Effects of peripheral inflammation on activation of p38 mitogen-activated protein kinase in the rostral ventromedial medulla.

In the present study, the activation of p38 mitogen-activated protein kinase (p38 MAPK) in the rostral ventromedial medulla (RVM) following the injection of complete Freund's adjuvant (CFA) into the rat hindpaw was examined in order to clarify the mechanisms underlying the dynamic changes in the descending pain modulatory system after peripheral inflammation. Phospho-p38 MAPK-immunoreactive (p-p38 MAPK-IR) neurons were observed in the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars alpha (GiA). Inflammation induced the activation of p38 MAPK in the RVM, with a peak at 30 min after the injection of CFA into the hindpaw, which lasted for 1 h. In the RVM, the number of p-p38 MAPK-IR neurons per section in rats killed at 30 min after CFA injection (19.4+/-2.0) was significantly higher than that in the naive group (8.4+/-2.4) [p<0.05]. At 30 min after CFA injection, about 40% of p-p38 MAPK-IR neurons in the RVM were serotonergic neurons (tryptophan hydroxylase, TPH, positive) and about 70% of TPH-IR neurons in the RVM were p-p38 MAPK positive. The number of p-p38 MAPK- and TPH-double-positive RVM neurons in the rats with inflammation was significantly higher than that in naive rats [p<0.05]. These findings suggest that inflammation-induced activation of p38 MAPK in the RVM may be involved in the plasticity in the descending pain modulatory system following inflammation.

Stress-induced hyperalgesia: animal models and putative mechanisms.

Stress has been shown to affect brain activity and promote long-term changes in multiple neural systems. A variety of environmental and/or stressful stimuli have been shown to produce analgesia, a phenomenon often referred to as stress-induced analgesia (SIA). However, acute and chronic stresses also produce hyperalgesia in various behavioral tests. There are now several animal models in which stress enhances nociceptive responses. The dysfunction of the hypothalamo-pituitary-adrenocortical axis (HPA axis) and multiple neurotransmitter systems in the central nervous system (CNS), including endogenous opioid, serotonergic and noradrenergic systems, has been reported. These stress-induced hyperalgesia models may contribute to a better understanding of chronic pain and provide a more rational basis for drug therapies in a variety of pain syndromes.

TMJ inflammation increases Fos expression in the nucleus raphe magnus induced by subsequent formalin injection of the masseter or hindpaw of rats.

The study was designed to examine the effect of persistent temporomandibular joint (TMJ) inflammation on neuronal activation in the descending pain modulatory system in response to noxious stimulus. Formalin was injected into the left masseter muscle or hindpaw of rats 10 days after injection of the left TMJ with saline or complete Freund's adjuvant (CFA). The results showed that 10-day persistent TMJ inflammation (induced by CFA) alone did not induce a significant increase in Fos-like immunoreactive (Fos-LI) neurons in the rostral ventromedial medulla (RVM) or locus coeruleus (LC), but that formalin injection of the masseter muscle or hindpaw induced a significant increase in Fos-LI neurons in the RVM and LC of rats with and without TMJ inflammation (P < 0.05). However, persistent TMJ inflammation significantly increased Fos-LI neurons in the nucleus raphe magnus (NRM) induced by subsequent formalin injection of the masseter muscle and hindpaw (70.2% increase and 53.8% increase, respectively, over the control TMJ-saline-injected rats; P < 0.05). The results suggest that persistent TMJ inflammation increases neuronal activity, in particularly in the NRM, by the plastic change of the descending pain modulatory system after ipsilateral application of a noxious stimulus to either orofacial area or a spatially remote body area.

Effects of peripheral inflammation on activation of ERK in the rostral ventromedial medulla.

In the present study, the activation of extracellular signal-regulated kinase (ERK) in the rostral ventromedial medulla (RVM) following the injection of complete Freund's adjuvant (CFA) into the rat hindpaw was examined in order to clarify the mechanisms underlying the dynamic changes in the descending pain modulatory system after peripheral inflammation. Phospho-extracellular signal-regulated kinase-immunoreactive (p-ERK-IR) neurons were observed in the nucleus raphe magnus (NRM) and nucleus reticularis gigantocellularis pars alpha (GiA). Inflammation induced the activation of ERK in the RVM, with a peak at 7 h after the injection of CFA into the hindpaw and a duration of 24 h. In the RVM, the number of p-ERK-IR neurons per section in rats killed at 7 h after CFA injection (14.2 +/- 1.7) was significantly higher than that in the control group (4.5 +/- 0.9) [P < 0.01]. At 7 h after CFA injection, about 60% of p-ERK-IR neurons in the RVM were serotonergic neurons. The percentage of RVM serotonergic neurons that are also p-ERK positive in the rats with inflammation (20.5% +/- 2.3%) was seven times higher than that in control rats (2.7% +/- 1.4%) [P < 0.01]. These findings suggest that inflammation-induced activation of ERK in the RVM may be involved in the plasticity in the descending pain modulatory system following inflammation.

