Satellite glial cell P2Y12 receptor in the trigeminal ganglion is involved in lingual neuropathic pain mechanisms in rats

<p>Abstract</p> <p>Background</p> <p>It has been reported that the P2Y₁₂receptor (P2Y₁₂R) is involved in satellite glial cells (SGCs) activation, indicating that P2Y₁₂R expressed in SGCs may play functional roles in orofacial neuropathic pain mechanisms. However, the involvement of P2Y₁₂R in orofacial neuropathic pain mechanisms is still unknown. We therefore studied the reflex to noxious mechanical or heat stimulation of the tongue, P2Y₁₂R and glial fibrillary acidic protein (GFAP) immunohistochemistries in the trigeminal ganglion (TG) in a rat model of unilateral lingual nerve crush (LNC) to evaluate role of P2Y₁₂R in SGC in lingual neuropathic pain.</p> <p>Results</p> <p>The head-withdrawal reflex thresholds to mechanical and heat stimulation of the lateral tongue were significantly decreased in LNC-rats compared to sham-rats. These nocifensive effects were apparent on day 1 after LNC and lasted for 17 days. On days 3, 9, 15 and 21 after LNC, the mean relative number of TG neurons encircled with GFAP-immunoreactive (IR) cells significantly increased in the ophthalmic, maxillary and mandibular branch regions of TG. On day 3 after LNC, P2Y₁₂R expression occurred in GFAP-IR cells but not neuronal nuclei (NeuN)-IR cells (i.e. neurons) in TG. After 3 days of successive administration of the P2Y₁₂R antagonist MRS2395 into TG in LNC-rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly decreased coincident with a significant reversal of the lowered head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue compared to vehicle-injected rats. Furthermore, after 3 days of successive administration of the P2YR agonist 2-MeSADP into the TG in naïve rats, the mean relative number of TG neurons encircled with GFAP-IR cells was significantly increased and head-withdrawal reflex thresholds to mechanical and heat stimulation of the tongue were significantly decreased in a dose-dependent manner compared to vehicle-injected rats.</p> <p>Conclusions</p> <p>The present findings provide the first evidence that the activation of P2Y₁₂R in SGCs of TG following lingual nerve injury is involved in the enhancement of TG neuron activity and nocifensive reflex behavior, resulting in neuropathic pain in the tongue.</p

Long-lasting adverse effects of short-term stress during the suckling–mastication transition period on masticatory function and intraoral sensation in rats

The version of record of this article, first published in Odontology, is available online at Publisher’s website: https://doi.org/10.1007/s10266-023-00887-w.Early-life stress affects brain development, eventually resulting in adverse behavioral and physical health consequences in adulthood. The present study assessed the hypothesis that short-term early-life stress during infancy before weaning, a period for the maturation of mastication and sleep, poses long-lasting adverse effects on masticatory function and intraoral sensations later in life. Rat pups were exposed to either maternal separation (MS) or intermittent hypoxia (IH-Infancy) for 6 h/day in the light/sleep phase from postnatal day (P)17 to P20 to generate “neglect” and “pediatric obstructive sleep apnea” models, respectively. The remaining rats were exposed to IH during P45–P48 (IH-Adult). Masticatory ability was evaluated based on the rats’ ability to chew pellets and bite pasta throughout the growth period (P21–P70). Intraoral chemical and mechanical sensitivities were assessed using two-bottle preference drinking tests, and hind paw pain thresholds were measured in adulthood (after P60). No differences were found in body weight, grip force, and hind paw sensitivity in MS, IH-Infancy, and IH-Adult rats compared with naïve rats. Masticatory ability was lower in MS and IH-Infancy rats from P28 to P70 than in naïve rats. MS and IH-Infancy rats exhibited intraoral hypersensitivity to capsaicin and mechanical stimulations in adulthood. The IH-Adult rats did not display inferior masticatory ability or intraoral hypersensitivity. In conclusion, short-term early-life stress during the suckling–mastication transition period potentially causes a persistent decrease in masticatory ability and intraoral hypersensitivity in adulthood. The period is a “critical window” for the maturation of oral motor and sensory functions

Effect of chronic intermittent hypoxia on ocular and intraoral mechanical allodynia mediated via the calcitonin gene-related peptide in a rat

