Peripheral Endings Research Articles

New perspectives for piezoelectric material-based cochlear implants: getting to nano

Sensorineural hearing loss (SNHL) occurs when the sound transduction mechanism in the inner ear is compromised, because of impairments affecting the sensory hair cells—the actual biological transducers (90% of cases)—or the neurons. SNHL results in a broad spectrum of developmental, cognitive and psycho-social damages. To date, only cochlear implants (CIs) can offer a therapeutic solution to patients. They are multi-component electronic devices, surgically implanted, which capture, elaborate and convert the sound into electric stimuli delivered to the cochlea. Due to inherent limitations of the current electronic-based CIs, a new class of devices has been envisioned, which is based on piezoelectric materials. However, using piezoelectric membranes, the obtained sensitivity was not enough. The new frontiers for piezoelectric material-based CI aim at synergizing micro/nanofabrication aided by multiscale materials modeling with an in vivo tissue engineering approach to provide an implantable biomaterial-based system for SNHL, acting as a next-generation CI. Specifically, the envisioned device will move forward the primitive concept of bulk-structured piezoelectric CIs by designing a nanostructured material (e.g., based on nanofibers) to be precisely delivered and be intimately and efficiently integrated with the cochlear microenvironment. Piezoelectric material-based CIs are indeed hypothesized to have a much higher resolution of electrical stimulation with more than hundreds of channels, compared to maximum 22 stimulating elements present in electronic-based CIs. Moreover, the stimulation site will be closest to peripheral nerve fiber endings for maximal resolution. This would be the first sensory implant with a feedback mechanism on a micrometer scale.

Distinct cellular expression and subcellular localization of Kv2 voltage-gated K+ channel subtypes in dorsal root ganglion neurons conserved between mice and humans.

The distinct organization of Kv2 voltage-gated potassium channels on and near the cell body of brain neurons enables their regulation of action potentials and specialized membrane contact sites. Somatosensory neurons have a pseudounipolar morphology and transmit action potentials from peripheral nerve endings through axons that bifurcate to the spinal cord and the cell body within ganglia including the dorsal root ganglia (DRG). Kv2 channels regulate action potentials in somatosensory neurons, yet little is known about where Kv2 channels are located. Here, we define the cellular and subcellular localization of the Kv2 paralogs, Kv2.1 and Kv2.2, in DRG somatosensory neurons with a panel of antibodies, cell markers, and genetically modified mice. We find that relative to spinal cord neurons, DRG neurons have similar levels of detectable Kv2.1 and higher levels of Kv2.2. In older mice, detectable Kv2.2 remains similar, while detectable Kv2.1 decreases. Both Kv2 subtypes adopt clustered subcellular patterns that are distinct from central neurons. Most DRG neurons co-express Kv2.1 and Kv2.2, although neuron subpopulations show preferential expression of Kv2.1 or Kv2.2. We find that Kv2 protein expression and subcellular localization are similar between mouse and human DRG neurons. We conclude that the organization of both Kv2 channels is consistent with physiological roles in the somata and stem axons of DRG neurons. The general prevalence of Kv2.2 in DRG as compared to central neurons and the enrichment of Kv2.2 relative to detectable Kv2.1 in older mice, proprioceptors, and axons suggest more widespread roles for Kv2.2 in DRG neurons.

Reduced Gray Matter Volume and Cortical Thickness in Patients With Small-Fiber Neuropathy

