Search Results (131)

We investigate the temperature evolution in the three-dimensional skin tissue exposed to a millimeter-wave electromagnetic beam that is not necessarily perpendicular to the skin surface. This study examines the effect of the beam’s incident angle. The incident angle influences the thermal heating in two aspects: (i) the beam spot projected onto the skin is elongated compared to the intrinsic beam spot in a perpendicular cross-section, resulting in a lower power per skin area; and (ii) inside the tissue, the beam propagates at the refracted angle relative to the depth direction. At millimeter-wavelength frequencies, the characteristic penetration depth is sub-millimeter, whereas the lateral extent of the beam spans at least several centimeters in applications. We explore the small ratio of the penetration depth to the lateral length scale in a nondimensional formulation and derive a leading-term asymptotic solution for the temperature distribution. This analysis does not rely on a small incident angle and is therefore applicable to arbitrary angles of incidence. Based on the asymptotic solution, we establish scaling laws for the three-dimensional skin temperature, the skin surface temperature, and the skin volume in which thermal nociceptors are activated. Full article

Peripheral tissue injury initiates a multifaceted cascade of structural and molecular modifications within nociceptors, the primary sensory neurons tasked with detecting noxious stimuli. These alterations play a crucial role in the induction and maintenance of pain states, encompassing acute and chronic pain. Structural remodeling includes alterations in axonal architecture, dendritic morphology, and synaptic connectivity, collectively impacting nociceptor excitability and functional integration. Simultaneously, molecular adaptations comprise the regulation of ion channels, receptor expression, and intracellular signaling pathways, as well as transcriptional reprogramming that modulates nociceptive signaling. This review synthesizes current evidence regarding the cellular and molecular bases of injury-induced plasticity in nociceptors, identifying prospective targets for therapeutic intervention to counteract maladaptive sensitization. Elucidating these processes is critical for the advancement of pain treatment strategies and for enhancing clinical outcomes in individuals experiencing neuropathic pain secondary to tissue injury. Full article

Nociceptors respond to noxious stimuli and transmit pain signals to the central nervous system. In the cornea, the nociceptors located in the most external layer provide a myriad of sensation modalities. Damage to these corneal nerve fibers can induce neuropathic pain. In response, corneal nerves become sensitized to previously non-noxious stimuli. Assessing corneal pain origin is a complex ophthalmic challenge due to variations in its causes and manifestations. Current FDA-approved therapies for corneal nociceptive pain, such as acetaminophen and NSAIDs, provide only broad-acting relief with unwanted side effects, highlighting the need for precision medicine for corneal nociceptive pain. A few targeted treatments, including perfluorohexyloctane (F6H8) eye drops and Optive Plus (TRPV1 antagonist), are FDA-approved, while others are in preclinical development. Treatments that target signaling pathways related to neurotrophic factors, such as nerve growth factors and ion channels, such as the transient receptor potential (TRP) family or tropomyosin receptor kinase A, may provide a potential combinatory therapeutic approach. This review describes the roles of nociceptors in corneal pain. In addition, it evaluates molecules within nociceptor signaling pathways for their potential to serve as targets for efficient therapeutic strategies for corneal nociceptive pain aimed at modulating neurotrophic factors and nociceptive channel sensitivity. Full article

Background/Objectives: Tentonin-3/TMEM150C is a pore-forming protein of a mechanically activated channel recently identified that typically displays rapid activation followed by slow inactivation. It has been detected in murine dorsal root ganglia, nodose ganglion baroreceptors, and muscle spindles. Nevertheless, primary sensory neurons expressing tentonin-3/TMEM150C fall into the categories of nociceptors, mechanoreceptors, and proprioceptors. Methods: We used immunohistochemistry and image analysis (examining the size of the neuronal bodies in the dorsal root ganglia) to investigate the distribution of tentonin-3/TMEM150C in human cervical dorsal root ganglia, sensory nerve formations in the glabrous skin, especially cutaneous end-organ complexes or sensory corpuscles, and muscle spindles. Results: In dorsal root ganglia, 41% of neurons were tentonin-3/TMEM150C-positive, with a distribution of small (12.0%), intermediate (18.1%), and large (10.9%). In the glabrous skin, tentonin-3/TMEM150C was observed in the axon of Meissner, Pacinian, and Ruffini corpuscles as well as in the axon of the Merkel cell–axon complexes. Furthermore, tentonin-3/TMEM150C-positive axons were observed in muscle spindles. No free nerve endings displaying immunoreactivity were found. Conclusions: This is the first report on the distribution of tentonin-3/TMEM150C immunoreactivity in the human peripheral somatosensory system, and although it is a brief preliminary study, it opens new perspectives for the study of this new mechano-gated ion channel. Full article

