Mayur Patil

Johns Hopkins University | JHU · Department of Medicine

Transient receptor potential ankyrin 1 (TRPA1) is a polymodal cation channel that is activated by electrophilic irritants, oxidative stress, cold temperature, and GPCR signaling. TRPA1 expression has been primarily identified in subsets of nociceptive sensory afferents and is considered a target for future analgesics. Nevertheless, TRPA1 has been i...

Airway hyperreactivity (AHR) is a hallmark of allergic asthma, and the major cause of exacerbations. Although acute bronchospasm can be mitigated by bronchodilators and corticosteroids, no therapeutics effectively target AHR. Recent studies have shown that airway afferent/sensory nerves play a critical role in AHR, but the mechanisms are not well u...

The esophagus is densely innervated by extrinsic sensory afferents projected from the dorsal root and vagal ganglia capable of sensing mechanical and chemical stimuli. In particular a major subset of vagal afferents innervating the esophagus are low-threshold mechanoreceptors whose activation by esophageal stretch regulates homeostatic processes li...

Chemotherapeutic agent-induced nausea and vomiting are the severe adverse effects that are induced by their stimulations on the peripheral and/or central emetic nerve pathways. Even though ginger has been widely used as an herbal medicine to treat emesis, mechanisms underlying its neuronal actions are still less clear. The present study aimed to de...

Pulmonary functions are controlled by afferent nerves which convey peripheral information to the central nervous system. Cell bodies of these afferent nerves are found predominantly in the vagal ganglia (VG) with some in the dorsal root ganglia (DRG). These neurons are highly heterogeneous based on their developmental origins, anatomical sources, a...

The proper function of airway vagal afferent nerves is essential for the dynamic regulation of breathing and initiation of adequate airway defensive reflexes. A better understanding of the mechanisms controlling their activation bears physiological and pathological significance. The voltage-gated potassium (KV ) channels exert powerful controls on...

Transient receptor potential ankyrin 1 (TRPA1) is a cation channel activated by electrophilic irritants and oxidative stress. It is expressed in nociceptive sensory neurons and plays a role in pain and reflex signaling. Its expression in other cell types is controversial. We generated a TRPA1‐Flp knock‐in mouse by incorporating a 2A‐Flp O after the...

The esophagus is innervated by nociceptive sensory afferent nerve fibers originating from the vagus nerve. The nature of the vagal nociceptive fiber innervation, specifically which esophageal layers, however, remains unknown. We hypothesized that the vagal nociceptive TRPV1+ afferent fibers innervate the esophageal mucosa. We evaluated our hypothes...

The airways are densely innervated by sensory afferent nerves, whose activation regulates respiration and triggers defensive reflexes (e.g., cough, bronchospasm). Airway innervation is heterogeneous, and distinct afferent subsets have distinct functional responses. However, little is known of the innervation patterns of subsets within the lung. A n...

The KV1/D‐type potassium current (ID) is an important determinant of neuronal excitability. This study explored whether and how ID channels regulate the activation of bronchopulmonary vagal afferent nerves. The single‐neuron RT‐PCR assay revealed that nearly all mouse bronchopulmonary nodose neurons expressed the transcripts of α‐dendrotoxin (α‐DTX...

Action potentials depend on voltage-gated sodium channels (Na V 1s), which have nine alpha subtypes. Na V 1 inhibition is a target for pathologies involving excitable cells such as pain. However, because Na V 1 subtypes are widely expressed, inhibitors may inhibit regulatory sensory systems. Here, we investigated specific Na V 1s and their inhibiti...

Key points Type I interferon receptors are expressed by the majority of vagal C‐fibre neurons innervating the respiratory tract Interferon alpha and beta acutely and directly activate vagal C‐fibers in the airways. The interferon‐induced activation of C‐fibers occurs secondary to stimulation of type 1 interferon receptors Type 1 interferons may con...

Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both pa...

The ATP-sensitive P2X2 ionotropic receptor plays a critical role in a number of signal processes including taste and hearing, carotid body detection of hypoxia, the exercise pressor reflex and sensory transduction of mechanical stimuli in the airways and bladder. Elucidation of the role of P2X2 has been hindered by the lack of selective tools. In p...

Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE 2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both p...

Vagal afferent nerves carry information from peripheral organs to the brainstem, where they synapse with central networks that govern physiological function through reflexes. Vagal afferent nerves are known to control respiratory functions. There are various subtypes of afferent nerves depending on its their developmental origin, expression of cert...