Small-fiber neuropathy (SFN) is defined by degeneration or dysfunction of peripheral sensory nerve endings. Central correlates have been identified on the level of gray matter volume (GMV) and cortical thickness (CT) changes. However, across SFN etiologies knowledge about a common structural brain signature is still lacking. Therefore, we recruited 26 SFN patients and 25 age- and sex-matched healthy controls to conduct voxel-based- and surface-based morphometry. Across all patients, we found reduced GMV in widespread frontal regions, left caudate, insula and superior parietal lobule. Surface-based morphometry analysis revealed reduced CT in the right precentral gyrus of SFN patients. In a region-based approach, patients had reduced GMV in the left caudate. Since pathogenic gain-of-function variants in voltage-gated sodium channels (Nav) have been associated with SFN pathophysiology, we explored brain morphological patterns in a homogenous subsample of patients carrying rare heterozygous missense variants. Whole brain- and region-based approaches revealed GMV reductions in the bilateral caudate for Nav variant carriers. Further research is needed to analyze the specific role of Nav variants for structural brain alterations. Together, we conclude that SFN patients have specific GMV and CT alterations, potentially forming potential new central biomarkers for this condition. Our results might help to better understand underlying or compensatory mechanisms of chronic pain perception in the future. PerspectiveThis study reveals structural brain changes in small-fiber neuropathy (SFN) patients, particularly in frontal regions, caudate, insula, and parietal lobule. Notably, individuals with SFN and specific Nav variants exhibit bilateral caudate abnormalities. These findings may serve as potential central biomarkers for SFN and provide insights into chronic pain perception mechanisms.

Vascular read-out for TRP channel functionality on distal peripheral nerve endings in healthy men

BackgroundQuantification of the vasodilation after topical application of capsaicin or cinnamaldehyde is often implemented to indirectly assess Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1) or Ankyrin 1 (TRPA1) functionality respectively. This method has been well-established on the human forearm. However, to enable TRP functionality assessments in distal peripheral neuropathy, the vascular response upon TRP activation on dorsal finger skin was characterized. MethodsTwo doses of cinnamaldehyde (3 % and 10 % v/v) and capsaicin (300 μg and 1000 μg) were topically applied (20 μL) on the skin of the mid three proximal phalanges in 17 healthy men. The dose-response, and inter-hand and inter-period reproducibility of the dermal blood flow (DBF) increase was assessed using Laser Speckle Contrast Imaging (LSCI) during 60 min post-application. Linear mixed models explored dose-driven differences, whereas the intra-class correlation coefficient (ICC) estimated the reproducibility of the vascular response. ResultsBoth doses of cinnamaldehyde and capsaicin induced a robust, dose-dependent increase in DBF. The vascular response to cinnamaldehyde 10 % on finger skin, expressed as area under the curve, correlated well over time (ICC = 0.66) and excellently between hands (ICC = 0.87). Similarly, the response to capsaicin 1000 μg correlated moderately over time (ICC = 0.50) and well between hands (ICC = 0.73). ConclusionThe vascular response upon topical cinnamaldehyde and capsaicin application on finger skin is an alternative approach for measurements on forearm skin. Thereby, it is a promising vascular read-out to investigate the pathophysiology, and TRP involvement in particular, of specific peripheral neuropathic pain syndromes.

Molecular and cellular changes underlying plasticity and regeneration of intact, injured and aged cold corneal nerves

The peripheral nerve endings from trigeminal neurons that innervate the cornea are key neural structures to detect and encode the features of the physical and chemical external stimuli at the ocular surface. These neurons are functionally diverse and have been classified into polymodal nociceptors, mechano‐nociceptors and cold thermoreceptors. Each functional type evokes qualitative different conscious sensations. The sensory modality that is generated from a nerve ending is determined by the type and specific characteristics of the ion channels involved in stimulus transduction and encoding. Among them, TRPM8 channels transduce both cold and osmotic stimuli in corneal cold nerve terminals. These cold thermoreceptors mediate sensations of ocular surface cooling and dryness, and play an important role in the regulation of basal tearing and blinking. Morphologically, cold thermosensitive neurons display a more complex branching of their peripheral nerve endings innervating the cornea in comparison to the other functional classes of sensory neurons.With aging, TRPM8‐expressing cold sensory neurons innervating the mouse cornea experience morphological and functional alterations. These changes occur earlier and are more prominent at the nerve terminal than at the neuron cell body. A drastic reduction of the nerve terminal branching complexity in addition to lower background impulse activity is observed in cold nerves of aged mice. Similarly, after performing photorefractive keratectomy (PRK) in the adult mouse cornea, both the nerve terminal branching and background activity are reduced in a fraction of the cold nerve terminals. An altered morphological configuration along with an aberrant transducing and coding ion channels expression at corneal cold nerve terminals are likely to contribute to the discomfort sensations experienced after corneal surgery and to the age‐related abnormal tearing in the elderly.(Supported by PID2021‐124460OB‐I00 from DOI: MCIN/AEI/ 10.13039/501100011033, and CIPROM/2021/48 from the Generalitat Valenciana, Spain)