Sensory signals generated by peripheral nociceptors are transmitted by peptidergic and nonpeptidergic nociceptive primary afferents to the superficial spinal dorsal horn, where their central axon terminals establish synaptic contacts with secondary sensory spinal neurons. In the case of suprathreshold activation, the axon terminals release glutamate into the synaptic cleft and stimulate postsynaptic spinal neurons by activating glutamate receptors located on the postsynaptic membrane. When overexcitation is evoked by peripheral inflammation, neuropathy or pruritogens, peptidergic nociceptive axon terminals may corelease various neuropeptides, neurotrophins and endomorphin, together with glutamate. However, in contrast to glutamate, neuropeptides, neurotrophins and endomorphin are released extrasynaptically. They diffuse from the site of release and modulate the function of spinal neurons via volume transmission, activating specific extrasynaptic receptors. Thus, the released neuropeptides, neurotrophins and endomorphin may evoke excitation, disinhibition or inhibition in various spinal neuronal populations, and together with glutamate, induce overall overexcitation, called central sensitization. In addition, the synaptic and extrasynaptic release of neurotransmitters is subjected to strong retrograde control mediated by various retrogradely acting transmitters, messengers, and their presynaptic receptors. Moreover, the composition of this complex chemical apparatus is heavily dependent on the actual patterns of nociceptive primary afferent activation in the periphery. This review provides an overview of the complexity of this signaling apparatus, how nociceptive primary afferents can activate secondary sensory spinal neurons via synaptic and volume transmission in the superficial spinal dorsal horn, and how these events can be controlled by presynaptic mechanisms. Full article

Hyperalgesic priming is a model of the transition from acute to chronic pain. Whether a similar mechanism exists for “pruritic priming” of itch is unknown. Here, we tested the hypothesis that itchy skin in a commonly used mouse model of dry skin pruritus develops latent sensitization after resolution. Acetone–ether–water (AEW) treatment induced a dry and itchy skin condition in the mouse cheek that elicited site-directed scratching behavior. After cessation of treatment and the complete resolution of AEW-induced scratching, histaminergic and non-histaminergic pruritogens were administered to the cheek to test for altered site-directed scratching and wiping behavior. Each pruritogen was also tested following the resolution of carrageenan-induced nociceptor hypersensitivity to test for cross-modality priming. Peak AEW-induced scratching occurred 24 h after the final day of treatment, and 5 days were required for scratching levels to return to baseline. Likewise, epidermal thickening was the greatest on the final treatment day and completely returned to baseline after 5 days. After the resolution of itchy cheek skin, acute histamine- and non-histamine-evoked scratching and wiping behaviors were unchanged, nor were scratching and wiping behaviors to acute pruritogens altered after the resolution of carrageenan-induced hypersensitivity. The results indicate that persistent itch due to dry skin likely resolves completely, without producing a latent primed response to subsequent pruritic stimuli. We conclude that the mechanisms regulating hyperalgesic priming are likely distinct from pruritic signaling in the dry and itchy skin model. Full article

Transient Receptor Potential (TRP) channels are ubiquitous proteins involved in a wide range of physiological functions. Some of them are expressed in nociceptors and play a major role in the transduction of painful stimuli of mechanical, thermal, or chemical origin. They have been described in both human and rodent systems. Among them, TRPV1 is a polymodal channel permeable to cations, with a highly conserved sequence throughout species and a homotetrameric structure. It is sensitive to temperature above 43 °C and to pH below 6 and involved in various functions such as thermoregulation, metabolism, and inflammatory pain. Several TRPV1 mutations have been associated with human channelopathies related to pain sensitivity or thermoregulation. TRPV1 is expressed in a large part of the peripheral and central nervous system, most notably in sensory C and Aδ fibers innervating the skin and internal organs. In this review, we discuss how the transduction of nociceptive messages is activated or impaired by natural compounds and peptides targeting TRPV1. From a pharmacological point of view, capsaicin—the spicy ingredient of chilli pepper—was the first agonist described to activate TRPV1, followed by numerous other natural molecules such as neurotoxins present in plants, microorganisms, and venomous animals. Paralleling their adaptive protective benefit and allowing venomous species to cause acute pain to repel or neutralize opponents, these toxins are very useful for characterizing sensory functions. They also provide crucial tools for understanding TRPV1 functions from a structural and pharmacological point of view as this channel has emerged as a potential therapeutic target in pain management. Therefore, the pharmacological characterization of TRPV1 using natural toxins is of key importance in the field of pain physiology and thermal regulation. Full article

