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

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.

Trigeminal Sensitization in a Closed Head Model for Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) is often accompanied by neurological and ocular symptoms that involve trigeminal nerve pathways. Laser-induced shock wave (LISW) was applied to the skull of male rats as a model for mTBI, while behavioral and neural recording methods were used to assess trigeminal function. The LISW caused greater eye wiping behavior to ocular instillation of hypertonic saline (Sham = 4.

Tear secretion by Diquafosol suppresses the excitability of trigeminal brainstem nuclear complex neurons by reducing excessive P2Y expression in the trigeminal ganglion in dry eye rats.

The P2Y receptor agonist, diquafosol sodium, is commonly used to treat the signs and symptoms of dry eye disease (DE) patients. Although diquafosol improves tear film stability, the neural mechanisms underlying the reduction in ocular pain are not well defined. This study determined if repeated application of diquafosol reduces the sensitization of nociceptive neurons in the lower trigeminal brainstem nuclear complex (TBNC) via peripheral P2Y mechanisms in a rat model for DE.

Diquafosol sodium reduces neuronal activity in trigeminal subnucleus caudalis in a rat model of chronic dry eye disease.

Patients with persistent and severe dry eye disease (DED) have corneal hypersensitivity, resulting in ocular pain, and diquafosol sodium, a potent P2Y receptor agonist, is commonly used to improve the resultant tear film stability. This study determined the effects of diquafosol instillation on the suppression of trigeminal subnucleus caudalis (Vc) neuronal activity and ocular pain by enhancing tear film stability in the model for chronic DED. The effects of diquafosol on the ocular surface were assessed by the topical application for 28 days, starting from the 14th day since unilateral exorbital gland removal (chronic DED).

Altered brain responses to noxious dentoalveolar stimuli in high-impact temporomandibular disorder pain patients.

High-impact temporomandibular disorder (TMD) pain may involve brain mechanisms related to maladaptive central pain modulation. We investigated brain responses to stimulation of trigeminal sites not typically associated with TMD pain by applying noxious dentoalveolar pressure to high- and low-impact TMD pain cases and pain-free controls during functional magnetic resonance imaging (fMRI). Fifty female participants were recruited and assigned to one of three groups based on the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) and Graded Chronic Pain Scale: controls (n = 17), low-impact (n = 17) and high-impact TMD (n = 16).

Title: P2x7 Receptor Activation and Estrogen Status Drive Neuroinflammatory Mechanisms in a Rat Model for Dry Eye.

Dry eye disease (DED) is recognized as a chronic inflammatory condition with an increase in tear osmolarity and loss of tear film integrity. DED is often accompanied by adverse ocular symptoms which are more prevalent in females than males. The basis for ocular hyperalgesia in DED remains uncertain; however, both peripheral and central neural mechanisms are implicated.

Role of Connexin 43 in an Inflammatory Model for TMJ Hyperalgesia.

Temporomandibular joint disorders (TMD) consist of a heterogeneous group of conditions that present with pain in the temporomandibular joint (TMJ) region and muscles of mastication. This project assessed the role of connexin 43 (Cx43), a gap junction protein, in the trigeminal ganglion (TG) in an animal model for persistent inflammatory TMJ hyperalgesia. Experiments were performed in male and female rats to determine if sex differences influence the expression and/or function of Cx43 in persistent TMJ hyperalgesia.

Temporomandibular disorders cases with high-impact pain are more likely to experience short-term pain fluctuations.

Temporomandibular disorders (TMD) patients can present clinically significant jaw pain fluctuations which can be debilitating and lead to poor global health. The Graded Chronic Pain Scale evaluates pain-related disability and its dichotomous grading (high/low impact pain) can determine patient care pathways and in general high-impact pain patients have worse treatment outcomes. Individuals with low-impact TMD pain are thought to have better psychosocial functioning, more favorable disease course, and better ability to control pain, while individuals with high-impact pain can present with higher levels of physical and psychological symptoms.

Enhanced Ocular Surface and Intraoral Nociception via a Transient Receptor Potential Vanilloid 1 Mechanism in a Rat Model of Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA), characterized by low arterial oxygen saturation during sleep, is associated with an increased risk of orofacial pain. In this study, we simulated chronic intermittent hypoxia (CIH) during the sleep/rest phase (light phase) to determine the role of transient receptor potential vanilloid 1 (TRPV1) in mediating enhanced orofacial nocifensive behavior and trigeminal spinal subnucleus caudalis (Vc) neuronal responses to capsaicin (a TRPV1 agonist) stimulation in a rat model of OSA. Rats were subjected to CIH (nadir O, 5%) during the light phase for 8 or 16 consecutive days.