Corneo‐conjunctival sensory neuron: Types, transduction channels and codification of nerve impulses

The cornea and the conjunctiva are innervated by the peripheral projections of a small number of primary sensory neurons whose somata are located at the ophthalmic region of the trigeminal ganglion. Most trigeminal neurons innervating the ocular surface are small and medium size, and contain neuropeptides such as SP and CGRP. Functionally, ocular surface neurons have been classified into five main neuronal types, based on their response to multiple modalities of stimuli (mechanical forces, heat, cold, H+, chemical substances, etc.). Polymodal nociceptors (activated by several modalities of stimulus, mechanical energy, heat, H+, and chemical irritants), mechanonociceptors (activated by mechanical energy), cold thermoreceptors (activated by temperature reductions and hyperosmolarity) are found in the cornea, the sclera and the conjunctiva. Besides, low‐threshold mechanoreceptors (activated by mechanical forces of low intensity) are found in the corneoscleral limbus and the lid border, and pruriceptors (activated by pruritogen substances) have been described in the tarsal conjunctiva, close to the lid margin.The ability to respond to the different modalities of stimulus lies in the types of transducing channels that each type of neuron expresses at its peripheral nerve endings. Sensory transduction involves the conversion of the physical or chemical stimuli acting on the nerve terminal into electrical energy, that is, into a local change of membrane potential that, if it is large enough, will generate action potentials that will travel along the axon to be processed by the CNS. So that, nerve terminals with TRPV1 channels are directly gated by heat, H+, and several chemical irritants such as capsaicin; nerve terminals with Piezo2 channels will be activated by mechanical forces; TRPM8 channels provide nerve terminals sensitivity to cold and osmolarity increases; et cetera.Ocular sensory neurons also express other ion channels that contribute to coding, that is to help the sensory neuron to establish a correspondence between the characteristics of the stimulus (intensity, temporal course, etc.) and specific parameters of the firing it induces. Voltage‐gated Ca2+, Na+ and K+ channels as well as cyclic nucleotide‐gated channels, among others, contribute to define the firing frequency and pattern to encode the traits of the stimulus. Thus, the ion channels present in the nerve terminals of each class of ocular sensory neuron provide the neurons the ability to detect and encode one or several modalities of stimulus, which constitutes the origin of the different sensations evoked on the ocular surface.(Supported by PID2020‐115934RB‐I00 from DOI: MCIN/AEI/10.13039/50110001103, and CIPROM/2021/48 from the Generalitat Valenciana, Spain)

Mechanisms of ocular surface pain

Ocular pain is evoked upon activation of a small number of nociceptive neurons located at the trigeminal ganglion whose peripheral projections profusely innervate the cornea and conjunctiva. In healthy conditions, nerve impulse activity originated at peripheral nerve endings of these primary sensory neurons in response to noxious or potentially noxious stimuli acting on the ocular surface travels centrally and reaches second‐order neurons located at the trigeminal brain stem complex. In turn, these brainstem neurons send their axons to the contralateral posterior thalamic nuclei, where the third neurons along the ocular nociceptive pathway are found. Thalamic neurons send their axons to the primary somatosensory area of the brain cortex and, after brain cortex processing if this sensory inflow, nociceptive pain sensation is experienced.The activity of ocular nociceptor neurons is modified under inflammation. Inflammatory mediators released at the ocular surface increase the excitability of the nerve terminals. As a result, the impulse response of primary nociceptor neurons to noxious stimuli is increased, which constitutes the basis of hyperalgesia and leads to pain and other sensations such as gritty eyes, foreign body sensation, etc. experienced under ocular inflammation.After a lesion (including surgery) or disease that affects any nerve or neuron of the ocular somatosensory pathway, the activity and connectivity of the neurons involved in ocular pain is altered, sometimes permanently. The excitability of damaged neurons is long‐lasting increased, leading to ocular dysesthesia and development of neuropathic pain referred to the eye.(Supported by PID2020‐115934RB‐I00 from DOI: MCIN/AEI/10.13039/50110001103, and CIPROM/2021/48 from the Generalitat Valenciana, Spain)

