Vacuolar-ATPase-mediated muscle acidification caused muscular mechanical nociceptive hypersensitivity after chronic stress in rats, which involved extracellular matrix proteoglycan and ASIC3.

Although widespread pain, such as fibromyalgia, is considered to have a central cause, peripheral input is important. We used a rat repeated cold stress (RCS) model with many characteristics common to fibromyalgia and studied the possible involvement of decreased muscle pH in muscle mechanical hyperalgesia. After a 5-day RCS, the muscle pH and the muscular mechanical withdrawal threshold (MMWT) decreased significantly.

Properties of heat-sensitive neurons in the premotor cortex of conscious monkeys.

To investigate neuronal activity involved in responses to noxious stimuli in conscious monkeys, the animals were subjected to a task that required them to detect a small change in facial skin temperature or light (second temperature: T2, second light: V2) relative to an initial condition (T1 or V1), and to detect changes in V2 along with a heat task. Recordings were obtained from 57 neurons in the ventral premotor cortex (PMv) during the heat or light detection task. T1 neurons and T2 neurons showed increased activity only during T1 or T2, and T1/T2 neurons were activated by both T1 and T2 stimuli.

Pathophysiological mechanisms of persistent orofacial pain.

Nociceptive stimuli to the orofacial region are typically received by the peripheral terminal of trigeminal ganglion (TG) neurons, and noxious orofacial information is subsequently conveyed to the trigeminal spinal subnucleus caudalis and the upper cervical spinal cord (C1-C2). This information is further transmitted to the cortical somatosensory regions and limbic system via the thalamus, which then leads to the perception of pain. It is a well-established fact that the presence of abnormal pain in the orofacial region is etiologically associated with neuroplastic changes that may occur at any point in the pain transmission pathway from the peripheral to the central nervous system (CNS).

Involvement of Satellite Cell Activation via Nitric Oxide Signaling in Ectopic Orofacial Hypersensitivity.

The mechanical head-withdrawal threshold (MHWT) was significantly reduced following inferior alveolar nerve transection (IANX) in rats. Nitrate and nitrite synthesis was dramatically increased in the trigeminal ganglion (TG) at 6 h after the IANX. The relative number of neuronal nitric oxide synthase (nNOS)-immunoreactive (IR) cells was significantly higher in IANX rats compared to sham-operated and N-propyl-L-arginine (NPLA)-treated IANX rats.

Involvement of TRPV4 ionotropic channel in tongue mechanical hypersensitivity in dry-tongue rats.

Although xerostomia can cause persistent oral pain, the mechanisms underlying such pain are not well understood. To evaluate whether a phosphorylated p38 (pp38)-TRPV4 mechanism in trigeminal ganglion (TG) neurons has a role in mechanical hyperalgesia of dry tongue, a rat model of dry tongue was used to study the nocifensive reflex and pp38 and TRPV4 expression in TG neurons. The head-withdrawal reflex threshold for mechanical stimulation of the tongue was significantly lower in dry-tongue rats than in sham rats.

Increase in IGF-1 Expression in the Injured Infraorbital Nerve and Possible Implications for Orofacial Neuropathic Pain.

Insulin-like growth factor-1 (IGF-1) is upregulated in the injured peripheral nerve bundle and controls nociceptive neuronal excitability associated with peripheral nerve injury. Here, we examined the involvement of IGF-1 signaling in orofacial neuropathic pain following infraorbital nerve injury (IONI) in rats. IONI promoted macrophage accumulation in the injured ION, as well as in the ipsilateral trigeminal ganglion (TG), and induced mechanical allodynia of the whisker pad skin together with the enhancement of neuronal activities in the subnucleus caudalis of the spinal trigeminal nucleus and in the upper cervical spinal cord.

Peripheral and Central Mechanisms of Persistent Orofacial Pain.

Neuroplastic changes in the neuronal networks involving the trigeminal ganglion (TG), trigeminal spinal subnucleus caudalis (Vc), and upper cervical spinal cord (C1/C2) are considered the mechanisms underlying the ectopic orofacial hypersensitivity associated with trigeminal nerve injury or orofacial inflammation. It has been reported that peripheral nerve injury causes injury discharges in the TG neurons, and a barrage of action potentials is generated in TG neurons and conveyed to the Vc and C1/C2 after trigeminal nerve injury. Long after trigeminal nerve injury, various molecules are produced in the TG neurons, and these molecules are released from the soma of TG neurons and are transported to the central and peripheral terminals of TG neurons.

A single administration of Neurotropin reduced the elongated immobility time in the forced swimming test of rats exposed to repeated cold stress.

Many people suffer from a major depressive disorder, and chronic pain conditions are often associated with depressive symptoms. Neurotropin, an extract from the inflamed skin of rabbits inoculated with vaccinia virus, has been used for pain relief. Decrease of brain-derived neurotrophic factor (BDNF) in the brain is one of the proposed mechanisms for the major depressive disorders, and Neurotropin has been reported to restore the decreased BDNF in the hippocampus.

Chondroitin sulfate attenuates acid-induced augmentation of the mechanical response in rat thin-fiber muscle afferents in vitro.