The vagus nerves provide afferent nerve fibers with nociceptive sensory properties to the esophagus. However, it is unknown which esophageal layers are innervated by these vagal nociceptive fibers. We hypothesized that the vagal nociceptive TRPV1‐positive afferent fibers innervate esophageal mucosa. We evaluated our hypothesis by using genetic neur...

Vagal afferent innervation of the airways and lungs comprises of afferent fibers from vagal nodose neurons (developmentally derived from epibranchial placodes) and vagal jugular neurons (derived from neural crest). Here we evaluated the structure and the location in tracheal wall of afferent nerve fibers innervating the trachea focusing on the noci...

Vagal afferent sensory nerves, originating in jugular and nodose ganglia, are composed of functionally distinct subsets whose activation evokes distinct thoracic and abdominal reflex responses. We used Cre-expressing mouse strains to identify specific vagal afferent populations and map their central projections within the brainstem. We show that Pi...

Unique features of sensory neuron subtypes are manifest by their distinct physiological and pathophysiological functions. Using patch‐clamp electrophysiology, Ca²⁺ imaging, calcitonin gene‐related peptide release assay from tissues, protein biochemistry approaches, and behavioral physiology on pain models, this study demonstrates the diversity of s...

Many clinical and preclinical studies report an increased prevalence and severity of chronic pain among females. Here, we identify a sex-hormone-controlled target and mechanism that regulates dimorphic pain responses. Prolactin (PRL), which is involved in many physiologic functions, induces female-specific hyperalgesia. A PRL receptor (Prlr) antago...

Sensory neurons exhibit sex‐dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The aim of this study is to elucidate mechanisms underlying sex‐dependent PRL sensitivity in sensory neurons. Quantitative RT‐PCR show that prolactin receptor (Prlr) long and short isoform mRNAs are ex...

Background Ginger has been used as an herbal medicine worldwide to relieve nausea/vomiting and gastrointestinal discomfort, but the cellular and molecular mechanisms of its neuronal action remain unclear. The present study aimed to determine the effects of ginger constituent 6‐shogaol on gastroesophageal vagal nodose C‐fibers. Methods Extracellula...

Activation of vagal C-fibers is likely involved in some types of pathological coughing, especially coughing that is associated with airway inflammation. This is because stimulation of vagal C-fibers leads to strong urge to cough sensations, and because C-fiber terminals can be strongly activated by mediators associated with airway inflammation. The...

Increased airway vagal sensory C-fiber activity contributes to the symptoms of inflammatory airway diseases. The KCNQ/Kv7/M-channel is a well-known determinant of neuronal excitability, yet whether it regulates the activity of vagal bronchopulmonary C-fibers and airway reflex sensitivity remains unknown. Here we addressed this issue using single-ce...

Key points Sphingosine‐1‐phosphate (S1P) strongly activates mouse vagal C‐fibres in the airways. Airway‐specific nodose and jugular C‐fibre neurons express mRNA coding for the S1P receptor S1PR3. S1P activation of nodose C‐fibres is inhibited by a S1PR3 antagonist. S1P activation of nodose C‐fibres does not occur in S1PR3 knockout mice. Abstract W...

Peptidergic sensory neurons play a critical role in nociceptive pathways. To precisely define the function and plasticity of sensory neurons in detail, new tools such as transgenic mouse models are needed. We employed electrophysiology and immunohistochemistry to characterize in detail dorsal root ganglion (DRG) neurons expressing an inducible CGRP...

Background Activation and sensitization of visceral afferent nerves by inflammatory mediators play important roles in visceral nociception. Sphingosine‐1‐phosphate (S1P) is a lipid with intracellular and extracellular functions. Extracellularly, it can act as an autacoid via interactions with S1P receptors. The present study aims to determine the e...

Introduction:. Suboptimal management of postoperative pain leads to increased risk of chronic opioid therapy, especially in elderly patients. Objectives:. Although this age-dependent phenomenon has been observed clinically, basic mechanisms including baseline nociception, postoperative hypersensitivity, and mu-opioid efficiency in aged animals have...

The primary complaint of burn victims is an intense, often devastating spontaneous pain, with persistence of mechanical and thermal allodynia. The transient receptor potential channels, TRPV1 and TRPA1, are expressed by a subset of nociceptive sensory neurons and contribute to inflammatory hypersensitivity. Although their function in the periphery...

