Trigeminal Neuralgia: Basic and Clinical Aspects.

The trigeminal nerve is the largest of all cranial nerves. It has three branches that provide the main sensory innervation of the anterior two-thirds of the head and face. Trigeminal neuralgia (TN) is characterized by sudden, severe, brief, and stabbing recurrent episodes of facial pain in one or more branches of the trigeminal nerve. Pain attacks can occur spontaneously or can be triggered by non-noxious stimuli, such as talking, eating, washing the face, brushing teeth, shaving, a light touch or even a cool breeze. In addition to pain attacks, a proportion of the patients also experience persistent background pain, which along with autonomic signs and prolonged disease duration, represent predictors of worse treatment outcomes. It is now widely accepted that the presence of a neurovascular compression at the trigeminal root entry zone is an anatomic abnormality with a high correlation with classical TN. However, TN may be related to other etiologies, thus presenting different and/or additional features. Since the 1960s, the anticonvulsant carbamazepine is the drug of choice for TN treatment. Although anti-epileptic drugs are commonly used to treat neuropathic pain in general, the efficacy of carbamazepine has been largely limited to TN. Carbamazepine, however, is associated with dose-limiting side-effects, particularly with prolonged usage. Thus, a better understanding and new treatment options are urgently warranted for this rare, but excruciating disease.

Comparison of antinociceptive effects of plain lidocaine versus lidocaine complexed with hydroxypropyl-ß-cyclodextrin in animal models of acute and persistent orofacial pain.

Herein, it was investigated whether a complex of lidocaine with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) would present a better antinociceptive profile in vivo when compared with plain lidocaine in models of orofacial pain. Plain lidocaine (LDC) and complexed lidocaine (LDC:HP-ß-CD) were initially evaluated in vitro to determine the release rate of the two formulations. Subsequently, the effect of both formulations was evaluated in independent groups of rats submitted to the orofacial formalin test, induction of facial heat hyperalgesia by capsaicin and carrageenan, and induction of facial heat and mechanical hyperalgesia by constriction of the infraorbital nerve. LDC:HP-ß-CD led to a reduction in the lidocaine release assessed in the in vitro release assay compared to plain LDC. Both formulations presented an antinociceptive effect in all models, but LDC:HP-ß-CD showed a better effect in the second phase of the formalin response, in carrageenan-induced heat hyperalgesia, and in the heat hyperalgesia associated to infraorbital nerve constriction. Our results show that complexation improved in vivo antinociceptive effects of LDC, but further studies are necessary to elucidate what properties contribute to the better effect of the complexed formulation on this models and/or what characteristics of the pain model facilitate the action of the complexed formulation.

Quality of Life and low back pain in primary caregivers of children with cerebral palsy / Qualidade de vida e dor lombar em cuidadores primários de crianças com paralisia cerebral

The aim of this study was to evaluate the quality of life of primary caregivers of children with CP, correlating with the presence of low back pain and motor impairment level of the child. For this research to have been carried out there was the participation of 55 primary caregivers that completed the questionnaires of Roland & Morris (QRM) and WHOQOL-Bref. The evaluation of children's motor impairment was measured by Gross Motor function Classification System (GMFCS). The results show that primary caregivers of children with CP had a loss in their quality of life, especially in the environmental domain and facet pain and discomfort (30.45), negative feelings (34.09), and recreation and leisure (37.27). There were no significant correlations between motor impairment in children with CP, the quality of life of their primary caregivers, and the symptoms of low back pain. However, it was observed that the average symptoms of low back pain are lower in caregivers of children with minor motor impairment (p=0.488), and that there is a significant negative correlation (r=-0.508, p<0.001) between the symptoms of back pain and quality of life of caregivers.

O objetivo deste estudo foi avaliar a qualidade de vida dos cuidadores primários de crianças com PC, correlacionando-a com a presença de dor lombar e o nível de comprometimento motor da criança. Para a realização dessa pesquisa houve a participação de 55 cuidadores primários com o preenchimento dos questionários de Roland & Morris (QRM) e WHOQOL-Bref. A avaliação do comprometimento motor das crianças foi verificada pelo Gross Motor function Classification System (GMFCS). Os resultados demonstram que os cuidadores primários de crianças com PC apresentaram um prejuízo na qualidade de vida, especialmente no domínio ambiente e nas facetas: dor e desconforto (30,45), sentimentos negativos (34,09) e recreação e lazer (37,27). Não foram observadas correlações significativas entre o comprometimento motor de crianças com PC, a qualidade de vida de seus cuidadores primários e os sintomas de dor lombar. Entretanto, observou-se que a média de sintomas de dor lombar é menor em cuidadores de crianças com menor comprometimento motor (p=0,488) e uma correlação negativa significativa (r=-0,508; p<0,001) entre os sintomas de dor lombar e a qualidade de vida do cuidadores.

Preventive and therapeutic oral administration of the pentacyclic triterpene α,ß-amyrin ameliorates dextran sulfate sodium-induced colitis in mice: the relevance of cannabinoid system.

