It is well known that trigeminal nerve injury causes hyperexcitability in trigeminal ganglion neurons, which become sensitized. Long after trigeminal nerve damage, trigeminal spinal subnucleus caudalis and upper cervical spinal cord (C1/C2) nociceptive neurons become hyperactive and are sensitized, resulting in persistent orofacial pain. Communication between neurons and non-neuronal cells is believed to be involved in these mechanisms. In this article, the authors highlight several lines of evidence that neuron-glial cell and neuron macrophage communication have essential roles in persistent orofacial pain mechanisms associated with trigeminal nerve injury and/or orofacial inflammation.
Cell Communication ; Cervical Cord ; Facial Pain ; Inflammation ; Macrophages ; Neurons ; Nociceptors ; Trigeminal Ganglion ; Trigeminal Nerve ; Trigeminal Nerve Injuries ; Trigeminal Nucleus, Spinal

Polyacrylamide hydrogel is a widely used filler material in cosmetic procedures performed on the face and breasts. Recently, however, complications including inflammation, deformity, and pain have been reported. The present article addresses unregulated materials/products injected as dermal fillers. The authors report a case involving a 29-year-old woman who developed severe facial pain after undergoing a cosmetic procedure with injectable triamcinolone and hyaluronidase. Two months later, the pain spread to her upper and lower limbs, and abdomen, which eventually led to the the development and diagnosis of complex regional pain syndrome (CRPS) in the upper limbs. The authors hypothesize that CRPS in the upper limbs was responsible for the facial pain through sensitization of third-order neurons and the trigeminal nucleus caudalis extending to the upper cervical segments.
Abdomen ; Adult ; Breast ; Congenital Abnormalities ; Dermal Fillers ; Diagnosis ; Facial Neuralgia ; Facial Pain* ; Female ; Humans ; Hyaluronic Acid ; Hyaluronoglucosaminidase ; Hydrogel ; Inflammation ; Lower Extremity ; Neurons ; Triamcinolone ; Trigeminal Nuclei ; Upper Extremity*

BACKGROUND: The trigeminal nucleus caudalis (Vc) is a primary central site for trigeminal transmitting. Noxious stimulation of the trigeminal nociceptors alters the central synaptic releases and neural expression of some inflammatory and trophic agents. Orexin-A and the orexin 1 receptor (OX1R) are expressed in pain pathways including trigeminal pain transmission. However, the the mechanism(s) underling orexin-A effects on trigeminal pain modulation have not been fully clarified. METHODS: Trigeminal pain was induced by subcutaneous injection of capsaicin in the upper lip in rats. The effect of trigeminal pain on cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) expression in the Vc of animals was determined by immunofluorescence. Subsequently, OX1R agonist (orexin-A) and antagonist (SB-334867-A) was administrated in the Vc to investigate the possible roles of the Vc OX1R on changes in COX-2 and BDNF levels following pain induction. RESULTS: The data indicated an increase in COX-2 and decrease in BDNF immuno-reactivity in the Vc of capsaicin, and capsaicin- pretreated with SB-334867-A (80 nM), groups of rat. However, the effect of capsaicin on COX-2 and BDNF expressions was reversed by a Vc microinjection of orexin-A (100 pM). CONCLUSIONS: Overall, the present data reveals that orexin-A can attenuate capsaicin-induced trigeminal pain through the modulation of pain effects on COX-2 and BDNF expressions in the Vc of rats.
Animals ; Brain-Derived Neurotrophic Factor ; Capsaicin ; Cyclooxygenase 2 ; Facial Pain ; Fluorescent Antibody Technique ; Injections, Subcutaneous ; Lip ; Microinjections ; Nociceptors ; Orexin Receptor Antagonists ; Orexins ; Pain Measurement ; Pain Perception ; Rats ; Trigeminal Caudal Nucleus ; Trigeminal Neuralgia ; Trigeminal Nuclei

Recently, we reported that astrocytes in the trigeminal caudal nucleus (Vc) of the brain stem express a purinergic receptor P2X₃, which is involved in the craniofacial pathologic pain. Although we observed protein expression of P2X₃ receptors (P2X₃ Rs) in the astrocyte of the Vc, it is still unclear that astrocyte has functional P2X₃Rs in Vc. To address this issue, we recorded asrtocytic P2X₃Rs by using whole cell voltage-clamp recording in the Vc of the GFAP-GFP mice, which was used as a guide to astrocytes with green fluorescence. While measuring voltage ramp-induced astrocytic membrane current, we found the amplitude of the current was increased when we applied P2-purinoreceptor agonist, α,β-meATP. This increase was blocked by co-application of A317491, P2X₃R antagonist. These results demonstrate that astrocytes in the Vc express functional P2X₃Rs, which might be critical in craniofacial pathologic pain.
Animals ; Astrocytes ; Brain Stem ; Electrophysiology ; Fluorescence ; Membranes ; Mice* ; Trigeminal Caudal Nucleus*