Surgical procedures lead to profound and sustained (up to 1–2 weeks) activation of the pituitary gland, resulting in changes in endocrine function. Questions remain on whether activation of the pituitary influences the threshold and development time-course of postoperative pain. To address these questions, we evaluated postoperative hypersensitivit...

To study the effects of a novel matrix metalloproteinase-2 (MMP-2) and MMP-9 inhibitor, AQU-118, on mechanical allodynia in the spinal nerve ligation (SNL) model of neuropathic pain and the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic orofacial pain. Five groups of SNL rats were given daily oral doses of AQU-...

Prolactin (PRL) activates PRL receptor isoforms to exert regulation of specific neuronal circuitries, and to control numerous physiological and clinically-relevant functions including; maternal behavior, energy balance and food intake, stress and trauma responses, anxiety, neurogenesis, migraine and pain. PRL controls these critical functions by re...

Our group has a long interest in studying trigeminal pain mechanisms and these studies would be advanced by gene therapy approaches to alter expression of target proteins. One such approach uses viruses, and adeno-associated viruses (AAV) are especially promising due to low immunogenicity and lack of toxicity. Although, the direct delivery (by inje...

Prolactin (PRL) regulates activity of nociceptors and causes hyperalgesia in pain conditions. PRL enhances nociceptive responses by rapidly modulating channels in nociceptors. The molecular mechanisms underlying PRL-induced transient signaling in neurons are not well understood. Here we use a variety of cell biology and pharmacological approaches t...

Prolactin (PRL) is a hormone produced in the anterior pituitary but also synthesized extra-pituitary where it can influence diverse cellular processes including inflammatory responses. Females experience greater pain in certain inflammatory conditions, but the contribution of the PRL system to sex-dependent inflammatory pain is unknown. We found th...

Although surgical trauma activates the anterior pituitary gland and elicits an increase in prolactin (PRL) serum levels that can modulate nociceptive responses, the role of PRL and the PRL-receptor (PRL-R) in thermal and mechanical hyperalgesia in postoperative pain is unknown. Acute postoperative pain condition was generated with the use of the hi...

Recently, specific oxidized linoleic acid metabolites (OLAMs) have been identified as transient receptor potential vanilloid 1 (TRPV1) channel agonists that contribute to inflammatory and heat hyperalgesia mechanisms, yet the specific mechanism responsible for OLAM synthesis in sensory neurons is unknown. Here, we use molecular, anatomical, calcium...

Prolactin (PRL) is a hormone and a neuromodulator. It sensitizes TRPV1 (transient receptor potential cation channel subfamily V member 1) responses in sensory neurons, but it is not clear whether peripheral inflammation results in the release of endogenous PRL, or whether endogenous PRL is capable of acting as an inflammatory mediator in a sex-depe...

There is an agreement that acute (in minutes) hydrolysis and accumulation of phosphatidylinositol 4,5-bisphosphate (PIP(2) ) modulate TRPV1 and TRPA1 activities. Because inflammation results in PIP(2) depletion, persisting for long periods (hours to days) in pain models and in the clinic, we examined whether chronic depletion and accumulation of PI...

Cannabinoid receptor antagonists have been utilized extensively in vivo as well as in vitro, but their selectivity has not been fully examined. We investigated activation of sensory neurons by two cannabinoid antagonists - AM251 and AM630. AM251 and AM630 activated trigeminal (TG) sensory neurons in a concentration-dependent fashion (threshold 1 μM...

Despite success in treating many forms of cancer, pain associated with malignancy remains a serious clinical issue with a poorly understood etiology. This study determined if certain sarcoma cell lines produced a soluble factor that activates the TRPV1 ion channel expressed on nociceptive sensory neurons, thereby activating a major pain transductio...

The transient receptor potential A1 (TRPA1) channel contributes to nociceptive signaling in certain pain models. It has been suggested that Ca(2+), which activates and modulates TRPA1, could play a critical regulatory role in this process. Since TRPA1 and transient receptor potential V1 (TRPV1) channels are co-expressed and interact in neurons, we...

Inflammatory pain is thought to be mediated in part through the action of inflammatory mediators on membrane receptors of peripheral nerve terminals, however, the downstream signaling events which lead to pain are poorly understood. In this study we investigated the nociceptive pathways induced by activation of protease-activated receptor 2 (PAR-2)...