To prepare to address the mechanisms of injury-induced nociceptor sensitization, we sequenced the translatome of the nociceptors of injured Drosophila larvae and those of uninjured larvae. Third-instar larvae expressing a green fluorescent protein (GFP)-tagged ribosomal subunit specifically in Class 4 dendritic arborization neurons, recognized as pickpocket-expressing primary nociceptors, via the GAL4/UAS method, were injured by ultraviolet light or sham-injured. Larvae were subjected to translating ribosome affinity purification for the GFP tag and nociceptor-specific ribosome-bound RNA was sequenced. Full article

Sensitization of primary afferents is essential for the development of pain, but the molecular events involved in this process and its reversal are poorly defined. Recent studies revealed that acid-sensing ion channels (ASICs) control the excitability of nociceptors in the urinary bladder. Using genetic and pharmacological tools we show that ASICs are functionally coupled with voltage-gated Ca²⁺ channels to mediate Ca²⁺ transients evoked by acidification in sensory neurons. Genetic deletion of Asic3 of these sensory neurons does not alter the mechanical response of bladder afferents to distension in naïve mice. Both control and sensory neuron conditional Asic3 knockout (Asic3-KO) mice with chemical cystitis induced by cyclophosphamide (CYP) administration exhibit frequent low volume voiding events. However, these changes are transient and revert over time. Of major significance, in Asic3-KO mice, CYP treatment results in the sensitization of a subset of bladder afferents and pelvic allodynia that persist beyond the resolution of the inflammatory process. Thus, ASICs function is necessary to prevent long-term sensitization of visceral nociceptors. Full article

Therapeutically, the Janus kinase (Jak) 1/Jak2 inhibitor baricitinib reduces the pathology of rheumatoid arthritis and may also reduce pain. Here, we investigated whether baricitinib directly affects joint nociceptors. We recorded action potentials from nociceptive C- and A∂-fibers of the normal and inflamed knee joint in anesthetized rats to monitor their responses to innocuous and noxious joint rotation. In isolated and cultured dorsal root ganglion (DRG) neurons, we examined Stat3 activation using Western blots and monitored excitability using patch-clamp recordings. Intra-articular injection of baricitinib did not alter C- and A∂-fiber responses to innocuous and noxious rotations of the normal knee but reduced C-fiber responses to these stimuli in inflamed joints. Baricitinib prevented the increase in C-fiber responses to joint rotation evoked by interleukin (IL)-6 plus soluble interleukin-6 receptor (sIL-6R) but not the increase evoked by TNF. In DRG neurons, baricitinib blocked Stat3 activation by hyper-IL-6, and baricitinib or the Stat3 inhibitor Sta21 prevented induction of hyperexcitability by IL-6 plus sIL-6R. Thus, neuronal Jaks are involved in the generation of C-fiber hyperexcitability induced by inflammation and IL-6. Pain reduction by baricitinib may result, at least in part, from direct effects on joint nociceptors. Full article

Background: Focused extracorporeal shock wave therapy (ESWT) has been successfully used to treat musculoskeletal conditions, but ESWT stimulates nociceptors, causing pain deep in the tissue during treatment. The occurrence of pain during ESWT is a side effect, but it can help identify painful sites and assess minimum (MiTI) and maximum (MaTI) pain thresholds to ESWT pressure stimuli. This topic has received limited attention in literature. Methods: This observational study describes a specific approach to using ESWT to study pain in 71 patients. The approach proposes moving the ESWT transducer head of the device over the entire joint surface, progressively increasing the energy level until the patient experiences pain. Results: In the study, MiTI and MaTI were 0.218 ± 0.090 and 0.416 ± 0.165 mJ/mm² in the affected joint and 0.282 ± 0.128 and 0.501 ± 0.174 mJ/mm² in the contralateral homologous healthy joint, being significantly lower in the affected joint (MiTI: p < 0.001 and MaTI: p = 0.003, respectively). ESWT induced pain in 94.37% of the sites with the highest subjective pain and in a greater number of sites (204) than digital pressure (123) (p < 0.001). All sites with digital pressure pain also had ESWT pain. Conclusions: These results suggest that the ESWT device may be useful in investigating pain in musculoskeletal conditions and tailoring therapy. Full article