SUMOylation Modulates Reactive Oxygen Species (ROS) Levels and Acts as a Protective Mechanism in the Type 2 Model of Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is the prevalent type of peripheral neuropathy; it primarily impacts extremity nerves. Its multifaceted nature makes the molecular mechanisms of diabetic neuropathy intricate and incompletely elucidated. Several types of post-translational modifications (PTMs) have been implicated in the development and progression of DPN, including phosphorylation, glycation, acetylation and SUMOylation. SUMOylation involves the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target proteins, and it plays a role in various cellular processes, including protein localization, stability, and function. While the specific relationship between high blood glucose and SUMOylation is not extensively studied, recent evidence implies its involvement in the development of DPN in type 1 diabetes. In this study, we investigated the impact of SUMOylation on the onset and progression of DPN in a type 2 diabetes model using genetically modified mutant mice lacking SUMOylation, specifically in peripheral sensory neurons (SNS-Ubc9-/-). Behavioural measurement for evoked pain, morphological analyses of nerve fibre loss in the epidermis, measurement of reactive oxygen species (ROS) levels, and antioxidant molecules were analysed over several months in SUMOylation-deficient and control mice. Our longitudinal analysis at 30 weeks post-high-fat diet revealed that SNS-Ubc9-/- mice exhibited earlier and more pronounced thermal and mechanical sensation loss and accelerated intraepidermal nerve fibre loss compared to control mice. Mechanistically, these changes are associated with increased levels of ROS both in sensory neuronal soma and in peripheral axonal nerve endings in SNS-Ubc9-/- mice. In addition, we observed compromised detoxifying potential, impaired respiratory chain complexes, and reduced levels of protective lipids in sensory neurons upon deletion of SUMOylation in diabetic mice. Importantly, we also identified mitochondrial malate dehydrogenase (MDH2) as a SUMOylation target, the activity of which is negatively regulated by SUMOylation. Our results indicate that SUMOylation is an essential neuroprotective mechanism in sensory neurons in type 2 diabetes, the deletion of which causes oxidative stress and an impaired respiratory chain, resulting in energy depletion and subsequent damage to sensory neurons.

Inflammatory loops in the epithelial-immune microenvironment of the skin and skin appendages in chronic inflammatory diseases.

The epithelial-immune microenvironment (EIME) of epithelial tissues has five common elements: (1) microbial flora, (2) barrier, (3) epithelial cells, (4) immune cells, and (5) peripheral nerve endings. EIME provides both constant defense and situation-specific protective responses through three-layered mechanisms comprising barriers, innate immunity, and acquired immunity. The skin is one of the largest organs in the host defense system. The interactions between the five EIME elements of the skin protect against external dangers from the environment. This dysregulation can result in the generation of inflammatory loops in chronic inflammatory skin diseases. Here, we propose an understanding of EIME in chronic skin diseases, such as atopic dermatitis, psoriasis, systemic lupus erythematosus, alopecia areata, and acne vulgaris. We discuss the current treatment strategies targeting their inflammatory loops and propose possible therapeutic targets in the future.