Katagiri Ayano, Kishimoto Saki, Okamoto Yoshie, et al. Effect of chronic intermittent hypoxia on ocular and intraoral mechanical allodynia mediated via the calcitonin gene-related peptide in a rat. SLEEP 7, 687 (2024); https://doi.org/10.1093/sleep/zsad332.Study Objectives: Obstructive sleep apnea, a significant hypoxic condition, may exacerbate several orofacial pain conditions. The study aims to define the involvement of calcitonin gene-related peptide (CGRP) in peripheral and central sensitization and in evoking orofacial mechanical allodynia under chronic intermittent hypoxia (CIH). Methods: Male rats were exposed to CIH. Orofacial mechanical allodynia was assessed using the eyeblink test and the two-bottle preference drinking test. The CGRP-immunoreactive neurons in the trigeminal ganglion (TG), CGRP-positive primary afferents projecting to laminae I–II of the trigeminal spinal subnucleus caudalis (Vc), and neural responses in the second-order neurons of the Vc were determined by immunohistochemistry. CGRP receptor antagonist was administrated in the TG. Results: CIH-induced ocular and intraoral mechanical allodynia. CGRP-immunoreactive neurons and activated satellite glial cells (SGCs) were significantly increased in the TG and the number of cFos-immunoreactive cells in laminae I–II of the Vc were significantly higher in CIH rats compared to normoxic rats. Local administration of the CGRP receptor antagonist in the TG of CIH rats attenuated orofacial mechanical allodynia; the number of CGRP-immunoreactive neurons and activated SGCs in the TG, and the density of CGRP-positive primary afferent terminals and the number of cFos-immunoreactive cells in laminae I–II of the Vc were significantly lower compared to vehicle-administrated CIH rats. Conclusions: An increase in CGRP in the TG induced by CIH, as well as orofacial mechanical allodynia and central sensitization of second-order neurons in the Vc, supported the notion that CGRP plays a critical role in CIH-induced orofacial mechanical allodynia

Brain perfusion asymmetry in patients with oral somatic delusions

Oral cenesthopathy is a somatic delusion or hallucination involving the oral area and is categorized as a delusional disorder, somatic type. The pathophysiology of this intractable condition remains obscure. In this study, we clarified the pathophysiology of oral cenesthopathy by evaluating regional brain perfusion. We performed single photon emission computed tomography (SPECT) using (99m)Tc-ethylcysteinate dimer in 16 subjects (cenesthopathy:control = 8:8). The SPECT images were visually assessed qualitatively, and quantitative analyses were also performed using a three-dimensional stereotactic region-of-interest template. The visual assessment revealed a right > left perfusion asymmetry in broad areas of the brain among the patients. The quantitative analysis confirmed that the regional cerebral blood flow values on the right side were significantly larger than those on the left side for most areas of the brain in the patients. A comparison of the R/(R + L) ratios in both groups confirmed the significant brain perfusion asymmetry between the two sides in the callosomarginal, precentral, and temporal regions in the patients. Qualitative evaluation of the SPECT images revealed right > left brain perfusion asymmetry in broad regions of the brain. Moreover, the quantitative analyses confirmed the perfusion asymmetry between the two sides in the frontal and temporal areas. Those may provide the key for elucidation of the pathophysiology of oral cenesthopathy

Basic research and clinical investigations of the neural basis of orofacial pain

Background: Trigeminal nerve injury or orofacial inflammation causes severe pain in the orofacial regions innervated by uninjured nerves or uninflamed tissues as well as injured or inflamed tissues. Pathological orofacial pain associated with trigeminal nerve injury or inflammation is difficult to diagnose and treat. Highlights: To develop appropriate treatments for patients with orofacial pathological pain, various animal models of trigeminal nerve injury or orofacial inflammation have been developed. Further, the possible mechanisms involving the trigeminal ganglion (TG), trigeminal spinal subnucleus caudalis (Vc), and upper cervical spinal cord (C1-C2) have been studied. Conclusions: 1) Neurotransmitters released from the somata of TG neurons are involved in peripheral sensitization. 2) Neurotransmitter release from TG neurons is decreased by botulinum toxin-type A administration, suggesting that this toxin suppressed neurotransmitter release and alleviated the neuropathic pain-related behavior. 3) Altered states of glial cells and nociceptive neurons, in the Vc and C1-C2 are involved in pathological orofacial pain associated with trigeminal nerve injury or orofacial inflammation. 4) The trigeminal sensory nuclear complex, especially the trigeminal spinal subnucleus oralis, is involved in normal and pathological orofacial pain conditions after peripheral nerve injury. 5) Neuroimaging analyses have suggested functional changes in the central and peripheral nervous systems in neuropathic pain conditions