The caudal subnucleus of the spinal trigeminal nucleus (medullary dorsal horn; MDH) receives direct inputs from small diameter primary afferent fibers that predominantly transmit nociceptive information in the orofacial region. Recent studies indicate that reactive oxygen species (ROS) is involved in persistent pain, primarily through spinal mechanisms. In this study, we aimed to investigate the role of xanthine/xanthine oxidase (X/XO) system, a known generator of superoxide anion (O₂(·−)), on membrane excitability in the rat MDH neurons. For this, we used patch clamp recording and confocal imaging. An application of X/XO (300 µM/30 mU) induced membrane depolarization and inward currents. When slices were pretreated with ROS scavengers, such as phenyl N-tert-butylnitrone (PBN), superoxide dismutase (SOD), and catalase, X/XO-induced responses decreased. Fluorescence intensity in the DCF-DA and DHE-loaded MDH cells increased on the application of X/XO. An anion channel blocker, 4,4-diisothiocyanatostilbene-2,2-disulfonic acid (DIDS), significantly decreased X/XO-induced depolarization. X/XO elicited an inward current associated with a linear current-voltage relationship that reversed near −40 mV. X/XO-induced depolarization reduced in the presence of La³⁺, a nonselective cation channel (NSCC) blocker, and by lowering the external sodium concentration, indicating that membrane depolarization and inward current are induced by influx of Na⁺ ions. In conclusion, X/XO-induced ROS modulate the membrane excitability of MDH neurons, which was related to the activation of NSCC.
Animals ; Catalase ; Facial Pain ; Fluorescence ; Ions ; Membranes ; Neurons* ; Oxidoreductases ; Posterior Horn Cells* ; Rats* ; Reactive Oxygen Species* ; Sodium ; Spinal Cord Dorsal Horn* ; Superoxide Dismutase ; Superoxides ; Trigeminal Nucleus, Spinal ; Xanthine Oxidase

The ultrastructural parameters related to synaptic release of endings which are presynaptic to tooth pulp afferent terminals (p-endings) were analyzed to understand the underlying mechanism for presynaptic modulation of tooth pulp afferents. Tooth pulp afferents were labelled by applying wheat-germ agglutinin conjugated horseradish peroxidase to the rat right lower incisor, whereafter electron microscopic morphometric analysis with serial section and reconstruction of p-endings in the trigeminal oral nucleus was performed. The results obtained from 15 p-endings presynaptic to 11 labeled tooth pulp afferent terminals were as follows. P-endings contained pleomorphic vesicles and made symmetrical synaptic contacts with labeled terminals. The p-endings showed small synaptic release-related ultrastructural parameters: volume, 0.82 ± 0.45 µm³ (mean ± SD); surface area, 4.50 ± 1.76 µm²; mitochondrial volume, 0.15 ± 0.07 µm³; total apposed surface area, 0.69 ± 0.24 µm²; active zone area, 0.10 ± 0.04 µm²; total vesicle number, 1045 ± 668.86; and vesicle density, 1677 ± 684/µm². The volume of the p-endings showed strong positive correlation with the following parameters: surface area (r=0.97, P<0.01), mitochondrial volume (r=0.56, P<0.05), and total vesicle number (r=0.73, P<0.05). However, the volume of p-endings did not positively correlate or was very weakly correlated with the apposed surface area (r=-0.12, P=0.675) and active zone area (r=0.46, P=0.084). These results show that some synaptic release-related ultrastructural parameters of p-endings on the tooth pulp afferent terminals follow the "size principle" of Pierce and Mendell (1993) in the trigeminal nucleus oralis, but other parameters do not. Our findings may demonstrate a characteristic feature of synaptic release associated with p-endings.
Animals ; Horseradish Peroxidase ; Incisor ; Mitochondrial Size ; Rats ; Tooth* ; Trigeminal Nuclei

The present study was aimed to evaluate the influence of glutaraldehyde (GA) concentration on multiple electron microscopic (EM) immunostaining using pre-embedding peroxidase and post-embedding immunogold method. Influence of various concentrations of GA included in the fixative on immuoreactivity was assessed in the multiple immunostaining using antisera against anti-transient receptor potential vanilloid 1 (TRPV1) for peroxidase staining and anti-GABA for immunogold labeling in the rat trigeminal caudal nucleus. Anti-TRPV1 antiserum had specificity in pre-embedding peroxidase staining when tissues were fixed with fixative containing paraformaldehyde (PFA) alone. Immunoreactivity for TRPV1 was specific in tissues fixed with fixative containing 0.5% GA at both perfusion and postfixation steps, though the immunoreactivity was weaker than in tissues fixed with fixative containing PFA alone. Tissues fixed with fixative containing 0.5% GA at the perfusion and postfixation steps showed specific immunogold staining for GABA. The results of the present study indicate that GA concentration is critical for immunoreactivity to antigens such as TRPV1 and GABA. This study also suggests that the appropriate GA concentration is 0.5% for multiple immunostaining with peroxidase labeling for TRPV1 and immunogold labeling for GABA.
Animals ; gamma-Aminobutyric Acid ; Glutaral* ; Immune Sera ; Microscopy, Electron ; Perfusion ; Peroxidase ; Rats ; Sensitivity and Specificity ; Trigeminal Caudal Nucleus

