open arms, but no difference was observed in any other groups. In the OFT Tac4-/- mice showed significantly reduced, while Tac1-/- and Tacr1-/- animals increased motility than the WTs, but CP99994 had no effect. NK1-/- consumed markedly more, while Tac4-/- less sucrose solution compared to WTs. In the TST and FST, Tac4-/- mice showed significantly increased immobility. However, depression-like behavior was decreased both in cases of genetic deletion and pharmacological blockade of the NK1 receptor. FST-induced neuronal activation in different nuclei involved in behavioral and neuroendocrine stress responses was significantly reduced in the brain of Tac4 -/- mice. Our results provide the first evidence for an anxiolytic and anti-depressant-like actions of HK-1 through a presently unknown target-mediated mechanism. Identification of its receptor and/or signaling pathways might open new perspectives for anxiolytic and anti-depressant therapies.

Introduction: Accurate preclinical modeling of diabetic complications such as retinopathy, nephropathy and neuropathy is crucial to enable the development of novel preventative therapies. The aims of this study were to establish a model of long-term diabetes with sustained medium scale hyperglycemia and characterize the pathological changes detectable after 4 months, with particular respect to dependence on the degree of hyperglycemia.Methods: Streptozotocin-induced diabetic CFY rats were subjected to four different insulin substitution protocols to achieve different levels of glycemic control (Diabetic 1-4 groups). Eyes were investigated by ophthalmoscopy, kidney function by urine analysis, and neuropathy by functional tests. Retinal and renal morphological evaluations were performed by histology, immuno-histochemistry and electron microscopy.Results: Rats of the Diabetic 3 group showed massive hyperglycemia-dependent anterior segment neovascularization, enhanced total retinal score and retinal apoptotic cell number, degeneration of dopaminergic amacrine cells, increased glomerular PAS-positivity, altered excreted total protein/creatinine ratio and cold allodynia, parallel with medium scale hyperglycemia (blood glucose level between 22 and 25 mmol/L) and satisfying state of health.Discussion: We established a treatment protocol in rats enabling complex investigation of diabetic retinopathy, nephropathy and neuropathy on a long-termperiod. Clearly hyperglycemic dependent parameters of these complications serve as good outcome measures for preclinical trials. Our results provide a useful basis for designing studies for testing preventative treatments as well as other translational medical research in this field. (C) 2015 Elsevier Inc. All rights reserved.

Aims: To investigate the roles of TRPV1 and TRPA1 channels in baseline and allyl isothiocyanate ( AITC)-evoked nociceptive responses by comparing wild-type and gene-deficient mice.Main methods: In contrast to conventional methods of thermonociception measuring reflex latencies, we used our novel methods to determine the noxious heat threshold.Key findings: It was revealed that the heat threshold of the tail measured by an increasing-temperature water bath is significantly higher in TRPV1(-/-), but not TRPA1(-/-), mice compared to respective wild-types. There was no difference between the noxious heat thresholds of the hind paw as measured by an increasing-temperature hot plate in TRPV1(-/-), TRPA1(-/-) and the corresponding wild-type mice. The withdrawal latency of the tail from 0 degrees C water was prolonged in TRPA1(-/-), but not TRPV1(-/-), mice compared to respective wild-types. In wild-type animals, dipping the tail or paw into 1% AITC induced an 8-14 degrees C drop of the noxious heat threshold (heat allodynia) of both the tail and paw, and 40-50% drop of the mechanonociceptive threshold ( mechanical allodynia) of the paw measured by dynamic plantar esthesiometry. These AITC-evoked responses were diminished in TRPV1(-/-), but not TRPA1(-/-), mice. Tail withdrawal latency to 1% AITC was significantly prolonged in both gene-deleted strains.Significance: Different heat sensors determine the noxious heat threshold in distinct areas: a pivotal role for TRPV1 on the tail is contrasted with no involvement of either TRPV1 or TRPA1 on the hind paw. Noxious heat threshold measurement appears appropriate for preclinical screening of TRP channel ligands as novel analgesics. (C) 2016 Elsevier Inc. All rights reserved.