The pentacyclic triterpene α,ß-amyrin has been previously reported as an effective compound in the treatment of several inflammatory conditions. Recent evidence indicates that α,ß-amyrin displayed its effects through interaction with the cannabinoid pathway. We assessed the anti-inflammatory effects of the α,ß-amyrin in the dextran sulfate sodium (DSS)-induced colitis in mice and investigated whether its effects were associated with the interaction with the cannabinoid system. Our results showed that the oral preventive or therapeutic treatment with α,ß-amyrin significantly reduced disease activity, body weight loss, colonic damage, as well as colonic myeloperoxidase and N-acetylglucosaminidase activities. Moreover, α,ß-amyrin decreases the colonic pro-inflammatory mediators tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and keratinocyte-derived chemokine (CXCL1/KC), while up-regulating the IL-4 levels. Additionally, we also observed that the α,ß-amyrin caused a significant reduction of the adhesion molecules mRNA expression for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), platelet cell adhesion molecule 1 (PCAM-1), ß(2)-integrin and protein expression for proliferation marker Ki67, the macrophage molecule CD68 and for adhesion molecule P-selectin. Interestingly, our results also showed that the cannabinoid receptor 1 (CB(1)), but not CB(2), pharmacological blockade significantly reversed the beneficial effects of α,ß-amyrin in DSS-induced colitis. Besides, our data demonstrated that mRNA expression for both the endocannabinoid hydrolase monoglyceride lipase 1 (MGL1) and fatty acid amide hydrolase (FAAH) were significantly reduced in the colon of α,ß-amyrin-treated mice. Altogether, these results suggest that the α,ß-amyrin might possess potential therapeutic interest for the treatment of IBD, and also provide new insights for the underlying mechanisms.

Evaluation of chemical mediators and cellular response during acute and chronic gut inflammatory response induced by dextran sodium sulfate in mice.

Inflammatory bowel disease (IBD) affects millions of people worldwide but its pathophysiology remains unclear. Therefore, experimental models of colitis have contributed crucially for the understanding of IBD, and also in the investigations for effective therapies. Herein we investigated the kinetics of inflammatory mediator production and cell infiltration during acute and chronic dextran sodium sulfate (DSS)-induced colitis. The induction phases with DSS were characterized by severe disease activity with massive colonic polymorphonuclear infiltration and increased levels of tumor necrosis factor-α (TNF-α), keratinocyte-derived chemokine (CXCL1/KC), interleukin (IL)-17 and vascular adhesion molecule-1 (VCAM-1). Interestingly, in the recovery periods, we found marked increase of anti-inflammatory mediators IL-10, IL-4, transforming growth factor-ß (TGF-ß) and cyclooxygenase 2 (COX-2) that seems be essential for the resolution of intestinal inflammation. Furthermore, nuclear factor κB (NFκB) and regulatory T cell marker forkhead box P3 (FoxP3) were increased gradually during experimental colitis, demonstrating a discrepant profile response and evident immune disbalance in the chronic phase of intestinal mucosal inflammation. Taken together, these results provide valuable information for studies on DSS-induced colitis and especially for the identification of biomarkers that predict disease course and possible therapeutic interventions.

Omega-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin-triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice.

Resolvins of the D series are generated from docosahexaenoic acid, which are enriched in fish oils and are believed to exert beneficial roles on diverse inflammatory disorders, including inflammatory bowel disease (IBD). In this study, we investigated the anti-inflammatory effects of the aspirin-triggered resolvin D1 (AT-RvD1), its precursor (17(R)-hydroxy docosahexaenoic acid [17R-HDHA]) and resolvin D2 (RvD2) in dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Our results showed that the systemic treatment with AT-RvD1, RvD2, or 17R-HDHA in a nanogram range greatly improved disease activity index, body weight loss, colonic damage, and polymorphonuclear infiltration in both colitis experimental models. Moreover, these treatments reduced colonic cytokine levels for TNF-α, IL-1ß, MIP-2, and CXCL1/KC, as well as mRNA expression of NF-κB and the adhesion molecules VCAM-1, ICAM-1, and LFA-1. Furthermore, AT-RvD1, but not RvD2 or 17R-HDHA, depended on lipoxin A4 receptor (ALX) activation to inhibit IL-6, MCP-1, IFN-γ, and TNF-α levels in bone marrow-derived macrophages stimulated with LPS. Similarly, ALX blockade reversed the beneficial effects of AT-RvD1 in DSS-induced colitis. To our knowledge, our findings showed for the first time the anti-inflammatory effects of resolvins of the D series and precursor 17R-HDHA in preventing experimental colitis. We also demonstrated the relevant role exerted by ALX activation on proresolving action of AT-RvD1. Moreover, AT-RvD1 showed a higher potency than 17R-HDHA and RvD2 in preventing DSS-induced colitis. The results suggest that these lipid mediators possess a greater efficacy when compared with other currently used IBD therapies, such as monoclonal anti-TNF, and have the potential to be used for treating IBD.