Differential Diagnosis Challenges of Facial Pain (Clinical Case)

Annotation. The diagnosis of facial pain falls within the realm of professional competence for dentists, orthopedic dentists, ophthalmologists, otolaryngologists, neurosurgeons, neurologists, and physiotherapists. The complex and highly subjective nature of clinical symptoms often poses challenges for practitioners across these specialties. Consequently, a patient with facial pain may undergo multiple consultations with different specialists before a definitive diagnosis is established and effective treatment is provided. The aim of this study is to demonstrate a developed routing protocol for a patient with atypical facial pain through a clinical case. The stages of interdisciplinary simultaneous consultation, a comprehensive approach to diagnosis and treatment of patients with facial pain, and differential diagnosis are considered using the example of a clinical case of a 15-year-old female patient K., who presented to a dental surgeon with complaints of constant facial pain and a preliminary diagnosis of “Temporomandibular joint dysfunction. Impacted wisdom teeth 38 and 28”. The pain was constant, dull, deep, and piercing. She experienced decreased sensitivity in the lower lip and the anterior half of the tongue on the left side, as well as stuffiness and ringing in the left ear. Consultations with a neurologist and an orthopedic dentist were conducted, which led to the prescription of additional diagnostic methods: needle electromyography and magnetic resonance imaging of the brain. The article assesses the relevance and effectiveness of a multidisciplinary approach to the comprehensive diagnosis of facial pain syndrome, including a thorough history-taking by a dental practitioner, conclusions of a neurologist, and the results of additional diagnostic methods. Based on the electromyographic signs, the trigeminal nerve damage was detected, and a voluminous brain tumor causing compression of the trigeminal nerve and its peripheral endings was visualized on magnetic resonance tomography. Following the consultation with the dental surgeon, the patient was referred for further treatment to the A.P. Romodanov Neurosurgery Institute of the National Academy of Medical Sciences of Ukraine. Thus, interdisciplinary consultation is recognized as the basis for the comprehensive management of patients with atypical facial pain, requiring the involvement of a primary care physician - a dentist, who develops a routing protocol for timely diagnosis and effective treatment of these kind of patients.

The efficacy and neural mechanism of acupuncture therapy in the treatment of visceral hypersensitivity in irritable bowel syndrome.

Irritable Bowel Syndrome (IBS) is a complex functional gastrointestinal disorder primarily characterized by chronic abdominal pain, bloating, and altered bowel habits. Chronic abdominal pain caused by visceral Hypersensitivity (VH) is the main reason why patients with IBS seek medication. Significant research effort has been devoted to the efficacy of acupuncture as a non-drug alternative therapy for visceral-hyperalgesia-induced IBS. Herein, we examined the central and peripheral analgesic mechanisms of acupuncture in IBS treatment. Acupuncture can improve inflammation and relieve pain by reducing 5-hydroxytryptamine and 5-HT3A receptor expression and increasing 5-HT4 receptor expression in peripheral intestinal sensory endings. Moreover, acupuncture can also activate the transient receptor potential vanillin 1 channel, block the activity of intestinal glial cells, and reduce the secretion of local pain-related neurotransmitters, thereby weakening peripheral sensitization. Moreover, by inhibiting the activation of N-methyl-D-aspartate receptor ion channels in the dorsal horn of the spinal cord and anterior cingulate cortex or releasing opioids, acupuncture can block excessive stimulation of abnormal pain signals in the brain and spinal cord. It can also stimulate glial cells (through the P2X7 and prokinetic protein pathways) to block VH pain perception and cognition. Furthermore, acupuncture can regulate the emotional components of IBS by targeting hypothalamic-pituitary-adrenal axis-related hormones and neurotransmitters via relevant brain nuclei, hence improving the IBS-induced VH response. These findings provide a scientific basis for acupuncture as an effective clinical adjuvant therapy for IBS pain.

Neural gut-to-brain communication for postprandial control of satiation and glucose metabolism.

