Shing-hong Lin - Academia.edu (original) (raw)

Papers by Shing-hong Lin

Nature, Dec 10, 2018

Animals and humans display two types of responses to noxious stimuli. The first includes reflexiv... more Animals and humans display two types of responses to noxious stimuli. The first includes reflexive-defensive responses to prevent or limit injury. A well-known example is the quick withdrawal of one's hand touching a hot object. When the first-line response fails to prevent tissue damage (e.g., a finger is burnt), the resulting pain invokes a second-line coping response, such as licking the injured area to soothe suffering. However, the underlying neural circuits driving these two strings of behaviors remain poorly understood. Here we show that in mice, spinal neurons marked by coexpression of T Cre and Lbx1 Flpo , called Tac1 Lbx1 , drive pain-related coping responses. Ablation of Tac1 Lbx1 neurons led to loss of persistent licking and conditioned aversion evoked by stimuli that produce sustained pain in humans, including skin pinching and burn injury, without affecting all tested reflexive-defensive reactions. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei 1-3. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

SUMMARYVisceral pain is among the most prevalent and bothersome forms of chronic pain, but their ... more SUMMARYVisceral pain is among the most prevalent and bothersome forms of chronic pain, but their transmission in the spinal cord is still poorly understood. Here we used a focal colorectal distention (fCRD) method to drive visceromotor responses (VMRs) plus affective pain-indicative aversive learning. We first found that spinal CCK neurons were necessary for noxious fCRD to drive both VMRs and aversion. We next showed that spinal VGLUT3 neurons mediate affective visceral allodynia, whose ablation caused loss of aversion evoked by low-intensity fCRD in mice with gastrointestinal (GI) inflammation or spinal circuit disinhibition. Importantly, these neurons are dispensable for driving VMRs. Anatomically, VGLUT3 neurons send projection to the parabrachial nuclei, whose photoactivation sufficiently generated aversion in mice with GI inflammation. Our studies suggest the presence of different spinal substrates that transmit nociceptive versus affective dimensions of visceral sensory infor...

International Journal of Molecular Sciences

Proprioceptors are low-threshold mechanoreceptors involved in perceiving body position and strain... more Proprioceptors are low-threshold mechanoreceptors involved in perceiving body position and strain bearing. However, the physiological response of proprioceptors to fatigue- and muscle-acidosis-related disturbances remains unknown. Here, we employed whole-cell patch-clamp recordings to probe the effect of mild acidosis on the mechanosensitivity of the proprioceptive neurons of dorsal root ganglia (DRG) in mice. We cultured neurite-bearing parvalbumin-positive (Pv+) DRG neurons on a laminin-coated elastic substrate and examined mechanically activated currents induced through substrate deformation-driven neurite stretch (SDNS). The SDNS-induced inward currents (ISDNS) were indentation depth-dependent and significantly inhibited by mild acidification (pH 7.2~6.8). The acid-inhibiting effect occurred in neurons with an ISDNS sensitive to APETx2 (an ASIC3-selective antagonist) inhibition, but not in those with an ISNDS resistant to APETx2. Detailed subgroup analyses revealed ISDNS was exp...

The Journal of Neuroscience, 2020

Innocuous mechanical stimuli, such as rubbing or stroking the skin, relieve itch through the acti... more Innocuous mechanical stimuli, such as rubbing or stroking the skin, relieve itch through the activation of low-threshold mechanoreceptors. However, the mechanisms behind this inhibition remain unknown. We presently investigated whether stroking the skin reduces the responses of superficial dorsal horn neurons to pruritogens in male C57BL/6J mice. Single-unit recordings revealed that neuronal responses to chloroquine were enhanced during skin stroking, and this was followed by suppression of firing below baseline levels after the termination of stroking. Most of these neurons additionally responded to capsaicin. Stroking did not suppress neuronal responses to capsaicin, indicating state-dependent inhibition. Vesicular glutamate transporter 3 (VGLUT3)-lineage sensory nerves compose a subset of low-threshold mechanoreceptors. Stroking-related inhibition of neuronal responses to chloroquine was diminished by optogenetic inhibition of VGLUT3-lineage sensory nerves in male and femaleVglut...