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Somatostatin regulates stress-related behavior and its expression is altered in mood disorders. However, little is known about the underlying mechanisms, especially about the importance of its receptors (sst(1)-sst(5)) in anxiety and depression-like behavior. Here we analyzed the potential role of sst(4) receptor in these processes, since sst(4) is present in stress-related brain regions, but there are no data about its functional relevance. Genetic deletion of sst(4) (Sstr4(-/-)) and its pharmacological activation with the newly developed selective non-peptide agonist J-2156 were used. Anxiety was examined in the elevated plus maze (EPM) and depression-like behavior in the forced swim (FST) and tail suspension tests (TST). Neuronal activation during the TST was monitored by Fos immunohistochemistry, receptor expression was identified by sst(4)(LacZ) immunostaining in several brain regions. Sstr4(-/-) mice showed increased anxiety in the EPM and enhanced depression-like behavior in the FST. J-2156 (100 mu g/kg i.p.) exhibited anxiolytic effect in the EPM and decreased immobility in the TST. J-2156 alone did not influence Fos immunoreactivity in intact mice, but significantly increased the stress-induced Fos response in the dorsal raphe nucleus, central projecting Edinger-Westphal nucleus, periaqueductal gray matter, the magnocellular, but not the parvocellular part of the hypothalamic paraventricular nucleus, lateral septum, bed nucleus of the stria terminalis and the amygdala. Notably, sst(4)(LacZ) immunoreactivity occurred in the central and basolateral amygdala. Together, these studies reveal that sst(4) mediates anxiolytic and antidepressant-like effects by enhancing the stress-responsiveness of several brain regions with special emphasis on the amygdala. (C) 2015 Elsevier Ltd. All rights reserved.

The aetiology of complex regional pain syndrome (CRPS), a highly painful, usually post-traumatic condition affecting the limbs, is unknown, but recent results have suggested an autoimmune contribution. To confirm a role for pathogenic autoantibodies, we established a passive-transfer trauma model. Prior to undergoing incision of hind limb plantar skin and muscle, mice were injected either with serum IgG obtained from chronic CRPS patients or matched healthy volunteers, or with saline. Unilateral hind limb plantar skin and muscle incision was performed to induce typical, mild tissue injury. Mechanical hyperalgesia, paw swelling, heat and cold sensitivity, weight-bearing ability, locomotor activity, motor coordination, paw temperature, and body weight were investigated for 8 days. After sacrifice, proinflammatory sensory neuropeptides and cytokines were measured in paw tissues. CRPS patient IgG treatment significantly increased hind limb mechanical hyperalgesia and oedema in the incised paw compared with IgG from healthy subjects or saline. Plantar incision induced a remarkable elevation of substance P immunoreactivity on day 8, which was significantly increased by CRPS-IgG. In this IgG-transfer-trauma model for CRPS, serum IgG from chronic CRPS patients induced clinical and laboratory features resembling the human disease. These results support the hypothesis that autoantibodies may contribute to the pathophysiology of CRPS, and that autoantibody-removing therapies may be effective treatments for long-standing CRPS. (C) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