The effects of estrogen on temporomandibular joint pain as influenced by trigeminal caudalis neurons.

The signs and symptoms of persistent temporomandibular joint (TMJ)/muscle disorder (TMJD) pain suggest the existence of a central neural dysfunction or a problem of pain amplification. The etiology of chronic TMJD is not known; however, female sex hormones have been identified as significant risk factors. Converging lines of evidence indicate that the junctional region between the trigeminal subnucleus caudalis (Vc) and the upper cervical spinal cord, termed the Vc/C1-2 region, is the primary site for the synaptic integration of sensory input from TMJ nociceptors.

Sex Differences in Estradiol Secretion by Trigeminal Brainstem Neurons.

Estrogen status is a significant risk factor in the development of temporomandibular joint disorders (TMD). Classically, estrogen status is thought to derive mainly from ovarian sources; however, it is well known that estradiol (E2) also is synthesized by neurons in the brain. This study tested the hypothesis that E2 is produced by neurons in trigeminal subnucleus caudalis (Vc), the principal site of termination for sensory afferents that supply the temporomandibular joint (TMJ), to modify evoked responses in a model of TMJ nociception in male and female rats.

Differential activation of ascending noxious pathways associated with trigeminal nerve injury.

Trigeminal spinal subnucleus caudalis (Vc) neurons that project to the ventral posteromedial thalamic nucleus (VPM) and parabrachial nucleus (PBN) are critical for orofacial pain processing. We hypothesized that persistent trigeminal nerve injury differentially alters the proportion of Vc neurons that project to VPM and PBN in a modality-specific manner. Neuroanatomical approaches were used to quantify the number of Vc neurons projecting to VPM or PBN after chronic constriction injury of the infraorbital nerve (ION-CCI) and subsequent upper-lip stimulation.

TRPV1 and TRPM8 Channels and Nocifensive Behavior in a Rat Model for Dry Eye.

Purpose: Persistent ocular surface pain occurs in moderate to severe dry eye disease (DE); however, the mechanisms that underlie this symptom remain uncertain. The aim of this study was to determine if the transient receptor potential vanilloid ion channels play a role in hypertonic saline (HS)-evoked corneal reflexes in a model for aqueous tear deficient DE.

Methods: Eye wipe behavior and orbicularis oculi muscle activity (OOemg) were measured after ocular instillation of HS, capsaicin, or menthol 14 days after exorbital gland removal.

Estrogen Status Gates Effects of Kappa-Opioid Receptor on Temporomandibular Joint-Responsive Neurons at the Spinomedullary Junction in Female Rats.

Aims: To determine whether estrogen status alters κ-opioid inhibition of nociceptive processing by affecting temporomandibular joint (TMJ) input to neurons in the trigeminal subnucleus caudalis [Vc]/C1-2 region at the spinomedullary junction in female rats.

Methods: TMJ-responsive neurons were recorded in laminae I-II of the Vc/C1-2 region at the spinomedullary junction of ovariectomized female rats treated for 2 days with low-dose estradiol (LE group; 2 mg/day) or high-dose estradiol (HE group; 20 mg/day). Under isoflurane anesthesia, TMJ neurons were activated by adenosine triphosphate (ATP; 1 mM, 20 μl), which was injected into the joint space before and after cumulative doses of a κ-opioid receptor (KOR) agonist (U50488) given systemically (0.

TFOS DEWS II pain and sensation report.

Pain associated with mechanical, chemical, and thermal heat stimulation of the ocular surface is mediated by trigeminal ganglion neurons, while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus.

Ascending projections of nociceptive neurons from trigeminal subnucleus caudalis: A population approach.

Second-order neurons in trigeminal subnucleus caudalis (Vc) and upper cervical spinal cord (C1) are critical for craniofacial pain processing and project rostrally to terminate in: ventral posteromedial thalamic nucleus (VPM), medial thalamic nuclei (MTN) and parabrachial nuclei (PBN). The contribution of each region to trigeminal nociception was assessed by the number of phosphorylated extracellular signal-regulated kinase-immunoreactive (pERK-IR) neurons co-labeled with fluorogold (FG). The phenotype of pERK-IR neurons was further defined by the expression of neurokinin 1 receptor (NK1).

Trigeminal brainstem modulation of persistent orbicularis oculi muscle activity in a rat model of dry eye.