Nociceptors are receptors that detect injurious stimuli and are necessary to convey such information from the periphery to the central nervous system. While nociception has been extensively studied in various taxa, there is relatively little electrophysiological evidence for the existence of nociceptors in decapod crustaceans. This study investigated putative nociceptive responses in the shore crabs, specifically their response to mechanical and noxious chemical stimuli. Extracellular multi-unit electrophysiological recordings were conducted from the anterior ganglion and the circumesophageal connective ganglia to assess nociceptive responses. Soft tissues at the joints of the chelae, antennae, and walking legs were stimulated using acetic acid (noxious stimulus) and von Frey hairs (mechanical stimulus), while nearby ganglion activity was recorded. The results indicate the existence of nociceptors in the tested areas, with mechanical stimuli eliciting shorter, more intense neural activity compared with acetic acid. Although acetic acid triggered responses in all areas, the antennae and antennules did not respond to mechanical stimuli. Though we acknowledge the challenges of conducting in vivo electrophysiological recordings, future research should focus on further characterizing nociceptor activity because the results suggest the presence of nociceptors. Full article

Background: Inflammation leads to a decrease in the excitation threshold and the sensitization of peripheral nociceptors. However, little is known about the effect of inflammation on the sensing of regional (CRegP) and widespread chronic pain (CWP) in older adults. This analysis aimed to characterize the prevalence and associates of both types of chronic pain in a population-based cohort. Methods: Our analysis was based on the Polish nationwide PolSenior study database. We excluded participants with moderate-to-severe dementia. Respondents answered questions concerning the occurrence of pain in 10 regions. CWP was defined as chronic pain present in the axial region (neck, upper back, lower back) and any part of both the lower (lower leg, hip, knee, foot) and upper (shoulder, hand) extremities. Inflammatory status was divided into three subgroups: no inflammation (CRP < 3 mg/dL), mild inflammation (CPR 3–10 mg/dL and IL-6 < 10 ng/mL), and significant inflammation (CRP ≥ 10 mg/dL or IL-6 ≥ 10 ng/mL). Results: CRegP was more frequent (33.9%) than CWP (8.8%). The occurrence of CWP was more frequent in subgroups with significant inflammation than in both subgroups with mild or no inflammation (11.4% vs. both 8.4%). Women (OR 3.67; 95% CI: 2.58–5.21) and subjects with major depression symptoms were more likely to experience CWP (OR 2.85; 95% CI: 1.68–4.82), while, malnourished participants were more likely to report CRegP (OR 2.00; 95% CI: 1.52–2.62). Conclusions: Significant inflammation is associated with increased occurrence of CWP in older adults. Female sex and major depression are the most significant associates of CWP, while malnutrition is the most significant associate of CRegP. Full article

Pain is a complex response to noxious stimuli. Upon detection of the nociceptive stimulus by first-order neurons or nociceptors, an action potential ascends to the spinal dorsal horn, a crucial site for synapsing with second-order neurons. These second-order neurons carry the nociceptive stimulus to supraspinal regions, notably the thalamus. Although extensive research has focused on spinal-level nociceptive mechanisms (e.g., neurotransmitters, receptors, and glial cells), the thalamus is still poorly elucidated. The role of the thalamus in relaying sensory and motor responses to the cortex is well known. However, a comprehensive understanding of the mechanisms in the synapse between the second-order and third-order neurons that transmit this impulse to the somatosensory cortex, where the response is processed and interpreted as pain, is still lacking. Thus, this review investigated the thalamus’s role in transmitting nociceptive impulses. Current evidence indicates the involvement of the neurotransmitters glutamate and serotonin, along with NMDA, P2X4, TLR4, FGR, and NLRP3 receptors, as well as signaling pathways including ERK, P38, NF-κB, cytokines, and glial cells at nociceptive synapses within the thalamus. Full article

Microarray patches (MAPs) offer a noninvasive and patient-friendly drug delivery method, suitable for self-administration, which is especially promising for low- and middle-income country settings. This study focuses on the development of dissolving bilayer MAPs loaded with norelgestromin (NGMN) as a first step towards developing a future potential drug delivery system for sustained hormonal contraception. The fabricated MAPs were designed with the appropriate needle lengths to penetrate the stratum corneum, while remaining minimally stimulating to dermal nociceptors. Ex vivo assessments showed that the MAPs delivered an average of 176 ± 60.9 μg of NGMN per MAP into excised neonatal porcine skin, representing 15.3 ± 5.3% of the loaded drug. In vivo pharmacokinetic analysis in Sprague Dawley rats demonstrated a Tmax of 4 h and a Cmax of 67.4 ± 20.1 ng/mL for the MAP-treated group, compared to a Tmax of 1 h and a Cmax of 700 ± 138 ng/mL for the intramuscular (IM) injection group, with a relative bioavailability of approximately 10% for the MAPs. The MAP-treated rats maintained plasma levels sufficient for therapeutic effects for up to 7 days after a single application. These results indicate the potential of NGMN-loaded dissolving bilayer MAPs, with further development focused on extending the release duration and improving bioavailability for prolonged contraceptive effects. Full article