OBJECTIVE:Hemokinin-1, the newest tachykinin encoded by the preprotachykinin C (Tac4) gene, is predominatly produced by immune cells. Similarly to substance P, it has the greatest affinity to the tachykinin NK1 receptor, but has different binding site and signaling mechanisms. Furthermore, several recent data indicate the existence of a not yet identified own receptor and divergent non-NK1-mediated actions. Since there is no information on its functions in the airways, we investigated its role in endotoxin-induced pulmonary inflammation. METHODS:Acute pneumonitis was induced in Tac4 gene-deleted (Tac4(-/-)) mice compared to C57Bl/6 wildtypes by intranasal E. coli lipopolysaccharide (LPS). Airway responsiveness to inhaled carbachol was measured with unrestrained whole body plethysmography 24h later. Semiquantitative histopathological scoring was performed; reactive oxygen species (ROS) production was measured with luminol bioluminescence, myeloperoxidase activity with spectrophotometry, and inflammatory cytokines with Luminex. RESULTS:All inflammatory parameters, such as histopathological alterations (perivascular edema, neutrophil/macrophage accumulation, goblet cell hyperplasia), myeloperoxidase activity, ROS production, as well as interleukin-1beta, interleukin-6, tumor necrosis factor alpha, monocyte chemoattractant protein-1 and keratinocyte chemoattractant concentrations were significantly diminished in the lung of Tac4(-/-) mice. However, bronchial hyperreactivity similarly developed in both groups. Interestingly, in LPS-treated Tac4(-/-) mouse lungs, bronchus-associated, large, follicle-like lymphoid structures developed. CONCLUSIONS:We provide the first evidence that hemokinin-1 plays a crucial pro-inflammatory role in the lung by increasing inflammatory cell activities, and might also be a specific regulator of lymphocyte functions.

Capsaicin-sensitive sensory neurons express several ion channels of the TRP family, such as transient receptor potential ankyrin 1 (TRPA1) receptors. TRPA1 can be activated by several chemical stimuli, such as allylisothiocyanate (AITC) or cinnamaldehyde resulting in the release of inflammatory neuropeptides, e.g. calcitonin gene-related peptide (CGRP) [1] . Recently, the gaseous mediator hydrogen sulfide (H2S) was suggested to have effect on capsaicin-sensitive sensory neurons acting via TRPA1 receptors. Microcirculatory changes in the mouse ear and hind paw have been investigated in this study. Balb/c, C57BL/6, TRPA1 KO and TRPV1 KO mice (20–30 g) were treated with sodium hydrogen sulfide (NaHS) or AITC. Ipsilateral ears of the animals were treated with 2% AITC or 5% NaHS. Contralateral ears received respective vehicles. Balb/c mice received selective TRPA1 receptor antagonist HC-030031 (i.p., 30 or 100 mg/kg). NaHS (0.5 μmol/10 μL Tyrode) was injected s.c. into hind paws of C57BL/6 and TRPA1 KO mice. Skin blood flow was detected by laser Doppler imaging. AITC treatment of mouse ears led to 29.8 ± 2.8% increase in blood flow. NaHS elevated cutaneous blood flow of the mouse ears by 61 ± 4.5%. Effect of NaHS on microcirculation was ameliorated by HC-030031. Blood flow of TRPA1 KO mice showed significantly smaller increase in response to NaHS compared to the wild-type counterparts. Vasodilatation in TRPV1 KO animals did not differ from control. CGRP8−37 peptide antagonist of CGRP only partly inhibited the response. Intraplantar administration of NaHS elevated blood flow of murine hind paws by 34.1 ± 2.8%. The plantar microcirculatory response to NaHS was unaffected by genetic lack of TRPA1 receptor or resiniferatoxin pretreatment. We conclude that NaHS-induced vasodilatation in the mouse ear is partly mediated by TRPA1 receptors, but is independent of sensory nerves in the skin of the hind paw.

Cross-talk between the nervous, endocrine and immune systems exists via regulator molecules, such as neuropeptides, hormones and cytokines. A number of neuropeptides have been implicated in the genesis of inflammation, such as tachykinins and calcitonin gene-related peptide. Development of their receptor antagonists could be a promising approach to anti-inflammatory pharmacotherapy. Anti-inflammatory neuropeptides, such as vasoactive intestinal peptide, pituitary adenylate cyclase-activating polypeptide, α-melanocyte-stimulating hormone, urocortin, adrenomedullin, somatostatin, cortistatin, ghrelin, galanin and opioid peptides, are also released and act on their own receptors on the neurons as well as on different inflammatory and immune cells. The aim of the present review is to summarize the most prominent data of preclinical animal studies concerning the main pharmacological effects of ligands acting on the neuropeptide receptors. Promising therapeutic impacts of these compounds as potential candidates for the development of novel types of anti-inflammatory drugs are also discussed.