Frontiers in Neuroscience, 2019

Acid-sensing ion channels (ASICs) are important acid sensors involved in neural modulation in the... more Acid-sensing ion channels (ASICs) are important acid sensors involved in neural modulation in the central nervous system and pain-associated tissue acidosis in the peripheral system. Among ASIC subtypes, ASIC1b is the most selectively expressed in peripheral sensory neurons. However, the role of ASIC1b is still elusive in terms of its functions and expression profile. In this study, we probed the role of ASIC1b in acid-induced muscle pain in Asic1b-knockout (Asic1b −/−) and Asic1b-Cre transgenic (Asic1b Cre) mice. We tested the effect of ASIC1b knockout in a mouse model of fibromyalgia induced by dual intramuscular acid injections. In this model, a unilateral acid injection to the gastrocnemius muscle induced transient bilateral hyperalgesia in wild-type (Asic1b +/+) but not Asic1b −/− mice; a second acid injection, spaced 1 or 5 days apart, to the same muscle induced chronic hyperalgesia lasting for 4 weeks in Asic1b +/+ mice, but the duration of hyperalgesia was significantly shortened in Asic1b −/− mice. Mambalgin-1, an ASIC1b-containing channel inhibitor that was mixed with acid saline at the first injection, dose-dependently blocked the acid-induced transient and chronic hyperalgesia in Asic1b +/+ mice. In contrast, psalmotoxin 1 (PcTx1), an ASIC1a-selective antagonist, had no effect on acid-induced transient or chronic hyperalgesia. We used whole-cell patch clamp recording to study the properties of acid-induced currents in ASIC1b-expressing dorsal root ganglia (DRG) neurons from Asic1b Cre-TdTomato reporter mice. Medium-to large-sized ASIC1b-expressing DRG neurons mainly exhibited an amiloride-sensitive ASIC-like biphasic current (I ASIC) in response to acid stimulation, whereas small-to medium-sized ASIC1b-expressing DRG neurons predominantly exhibited an amiloride-insensitive sustained current. Specifically, mambalgin-1 selectively inhibited the I ASIC in most ASIC1b-expressing DRG neurons. However, PcTx1 or APETx2 (an ASIC3-selective antagonist) had only a mild inhibitory effect on I ASIC in about half of the ASIC1b-expressing DRG neurons. In situ hybridization revealed that ASIC1b-positive DRG neurons co-expressed highly with ASIC1a and ASIC2a mRNA and partially with ASIC3 and ASIC2b. Thus, ASIC1b might form a wide variety of heteromeric channels. ASIC1b-containing heteromeric channels might be promising targets for the therapeutic treatment of acid-induced chronic muscle pain.

Frontiers in Cellular Neuroscience, 2019

The Journal of investigative dermatology, 2017

Itch and pain are closely related but are distinct sensations. Intradermal injection of acid gene... more Itch and pain are closely related but are distinct sensations. Intradermal injection of acid generates pain in both rodents and humans; however, few studies have addressed the intriguing question of whether acid (protons) can evoke itch like other algogens by spatial contrast activation of single nociceptors. Here, we report that (i) citric acid (0.2 mol/L) pH-dependently induced a scratching response in mice when applied intradermally to nape or cheek skin, (ii) acidified buffer elevated intracellular calcium levels in dorsal root ganglion pruriceptors, and (iii) injection of intradermal citric acid (pH 3.0) into the nape induced a pruritogen-like but not algogen-like c-Fos immunoreactivity pattern in the cervical spinal cord. Using pharmacological and genetic approaches, we identified potential acid-sensing channels/receptors involved in acidic citrate-evoked itch. Results indicate that TRPV1, but neither ASIC3 nor TRPA1, is involved in the acidic citrate-induced scratching respon...

Nature communications, Jan 10, 2016

Acid-sensing ion channel 3 (ASIC3) is involved in acid nociception, but its possible role in neur... more Acid-sensing ion channel 3 (ASIC3) is involved in acid nociception, but its possible role in neurosensory mechanotransduction is disputed. We report here the generation of Asic3-knockout/eGFPf-knockin mice and subsequent characterization of heterogeneous expression of ASIC3 in the dorsal root ganglion (DRG). ASIC3 is expressed in parvalbumin (Pv+) proprioceptor axons innervating muscle spindles. We further generate a floxed allele of Asic3 (Asic3(f/f)) and probe the role of ASIC3 in mechanotransduction in neurite-bearing Pv+ DRG neurons through localized elastic matrix movements and electrophysiology. Targeted knockout of Asic3 disrupts spindle afferent sensitivity to dynamic stimuli and impairs mechanotransduction in Pv+ DRG neurons because of substrate deformation-induced neurite stretching, but not to direct neurite indentation. In behavioural tasks, global knockout (Asic3(-/-)) and Pv-Cre::Asic3(f/f) mice produce similar deficits in grid and balance beam walking tasks. We conclu...

The European journal of neuroscience, Jan 31, 2015

Although ASIC4 is a member of the Acid-Sensing Ion Channel (ASIC) family, we have limited knowled... more Although ASIC4 is a member of the Acid-Sensing Ion Channel (ASIC) family, we have limited knowledge of its expression and physiological function in vivo. To trace the expression of this ion channel, we generated the ASIC4-knockout/CreERT(2) -knockin (Asic4(Cre) (ERT) (2) ) mouse line. After tamoxifen induction in the Asic4(Cre) (ERT) (2) ::CAG-STOP(floxed) -Td-tomato double transgenic mice, we mapped the expression of ASIC4 at the cellular level in the central nervous system (CNS). ASIC4 was expressed in many brain regions, including the olfactory bulb, cerebral cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, brain stem, cerebellum, spinal cord and the pituitary gland. Colocalization studies further revealed that ASIC4 was expressed mainly in 3 types of cells in the CNS: (1) calretinin (CR)-positive and/or vasoactive intestine peptide (VIP)-positive interneurons; (2) neural/glial antigen 2 (NG2)-positive glia, also known as oligodendrocyte precursor cells; and (3) c...