The brain is tuned to integrate food-derived signals from the gut, allowing it to accurately adjust behavioral and physiological responses in accordance with nutrient availability. A key element of gut-to-brain communication is the relay of neural cues via peripheral sensory neurons (PSN) which harbor functionally specialized peripheral endings innervating the muscular and mucosal layers of gastrointestinal (GI) tract organs. In this review, we detail the properties of GI tract innervating PSN and describe their roles in regulating satiation and glucose metabolism in response to food consumption. We discuss the complex anatomical organization of vagal and spinal PSN subtypes, their peripheral and central projection patterns, and describe the limitations of unselective lesion and ablation approaches to investigate them. We then highlight the recent identification of molecular markers that allow selective targeting of PSN subtypes that innervate GI tract organs. This has facilitated accurately determining their projections, monitoring their responses to gut stimuli, and manipulating their activity. We contend that these recent developments have significantly improved our understanding of PSN-mediated gut-to-brain communication, which may open new therapeutic windows for the treatment of metabolic disorders, such as obesity and type 2 diabetes.

Molecular determinants of TRPM8 function: key clues for a cool modulation.

Cold thermoreceptor neurons detect temperature drops with highly sensitive molecular machinery concentrated in their peripheral free nerve endings. The main molecular entity responsible for cold transduction in these neurons is the thermo-TRP channel TRPM8. Cold, cooling compounds such as menthol, voltage, and osmolality rises activate this polymodal ion channel. Dysregulation of TRPM8 activity underlies several physiopathological conditions, including painful cold hypersensitivity in response to axonal damage, migraine, dry-eye disease, overactive bladder, and several forms of cancer. Although TRPM8 could be an attractive target for treating these highly prevalent diseases, there is still a need for potent and specific modulators potentially suitable for future clinical trials. This goal requires a complete understanding of the molecular determinants underlying TRPM8 activation by chemical and physical agonists, inhibition by antagonists, and the modulatory mechanisms behind its function to guide future and more successful treatment strategies. This review recapitulates information obtained from different mutagenesis approaches that have allowed the identification of specific amino acids in the cavity comprised of the S1-S4 and TRP domains that determine modulation by chemical ligands. In addition, we summarize different studies revealing specific regions within the N- and C-terminus and the transmembrane domain that contribute to cold-dependent TRPM8 gating. We also highlight the latest milestone in the field: cryo-electron microscopy structures of TRPM8, which have provided a better comprehension of the 21years of extensive research in this ion channel, shedding light on the molecular bases underlying its modulation, and promoting the future rational design of novel drugs to selectively regulate abnormal TRPM8 activity under pathophysiological conditions.

Labeling PIEZO2 activity in the peripheral nervous system

Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch, proprioception, and bladder stretch sensation, yet its broad expression in sensory neurons suggests it has undiscovered physiological roles. To fully understand mechanosensory physiology, we must know where and when PIEZO2-expressing neurons detect force. The fluorescent styryl dye FM 1-43 was previously shown to label sensory neurons. Surprisingly, we find that the vast majority of FM 1-43 somatosensory neuron labeling in mice invivo is dependent on PIEZO2 activity within the peripheral nerve endings. We illustrate the potential of FM 1-43 by using it to identify novel PIEZO2-expressing urethral neurons that are engaged by urination. These data reveal that FM 1-43 is a functional probe for mechanosensitivity via PIEZO2 activation invivo and will facilitate the characterization of known and novel mechanosensory processes in multiple organ systems.

Examining the Relationship Between Gamma Delta T Cells and Sensory Peripheral Nerves in the Skin