Altered corneal reflex activity is a common feature of dry eye disease (DE). Trigeminal sensory nerves supply the ocular surface and terminate at the trigeminal interpolaris/caudalis (ViVc) transition and spinomedullary (VcC1) regions. Although both regions contribute to corneal reflexes, their role under dry eye conditions is not well defined.

Amplified Brain Processing of Dentoalveolar Pressure Stimulus in Persistent Dentoalveolar Pain Disorder Patients.

Aims: (1) To determine the brain regions activated by dentoalveolar pressure stimulation in persistent dentoalveolar pain disorder (PDAP) patients, and (2) to compare these activation patterns to those seen in pain-free control subjects.

Methods: A total of 13 PDAP patients and 13 matched controls completed the study. Clinical pain characteristics and psychosocial data were collected.

Sensitization of trigeminal brainstem pathways in a model for tear deficient dry eye.

Chronic dry eye disease (DE) is associated with an unstable tear film and symptoms of ocular discomfort. The characteristics of symptoms suggest a key role for central neural processing; however, little is known about central neuroplasticity and DE. We used a model for tear deficient DE and assessed effects on eye blink behavior, orbicularis oculi muscle activity (OOemg), and trigeminal brainstem neural activity in male rats.

Activation of rostral ventromedial medulla neurons by noxious stimulation of cutaneous and deep craniofacial tissues.

The rostral ventromedial medulla (RVM) projects to the medullary and spinal dorsal horns and is a major source of descending modulation of nociceptive transmission. Traditionally, neurons in the RVM are classified functionally as on, off, and neutral cells on the basis of responses to noxious cutaneous stimulation of the tail or hind paw. On cells facilitate nociceptive transmission, off cells are inhibitory, whereas neutral cells are unresponsive to noxious stimuli and their role in pain modulation is unclear.

Posterior hypothalamic modulation of ocular-responsive trigeminal subnucleus caudalis neurons is mediated by Orexin-A and Orexin1 receptors.

Orexin-A (OxA) is synthesized in posterior and lateral regions of the hypothalamus and contributes to homeostatic regulation of body functions including pain modulation. To determine if orexinergic mechanisms contribute to posterior hypothalamus (PH)-induced modulation of ocular input to subnucleus caudalis/upper cervical (Vc/C1) neurons, the orexin-1 receptor antagonist SB334867 was applied to the dorsal brainstem surface prior to PH disinhibition, by bicuculline methiodide, in male rats under isoflurane anesthesia. Ocular input to Vc/C1 units by bright light or hypertonic saline was markedly reduced by PH disinhibition and reversed completely by local Vc/C1 application of SB334867.

The TFOS International Workshop on Contact Lens Discomfort: report of the subcommittee on neurobiology.

This report characterizes the neurobiology of the ocular surface and highlights relevant mechanisms that may underpin contact lens-related discomfort. While there is limited evidence for the mechanisms involved in contact lens-related discomfort, neurobiological mechanisms in dry eye disease, the inflammatory pathway, the effect of hyperosmolarity on ocular surface nociceptors, and subsequent sensory processing of ocular pain and discomfort have been at least partly elucidated and are presented herein to provide insight in this new arena. The stimulus to the ocular surface from a contact lens is likely to be complex and multifactorial, including components of osmolarity, solution effects, desiccation, thermal effects, inflammation, friction, and mechanical stimulation.

Estrogen status and psychophysical stress modify temporomandibular joint input to medullary dorsal horn neurons in a lamina-specific manner in female rats.

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.

Trigeminal interpolaris/caudalis transition neurons mediate reflex lacrimation evoked by bright light in the rat.

Abnormal sensitivity to bright light can cause discomfort or pain and evoke protective reflexes such as lacrimation. Although the trigeminal nerve is probably involved, the mechanism linking luminance to somatic sensory nerve activity remains uncertain. This study determined the effect of bright light on second-order ocular neurons at the ventral trigeminal interpolaris/caudalis transition (Vi/Vc) region, a major termination zone for trigeminal sensory fibers that innervate the eye.

Temporomandibular joint-evoked responses by spinomedullary neurons and masseter muscle are enhanced after repeated psychophysical stress.

Psychological stress is a risk factor for the development of musculoskeletal pain of the head and neck; however, the basis for this relationship remains uncertain. This study tested the hypothesis that psychophysical stress alone was sufficient to alter the encoding properties of spinomedullary dorsal horn neurons and masseter muscle activity in male rats. Repeated forced swim conditioning increased markedly both the background firing rate and temporomandibular joint (TMJ)-evoked activity of neurons in deep dorsal horn, while neurons in superficial laminae were less affected.