Neuropharmacology, Jan 9, 2015

Advanced gene targeting technology and related tools in mice have been incorporated into studies ... more Advanced gene targeting technology and related tools in mice have been incorporated into studies of acid-sensing ion channels (ASICs). A single ASIC subtype can be knocked out specifically and screened thoroughly for expression in the nervous system at the cellular level. Mapping studies have further shed light on the initiation and identification of related behavioral phenotypes. Here we review studies involving genetically engineered mouse models used to investigate the physiological function of individual ASIC subtypes: ASIC1 (and ASIC1a), ASIC2, ASIC3 and ASIC4. We discuss the detailed expression studies and significant phenotypes revealed with gene knockout for most known Asic subtypes. Each strategy designed to manipulate mouse genetics has advantages and disadvantages. We discuss the limitations of these Asic-knockout models and propose future directions to solve the genetic issues. This article is part of a Special Issue entitled 'ASIC Channels'.

Molecular pain, Jan 23, 2014

Tissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors cont... more Tissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors contribute to the transition from acute to chronic pain is largely unknown. Here we showed that a single intramuscular acid injection induced a priming effect on muscle nociceptors of mice. The primed muscle nociceptors were plastic and permitted the development of long-lasting chronic hyperalgesia induced by a second acid insult. The plastic changes of muscle nociceptors were modality-specific and required the activation of acid-sensing ion channel 3 (ASIC3) or transient receptor potential cation channel V1 (TRPV1). Activation of ASIC3 was associated with increased activity of tetrodotoxin (TTX)-sensitive voltage-gated sodium channels but not protein kinase Cϵ (PKCϵ) in isolectin B4 (IB4)-negative muscle nociceptors. In contrast, increased activity of TTX-resistant voltage-gated sodium channels with ASIC3 or TRPV1 activation in NaV1.8-positive muscle nociceptors was required for the develop...

Circulation Journal, 2011

Background: The mechanically sensitive volume receptors, primarily located in the venoatrial junc... more Background: The mechanically sensitive volume receptors, primarily located in the venoatrial junction area, are essential for blood volume homeostasis. However, the molecular basis of the volume receptors is still unknown. Methods and Results: We hypothesized that the acid-sensing ion channel 3 (ASIC3) might be a candidate for the mechanically sensitive molecules expressed in the volume receptors. We examined the effect of Asic3 null mutation (Asic3-/-) on blood volume expansion (BVE)-induced urine flow, neural activation, and atrial natriuretic peptide (ANP) release in mice. BVE-induced urine flow was lower in Asic3-/mice than in wild-type littermates. In addition, the stretch-activated channel blocker GdCl3 further reduced the BVE-induced urine flow in Asic3-/mice. BVE increased phosphorylated extracellular signal-related kinase (pERK) immunoreactivity in nodose ganglia and many segments of dorsal root ganglia (DRG) in all mice, but pERK-positive neurons were fewer in Asic3-/mice or mice pretreated with GdCl3 than in wild-type mice. Asic3 knockout selectively decreased BVE-induced pERK-immunoreactive neurons in nodose ganglia, and in C8 and T2 DRG. Moreover, BVE increased the circulating ANP level, which was abolished in Asic3-/mice and wild-type mice treated with GdCl3. Asic3 knockout reduced the BVE-induced plasma ANP elevation in a GdCl3-independent manner. Conclusions: ASIC3 is a molecular substrate involved in detecting the vessel stretch caused by BVE.

Pain, 2021

Prolotherapy is widely used in pain control and tissue repair in pain medicine. The classical mod... more Prolotherapy is widely used in pain control and tissue repair in pain medicine. The classical mode is injection with hypertonic dextrose in muscle or perimysium. However, the analgesic mechanism is still not known. Here, we successfully established dextrose-mediated antinociception in a mouse model of fibromyalgia. The antinociceptive effects of dextrose injections were evaluated in a mouse model of fibromyalgia, in which bilateral chronic mechanical hyperalgesia was induced by unilateral intramuscular acid injection. The injectant (dextrose), dose (≥5%), and volume (>10 μL), but not osmolarity, were essential for the prolotherapy. Further studies showed that the activation of acid-sensing ion channel 1a (ASIC1a), neural activation, and the release of substance P from muscle afferents were required in the dextrose-induced reduction of mechanical hypersensitivity. Both pharmacological blockade and genetic deletion of ASIC1a or substance P as well as lidocaine abolished the dextros...

Nature, 2018