Abstract Wound repair involves a complex system of immune cells and mechanisms to induce proper healing of a laceration. The transmission of pain signals and immune functions occur simultaneously, suggesting a collaboration between immune and nervous systems. Gamma delta (γδ) T cells are present in the epidermis and dermis where they participate in wound repair by producing growth factors, cytokines, and chemokines. Dermal γδ T cells are adjacent to nerves in the skin. We set out to determine whether sensory peripheral nerve endings and γδ T cells exhibit crosstalk during wound repair. Using immunofluorescent microscopy we found that peripheral neurons and γδ T cells are in close proximity in both the epidermis and the dermis suggesting a transmission of signals. To determine whether γδ T cell dysfunction impacts neurons, we examined non-wounded and wounded skin derived from lean versus diet-induced obese (DIO) mice. There was less interaction between γδ T cells and sensory peripheral nerves in both nonwounded and wounded DIO mouse skin. To determine whether the lack of γδ T cells impacts peripheral nerve repair and wound healing responses, we compared wildtype and T-cell receptor knockout (TCRd −/−) mice. TCRd −/−mice did not exhibit any differences in the number of sensory peripheral nerves in nonwounded skin. However, there were fewer sensory peripheral nerves surrounding the wound edge in mice lacking γδ T cells. Together this data indicates that γδ T cells regulate how sensory peripheral nerves innervate a wound, but are not required for neuronal development. Understanding the mechanism that regulate the interdependent relationship between γδ T cells and sensory peripheral nerves could further our understanding of how to improve wound repair.

The effect of repetitive topical applications of local anesthetics (EMLA) on experimental pain and itch (histaminergic and nonhistaminergic)

Background: The effects of repeated topical applications of local anesthetics are poorly investigated as they may, in addition to analgesia, impact peripheral nerve endings in a cumulative manner. In the present study, the effects of 6 repetitive applications of eutectic mixture of lidocaine (EMLA 2.5% and prilocaine 2.5%) were investigated on experimentally induced pain, histaminergic and nonhistaminergic itch, and neurogenic inflammation. Methods: Four skin areas on the forearms of 24 subjects were randomized to receive 3 hours of application of EMLA or placebo twice a day for 3 consecutive days. After each application, superficial blood perfusion (SBP), mechanical (mechanically evoked itch, mechanical pain threshold, and mechanical pain sensitivity), and thermal sensitivity (warm detection threshold, heat pain threshold, and suprathreshold heat sensitivity) were assessed. After the last application of EMLA/placebo, histamine and cowhage was applied (2 areas each) and itch and pain intensity and SBP were assessed. Results: After 3 hours of EMLA application, significant mechanical and thermal hypoalgesia were found with no cumulative efficacy over the 3 days. EMLA alone had no effect on SBP. Significantly increased SBP, reduced cowhage-induced itch, but the unaffected histamine-induced itch was found when applying EMLA ahead of histamine and cowhage. Conclusions: EMLA induced a reduction of mechanical and thermal sensitivity without a cumulative-dose effect. EMLA reduced nonhistaminergic itch and pain but not the experimentally provoked histaminergic itch. Selective action of EMLA on polymodal C-fibers could explain these effects.

Reactive oxygen species-specific characteristics of transient receptor potential ankyrin 1 receptor and its pain modulation

Transient receptor potential ankyrin 1 (TRPA1) receptors are major polymodal nociceptors that generate primary pain responses in the peripheral nerve endings of the dorsal root ganglion neurons. Recently, we reported that the activation of TRPA1 receptors by reactive oxygen species (ROS) signaling, which is triggered by Ca<sup>2+</sup> influx through T-type Ca<sup>2+</sup> channels, contributes to prolonged pain responses induced by jellyfish toxin. In this review, we focus on the characteristics of the TRPA1 receptor involved in intracellular signaling as a secondary pain modulator. Unlike other transient receptor potential receptors, TRPA1 receptors can induce membrane depolarization by ROS without exogenous stimuli in peripheral and central sensory neurons. Therefore, it is important to identify the functional characteristics of TRPA1 receptors to understand pain modulation under several pathogenic conditions such as neuropathic pain syndromes and autoimmune diseases, which are mediated by oxidative signaling to cause chronic pain in the sensory system.