Exercise-induced tissue acidosis augments the exercise pressor reflex (EPR). One reason for this may be acid-induced mechanical sensitization in thin-fiber muscle afferents, which is presumably related to EPR. Acid-induced sensitization to mechanical stimulation has been reported to be attenuated in cultured primary-sensory neurons by exogenous chondroitin sulfate (CS) and chondroitinase ABC, suggesting that the extracellular matrix CS proteoglycan is involved in this sensitization.

Phenotypic change in trigeminal ganglion neurons associated with satellite cell activation via extracellular signal-regulated kinase phosphorylation is involved in lingual neuropathic pain.

Iatrogenic trigeminal nerve injuries remain a common and complex clinical problem. Satellite glial cell (SGC) activation, associated phosphorylation of extracellular signal-regulated kinase (ERK), and neuropeptide expression in the trigeminal ganglion (TG) are known to be involved in trigeminal neuropathic pain related to trigeminal nerve injury. However, the involvement of these molecules in orofacial neuropathic pain mechanisms is still unknown.

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).

Oxytocin alleviates orofacial mechanical hypersensitivity associated with infraorbital nerve injury through vasopressin-1A receptors of the rat trigeminal ganglia.

Oxytocin (OXT) is a neuropeptide hormone synthesized and secreted by hypothalamic neurons and has been reported to play a significant role in pain modulation. However, the mechanisms underlying OXT's antinociceptive effect on neuropathic pain are not fully understood. In this study, we examined the peripheral effect of OXT on mechanical hypersensitivity induced by partial ligation of the infraorbital nerve (PNL) in rats.

ERK-GluR1 phosphorylation in trigeminal spinal subnucleus caudalis neurons is involved in pain associated with dry tongue.

Background: Dry mouth is known to cause severe pain in the intraoral structures, and many dry mouth patients have been suffering from intraoral pain. In development of an appropriate treatment, it is crucial to study the mechanisms underlying intraoral pain associated with dry mouth, yet the detailed mechanisms are not fully understood. To evaluate the mechanisms underlying pain related to dry mouth, the dry-tongue rat model was developed.

ATP decreases mechanical sensitivity of muscle thin-fiber afferents in rats.

ATP is an energy rich substance contained in cells in the order of mM. It is released when cells are damaged and when muscle is compressed or contracted. Subcutaneous injection of ATP induces pain-related behavior and hyperalgesia to mechanical and heat stimulation in rats.

Effect of protons on the mechanical response of rat muscle nociceptive fibers and neurons in vitro.

Strong exercise makes muscle acidic, and painful. The stimulus that activates muscle nociceptors in such instance may be protons. Reportedly, however, not many afferents are excited by protons alone.

Monocyte chemoattractant protein-1-induced excitation and sensitization to mechanical stimulation of mechanosensitive C-fiber afferents in rat skin.

It has been previously demonstrated that chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) increases the excitability of nociceptive neurons after peripheral nerve injury or inflammation. Moreover, decreased nocifensive mechanical threshold in behavioral tests and increased calcium influx in cultured dorsal root ganglion neurons by MCP-1 application have been reported. However, the effects of MCP-1 on peripheral afferent terminals have not been studied yet.

Nociception originating from the crural fascia in rats.

Little is documented in the literature as to the function of muscle fascia in nociception and pain. The aim of this study was to examine the distribution of presumptive nociceptive nerve fibers, to characterize fascial thin-fiber sensory receptors, and to examine the spinal projection of nociceptive input from the rat crural fascia (CF). Nerve fibers labeled with specific antibodies to calcitonin gene-related peptide (CGRP) and peripherin were found to be densely distributed in the distal third of the CF.

Extracellular matrix proteoglycan plays a pivotal role in sensitization by low pH of mechanosensitive currents in nociceptive sensory neurones.

Ischaemia, inflammation, and exercise lead to tissue acidosis, which induces pain and mechanical hyperalgesia. Corresponding to this, enhanced thin-fibre afferent responses to mechanical stimulation have been recorded in vitro at low pH. However, knowledge about how this sensitization by low pH occurs is lacking.

Absence of mechanical hyperalgesia after exercise (delayed onset muscle soreness) in neonatally capsaicin-treated rats.

Delayed onset muscle soreness (DOMS) appears with some delay after unaccustomed, strenuous exercise, especially after lengthening contraction (LC). It is characterized by tenderness and movement related pain, namely muscular mechanical hyperalgesia. To clarify the involvement of C-fibers in this mechanical hyperalgesia, we examined whether DOMS could be induced in rats treated neonatally with capsaicin.

Novel non-steroidal/non-anilide type androgen antagonists with an isoxazolone moiety.

3-Substituted (Z)-4-(4-N,N-dialkylaminophenylmethylene)-5(4H)-isoxazolones and related compounds were designed and prepared as candidates for structurally novel androgen antagonists. Several compounds showed potent anti-androgenic activity as assessed by nuclear androgen receptor binding assay and growth inhibition assay using androgen-dependent Shionogi carcinoma cells SC-3. They were approximately 10--220 times more potent than flutamide in these assay systems.