Involvement of peripheral ionotropic glutamate receptors in orofacial thermal hyperalgesia in rats

<p>Abstract</p> <p>Background</p> <p>The purpose of the present study was to elucidate the mechanisms that may underlie the sensitization of trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2) neurons to heat or cold stimulation of the orofacial region following glutamate (Glu) injection.</p> <p>Results</p> <p>Glu application to the tongue or whisker pad skin caused an enhancement of head-withdrawal reflex and extracellular signal-regulated kinase (ERK) phosphorylation in Vc-C2 neurons. Head-withdrawal reflex and ERK phosphorylation were also enhanced following cold stimulation of the tongue but not whisker pad skin in Glu-injected rats, and the head-withdrawal reflex and ERK phosphorylation were enhanced following heat stimulation of the tongue or whisker pad skin. The enhanced head-withdrawal reflex and ERK phosphorylation after heat stimulation of the tongue or whisker pad skin, and those following cold stimulation of the tongue but not whisker pad skin were suppressed following ionotropic glutamate receptor antagonists administration into the tongue or whisker pad skin. Furthermore, intrathecal administration of MEK1/2 inhibitor PD98059 caused significant suppression of enhanced head-withdrawal reflex in Glu-injected rats, heat head-withdrawal reflex in the rats with Glu injection into the tongue or whisker pad skin and cold head-withdrawal reflex in the rats with Glu injection into the tongue.</p> <p>Conclusions</p> <p>The present findings suggest that peripheral Glu receptor mechanisms may contribute to cold hyperalgesia in the tongue but not in the facial skin, and also contribute to heat hyperalgesia in the tongue and facial skin, and that the mitogen-activated protein kinase cascade in Vc-C2 neurons may be involved in these Glu-evoked hyperalgesic effects.</p

2017 July CGRP paper Fig. EJN.pdf

<p> </p><p><b>Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain</b></p><p> </p><p>Lou Mikuzuki ^{1, 2)}, Hiroto Saito ^{1, 3)}, Ayano Katagiri ^{1) *}, Shinji Okada ^{1, 3)}, Shiori Sugawara ^{1, 2)}, Asako Kubo ¹⁾, Kinuyo Ohara ⁴⁾, Jun Lee ³⁾, Akira Toyofuku ²⁾ and Koichi Iwata ¹⁾</p><p> </p><p> </p><p> </p><ol><li><p>Department of Physiology, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku Tokyo, 101-8310, Japan </p></li><li><p>Department of Psychosomatic Dentistry, Tokyo Medical and Dental University (TMDU) Graduate School, 1-5-45 Yushima Bunkyo-ku Tokyo, 113-8510, Japan </p></li><li><p>Department of Complete Denture Prosthodontics, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku Tokyo, 101-8310, Japan</p></li><li><p>Department of Endodontics, Nihon University School of Dentistry, 1-8-13 Kandasurugadai, Chiyoda-ku Tokyo, 101-8310, Japan</p></li></ol><p> <br></p

Intranasal Administration of Rotenone Reduces GABAergic Inhibition in the Mouse Insular Cortex Leading to Impairment of LTD and Conditioned Taste Aversion Memory

The pesticide rotenone inhibits mitochondrial complex I and is thought to cause neurological disorders such as Parkinson&rsquo;s disease and cognitive disorders. However, little is known about the effects of rotenone on conditioned taste aversion memory. In the present study, we investigated whether intranasal administration of rotenone affects conditioned taste aversion memory in mice. We also examined how the intranasal administration of rotenone modulates synaptic transmission and plasticity in layer V pyramidal neurons of the mouse insular cortex that is critical for conditioned taste aversion memory. We found that the intranasal administration of rotenone impaired conditioned taste aversion memory to bitter taste. Regarding its cellular mechanisms, long-term depression (LTD) but not long-term potentiation (LTP) was impaired in rotenone-treated mice. Furthermore, spontaneous inhibitory synaptic currents and tonic GABA currents were decreased in layer V pyramidal neurons of rotenone-treated mice compared to the control mice. The impaired LTD observed in pyramidal neurons of rotenone-treated mice was restored by a GABAA receptor agonist muscimol. These results suggest that intranasal administration of rotenone decreases GABAergic synaptic transmission in layer V pyramidal neurons of the mouse insular cortex, the result of which leads to impairment of LTD and conditioned taste aversion memory