Targeting the Receptor at Synapse of Keratinocyte and Peripheral Nerve Ending: A Therapeutic Hope for Post-Burn Pruritus

Chronic itch or Pruritus is an unpleasant sensation that provokes the desire to scratch. In post burn patients, it is a significant health burden with few effective treatments. Pruritus is a common distressing consequence of postburn scars which affects burn survivors’ quality of life by causing sleep disturbance, daily activity impairment, and psychological problems. The mechanism of such abnormal scars with pruritus is not yet clear. The field of pruritus research is a dynamic field which involves neural component and various receptors at skin. The receptor present at the synapse of keratinocytes and peripheral nerve ending are responsible for itching. Many recent studies have worked to define the various receptors and the itch mediations in skin. However, considering that post-burn patients mainly report itch to be localized in the burn scars, spontaneous itch might be strongly based on peripheral input. The detailed characteristic and the factors for persistence of pruritus in post burn patients have not yet been clearly understood. Experimental evidences suggest that transient receptor potential (TRP) channels in skin and their expression patterns, activation mechanisms play regulatory roles in pruritus pathogenesis. In this article author collected the pruritus related data from post burn pruritus patients, isolated keratinocytes checked the receptor expression by immunocytochemistry and discussed the complex interplay between the central and peripheral factors that causes pruritus. It would be helpful to identify novel anti-pruritic agents that target the molecular itch pathogenesis pathways and the clinical assessment for burn patients with pruritus.

Age-related changes to adipose tissue and peripheral neuropathy in genetically diverse HET3 mice differ by sex and are not mitigated by rapamycin longevity treatment.

Neural communication between the brain and adipose tissues regulates energy expenditure and metabolism through modulation of adipose tissue functions. We have recently demonstrated that under pathophysiological conditions (obesity, diabetes, and aging), total subcutaneous white adipose tissue (scWAT) innervation is decreased ('adipose neuropathy'). With advanced age in the C57BL/6J mouse, small fiber peripheral nerve endings in adipose tissue die back, resulting in reduced contact with adipose-resident blood vessels and other cells. This vascular neuropathy and parenchymal neuropathy together likely pose a physiological challenge for tissue function. In the current work, we used the genetically diverse HET3 mouse model to investigate the incidence of peripheral neuropathy and adipose tissue dysregulation across several ages in both male and female mice. We also investigated the anti-aging treatment rapamycin, an mTOR inhibitor, as a means to prevent or reduce adipose neuropathy. We found that HET3 mice displayed a reduced neuropathy phenotype compared to inbred C56BL/6J mice, indicating genetic contributions to this aging phenotype. Compared to female HET3 mice, male HET3 mice had worse neuropathic phenotypes by 62 weeks of age. Female HET3 mice appeared to have increased protection from neuropathy until advanced age (126 weeks), after reproductive senescence. We found that rapamycin overall had little impact on neuropathy measures, and actually worsened adipose tissue inflammation and fibrosis. Despite its success as a longevity treatment in mice, higher doses and longer delivery paradigms for rapamycin may lead to a disconnect between life span and beneficial health outcomes.

The effect of ice gel pack on pain reduction of sheath removal in post-cardiac catheterization patients

Background: Cardiac catheterization is a minimally invasive intervention that can cause complications of vascular access after compression of the femoral artery or sheath removal. Cold pack gel is a non-pharmacological therapy given after sheat removal to reduce pain. Objective:This study aimed to measure the effect of ice pack gel on pain reduction in arterial sheath removal post-cardiac catheterization patients. Methods: This interventional clinical study with control and group treatment was conducted in the cardiology room of Saiful Anwar Hospital Malang, Indonesia. The respondents (n=32) were divided into two groups in pre and post-test control group design. Group A receives pressure bandages as a standard protocol (control groups) while group B, ice-packed gel. Pain scale measured by Visual Analog Scale (VAS) by 1-10. Results: The Mann-Whitney test in two groups shows that there are differences in scores of pain reduction. The pain reduction difference in the treatment group (ice pack gel) was higher than the control ones (p < 0.001). The cold temperature of the cold-packed gel decreased the peripheral free nerve ending conductivity, furthermore, it made sensitivity stimulus or pain impulses slowed down then reduced the perception of pain. Conclusions: The intervention of ice-packed gel is more effective than the standard protocols to reduce the pain in the removal sheath post cardiac catheterization.