Morphological classification of mandibular dental arch forms by correlation and principal component analyses.

To evaluate the morphology of dental arches, 53 (male: 29, female: 24) paired casts having normal dentitions and occlusion were selected from 396 (age: 18 to 26 years old; male: 257, female: 139) sets of dental study models. The mandibular dentitions were preliminarily classified as square, round-square, round and round V-shaped arches based on the conventional morphological descriptions. Midpoints of the incisor edge (I1R, I1L, I2R, & I2L), summits of the cuspids (CR & CL), buccal cusps of the premolars (P1R, P1L, P2R, & P2L), mesial buccal cusps of the first and second molars (M1R, M1L, M2R, & M2L), and the midpoint (A) of line I1R-I1L were designated as reference points. From A, let a vertical line intersected line M2R-M2L at reference point B. The line A-B intersected CR-CL at reference point E. We evaluated 1) the protrusion of the cuspids by 1. angle I2R-CR-P1R (angle R) + angle I2L-CL-P1L (angle L); 2) the curvature of the anterior teeth by 2. (A-B)/(CR-CL), 3. (180 degrees-angle(CR-A-CL), and 4. (A-E)/(CR-CL); 3) the length to width ratio of the dental arch by 5. (A-B)/(M2R-M2L); 4) the degree of roundness of the mandibular arch by estimation of 6. (rtheta5 - rtheta4)R + (rtheta5 - rtheta4)L; and 5) an item 7. for the differentiation of type I and type II round-square arches by relating the bilateral contour and position of break line P1-P2-M1-M2 (i) to line P1-M2 (ii). The data of items 1., 2., 3., 4., 5., and 6. were further standardized and summarized into three essential principal components: 1) the curvature of the anterior teeth, 2) the curvilinear contour of the dental arch, and 3) the length-to-width ratio of the dental arch. The results indicated that: 1) 36 cases (67.9%) of the mandibular dentitions were round-square arches which showed no prominent principal component. 11 cases (20.8%) were square arches and 6 cases (11.3%) were round V-shaped arches; no round arches was found in mandibular dentitions. 2) Statistical analysis indicated significant differences of items 3., 4. and 6. in various mandibular arches (Student's t-test). 3) By examination of the three principal components, significant differences of item 5. between the round V-shaped arches and square and round-square mandibular arches were evident (Student's t-test). The present study elucidated that morphology of the mandibular arch was determined by a parameters representing the curvature of anterior teeth (composed of items 2., 3. and 4., and another parameter (item 6.) representing roundness of the mandibular arch.

The effects of acute and chronic restraint stress on activation of ERK in the rostral ventromedial medulla and locus coeruleus.

Extracellular signal-regulated kinase (ERK) is a key molecule in numerous cellular and physiological processes in the CNS. Exposure to stressors causes substantial effects on the perception and response to pain. The rostral ventromedial medulla (RVM) and the locus coeruleus (LC) play crucial roles in descending pain modulation system. In the present study, the activation of ERK in the RVM and the LC in rats following acute and chronic restraint stress was examined in order to characterize the mechanisms underlying stress induced analgesic and hyperalgesic responses. Rats were stressed by restraint 6h daily for 3 weeks. The acute and chronic restraint stresses produced analgesic and hyperalgesic reactions, respectively, to thermal stimuli applied to the tail. The phospho-ERK-immunoreactive (p-ERK-IR) neurons were observed in the nucleus raphe magnus (NRM), nucleus reticularis gigantocellularis pars alpha (GiA) and LC. In the RVM, the number of p-ERK-IR neurons per section in the 3-week restraint rats (14.3+/-1.2) was significantly higher than that in the control rats (8.9+/-0.7) [P<0.01]. About 75% of p-ERK-IR neurons in the RVM in the 3-week restraint rats were serotonergic neurons. Protein levels of tryptophan hydroxylase were significantly increased in the RVM region in the 3-week restraint rats. On the other hand, the chronic restraint stress significantly decreased p-ERK-IR in the LC [P<0.05]. These findings suggest that chronic restraint stress-induced activation of ERK in the RVM and the suppression in the LC may be involved in the modulation of the pain threshold by chronic stress.