PRZEDRUK POLSKIEGO TŁUMACZENIA ARTYKUŁU ZA ZGODĄ INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN (IASP) - PAIN 154 (2013) 1057-1064 Status względem estrogenu oraz stres psychofizyczny modyfikują informację płynącą ze stawu skroniowo-żuchwowego do neuronów rogów tylnych rdzenia kręgowego w sposób swoisty dla blaszki u samic szczurów

Estrogen status and psychological stress contribute to the expression of several chronic pain conditions including temporomandibular muscle and joint disorders (TMJD). Sensory neurons that supply the temporomandibular joint (TMJ) region terminate in laminae I and V of the spinal trigeminal nucleus (Vc/C1-2 region); however, little is known about lamina-specificity and environmental influences on the encoding properties of TMJ brainstem neurons. To test the hypothesis that Vc/C1-2 neurons integrate both interoceptive and exteroceptive signals relevant for TMJ nociception, we recorded TMJ-evoked activity in superficial and deep laminae of ovariectomized rats under high and low estradiol (E2) and stress conditions. Rats received daily injections of low (LE) or high (HE) dose E2 and were subjected to forced swim (FS) or sham swim conditioning for 3 days. The results revealed marked lamina-specificity in that HE rats displayed enhanced TMJ-evoked activity in superficial, but not deep, laminae independent of stress conditioning. By contrast, FS conditioned rats displayed increased background firing and TMJ-evoked activity of neurons in deep, but not superficial, laminae independent of E2 status. FS also enhanced TMJ-evoked masseter muscle activity and suggested the importance of deep dorsal horn neurons in mediating evoked jaw muscle activity. In conclusion, E2 status and psychophysical stress play a significant role in modifying the encoding properties of TMJ-responsive medullary dorsal horn neurons with a marked laminaspecificity.Status względem estrogenu oraz stres psychologiczny wpływają na ekspresję kilku schorzeń przebiegających z bólem przewlekłym, w tym schorzeń mięśni i stawów skroniowo-żuchwowych. Neurony czuciowe, które zaopatrują okolicę stawu skroniowo-żuchwowego (temporomandibular joint, TMJ ) kończą Wykorzystasię w blaszkach I i V jądra rdzeniowego nerwu trójdzielnego (obszar Vc/C1-2); niewiele jednak wiadomo na temat swoistości tych blaszek lub oddziaływań środowiskowych na własności kodowania neuronów pnia mózgu związanych z TMJ. W celu sprawdzenia hipotezy, zgodnie z którą neurony Vc/C1-2 integrują zarówno interoceptywne jak i eksteroceptywne sygnały istotne dla nocycepcji z TMJ, rejestrowaliśmy aktywność neuronów w blaszkach powierzchownych i głębokich wywołaną przez drażnienie TMJ u szczurów po owariektomii, w warunkach dużego i małego stężenia estradiolu (E2) i podczas stresu. Szczurom wstrzykiwano codziennie małe (LE) lub duże (HE) dawki E2 i przez 3 dni poddawano warunkowaniu w postaci wymuszonego pływania (forced swimming, FS ) lub pływania pozorowanego. Wyniki wykazały znaczącą swoistość blaszek w tym znaczeniu, że szczury otrzymujące HE wykazywały zwiększoną, wywołaną drażnieniem TMJ aktywność w blaszkach powierzchownych (ale nie głębokich) niezależnie od warunkowania stresem. W przeciwieństwie do tego szczury warunkowane FS wykazywały zwiększone wyładowania wyjściowo i zwiększoną, wywołaną drażnieniem TMJ aktywność neuronów w blaszkach głębokich (ale nie powierzchownych) w sposób niezależny od statusu względem E2. Wymuszone pływanie zwiększało również wywołaną drażnieniem TMJ aktywność mięśnia żwacza, co wskazuje na znaczenie neuronów blaszek głębokich rogów tylnych w pośredniczeniu w wywołanej aktywności mięśni związanych z żuciem. Wyciągamy stąd wniosek, że status względem E2 oraz stres psychofizyczny odgrywają istotną rolę w modyfikowaniu własności kodowania w neuronach rogów tylnych rdzenia kręgowego reagujących na drażnienie TMJ ze znaczącą swoistością blaszek