Migraine headache is commonly associated with signs of exaggerated intracranial and extracranial mechanical sensitivities. Patients exhibiting signs of intracranial hypersensitivity testify that their headache throbs and that mundane physical activities that increase intracranial pressure (such as bending over or coughing) intensify the pain. Patients exhibiting signs of extracranial hypersensitivity testify that during migraine their facial skin hurts in response to otherwise innocuous activities such as combing, shaving, letting water run over their face in the shower, or wearing glasses or earrings (termed here cephalic cutaneous allodynia). Such patients often testify that during migraine their bodily skin is hypersensitive and that wearing tight cloth, bracelets, rings, necklaces and socks or using a heavy blanket can be uncomfortable and/or painful (termed her extracephalic cutaneous allodynia). This review summarizes the evidence that support the view that activation of the trigeminovascular pathway contribute to the headache phase of a migraine attack, that the development of throbbing in the initial phase of migraine is mediated by sensitization of peripheral trigeminovascular neurons that innervate the meninges, that the development of cephalic allodynia is propelled by sensitization of second-order trigeminovascular neurons in the spinal trigeminal nucleus which receive converging sensory input from the meninges as well as from the scalp and facial skin, and that the development of extracephalic allodynia is mediated by sensitization of third-order trigeminovascular neurons in the posterior thalamic nuclei which receive converging sensory input from the meninges, facial and body skin.
Animals ; Comb and Wattles ; Ear ; Eyeglasses ; Glass ; Headache ; Humans ; Hyperalgesia ; Hypersensitivity ; Intracranial Pressure ; Linear Energy Transfer ; Meninges ; Migraine Disorders ; Motor Activity ; Neurons ; Posterior Thalamic Nuclei ; Scalp ; Skin ; Thalamus ; Trigeminal Nucleus, Spinal ; Tryptamines ; Water

Discogenic low back pain is the common type of chronic low back pain. However,its mechanism has not been completely clarified. Considerable evidence shows that neurotrophins play an important role in discogenic low back pain. The paper summarizes the mechanism of neurotrophins on discogenic low back pain according to the pain transfer pathway of neurotrophins in intervertebral disc, dorsal horn ganglia and spinal trigeminal nucleus. Changing the pain transmission by regulating neurotrophins and its receptor will provide a new way for the treatment of discogenic low back pain.
Humans ; Intervertebral Disc ; metabolism ; pathology ; Low Back Pain ; metabolism ; pathology ; Nerve Growth Factors ; metabolism ; Posterior Horn Cells ; pathology ; Trigeminal Nucleus, Spinal ; pathology

OBJECTIVETo evaluate the potential role of p38 mitogen-activated protein kinase (MAPK) in the orofacial inflammatory pain.

METHODSSD rats received subcutaneous injection of 2.5% formalin 50 µl in the left vibrissa pad to establish the inflammatory pain model. The rats were grouped into the control group, the formalin group (FOR group), the formalin + saline group (FOR + NS group) and the formalin + SB203580 group (FOR + SB group). SB203580 or saline was inserted into the rat's cisterna magna 20 minutes prior to the formalin injection, then the behavioral changes were tested. The immunofluorescence staining and Western blotting analysis were performed to examine c-fos, p38MAPK and phosphorylated p38 (p-p38) activity in Vc at 20, 60, 120, 180 minutes after formalin injection.

RESULTSp38MAPK was constitutively expressed in Vc (P > 0.05) and p38MAPK was activated following formalin injection.Compared with the control group at 20 min (0.12 ± 0.01), the level of p-p38 in FOR group (0.66 ± 0.04) and FOR + NS group (0.64 ± 0.04) increased significantly (P < 0.001). The expression of p-p38 peaked at 20 minutes, and then declined in each group. Intracisterna magna pretreatment of p38MAPK inhibitor SB203580 resulted in potent attenuation of phase II of pain behavior (P < 0.05), while the expression of c-fos was also inhibited, especially at the point of 120 min (P < 0.01).

CONCLUSIONSActivation of p38 mitogen-activated protein kinase played a major role in the development of orofacial inflammatory pain and it was verified by the experimental result that p38MAPK inhibitor SB203580 inhibited the formalin-induced orofacial pain.

Animals ; Anti-Inflammatory Agents, Non-Steroidal ; pharmacology ; Behavior, Animal ; Enzyme Inhibitors ; pharmacology ; Facial Pain ; chemically induced ; metabolism ; Formaldehyde ; Imidazoles ; pharmacology ; Male ; Phosphorylation ; Proto-Oncogene Proteins c-fos ; metabolism ; Pyridines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Trigeminal Caudal Nucleus ; metabolism ; p38 Mitogen-Activated Protein Kinases ; metabolism