ß-Caryophyllene inhibits dextran sulfate sodium-induced colitis in mice through CB2 receptor activation and PPARγ pathway.

Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-γ (PPARγ) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-ß-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the anti-inflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPARγ. Oral treatment with BCP reduced disease activity, colonic macro- and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-α, IL-1ß, interferon-γ, and keratinocyte-derived chemokine. BCP treatment also inhibited the activation of extracellular signal-regulated kinase 1/2, nuclear factor κB, IκB-kinase α/ß, cAMP response element binding and the expression of caspase-3 and Ki-67. Moreover, BCP enhanced IL-4 levels and forkhead box P3 mRNA expression in the mouse colon and reduced cytokine levels (tumor necrosis factor-α, keratinocyte-derived chemokine, and macrophage-inflammatory protein-2) in a culture of macrophages stimulated with lipopolysaccharide. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effect of BCP. Confirming our results, AM630 reversed the beneficial effect of BCP on pro-inflammatory cytokine expression in IEC-6 cells. These results demonstrate that the anti-inflammatory effect of BCP involves CB2 and the PPARγ pathway and suggest BCP as a possible therapy for the treatment of inflammatory bowel disease.

Endothelins implicated in referred mechanical hyperalgesia associated with colitis induced by TNBS in mice.

This study evaluated the contribution of endothelins to changes in sensitivity to mechanical stimulation of the lower abdomen and hind paw associated with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. The frequency of withdrawal responses to 10 consecutive applications of von Frey probes to the lower abdomen (0.07 g) or hind paw (0.4 g) was assessed in male BALB/c mice before and after intracolonic TNBS injection (0.5 mg in 100 microL of 35% ethanol). TNBS (0.5 mg) induced referred mechanical hyperalgesia in the abdomen (response frequencies at 24 h: saline 11.0% +/- 3.1%, TNBS 48.0% +/- 6.9%) and hind paw (frequencies at 24 h: saline 12.5% +/- 4.7%, TNBS 47.1% +/- 7.1%) lasting up to 72 and 48 h, respectively. Mice receiving 1.0 or 1.5 mg TNBS assumed hunch-backed postures and became immobile during abdominal mechanical stimulation, suggestive of excessive ongoing pain. Atrasentan (ETA receptor antagonist; 10 and 30 mg/kg, i.v.) given 24 h after TNBS abolished hind paw and abdominal mechanical hyperalgesia for 2-3 h. A-192621 (ETB receptor antagonist; 20 mg/kg, i.v.) attenuated abdominal mechanical hyperalgesia at the 3 h time point only. Thus, endothelins contribute importantly to abdominal and hind paw referred mechanical hyperalgesia during TNBS-induced colitis mainly through ETA receptor-signaled mechanisms.

Endothelins as pronociceptive mediators of the rat trigeminal system: role of ETA and ETB receptors.

The trigeminal nerve is comprised of three main divisions, ophthalmic, maxillary and mandibular, each providing somatosensory innervation to distinct regions of the head, face and oral cavity. Recently, a role for endothelins in nociceptive signaling in the trigeminal system has been proposed. The present study aimed to gain better insight into the participation of the endothelin system in trigeminal nociceptive transmission. Herein ET-1 and ET-3 mRNA was detected in the rats' trigeminal ganglion (TG). Fluorescent labeling of TG neurons revealed that ET(A) and ET(B) receptors are distributed along the entire TG, but ET(A) receptor expression slightly predominated within the three divisions. TRPV1 receptors were also detected throughout the entire TG, and a significant proportion of TRPV1-positive neurons (approximately 30%) co-expressed either ET(A) or ET(B) receptors. Our behavioral data showed that ET-1 (3 to 30 pmol/site) induced overt nociceptive responses after injection into the upper lip or temporomandibular joint (TMJ) and hyperalgesic actions when applied to the eye, while ET-3 and the selective ET(B) receptor agonist IRL-1620 (each at 3 to 30 pmol/site) showed only the first two effects. Injection of BQ-123, but not BQ-788 (ET(A) and ET(B) receptor antagonists, respectively, 10 nmol/site each, 30 min beforehand), into the ipsilateral upper lip abolished ET-1 induced facial grooming, but both antagonists markedly reduced the nociceptive responses induced by ET-1 injected into the TMJ. Taken together, these findings suggest that endothelins, acting through ET(A) and/or ET(B) receptors, may play an important role in mediating pain resulting from activation of most trigeminal nerve branches.

The selective nonpeptide CXCR2 antagonist SB225002 ameliorates acute experimental colitis in mice.

Although neutrophils are strongly implicated in eliminating pathogens, excessive recruitment may cause tissue damage. Therefore, reducing cell influx during an inflammatory process may be a potential target for treating inflammatory bowel diseases (IBD). As CXCR2 is involved in neutrophil migration, this study aimed to evaluate whether the systemic therapeutic treatment with selective CXCR2 antagonist SB225002 ameliorates experimental colitis, which was induced in mice by 2,4,6-trinitrobenzene sulfonic acid (TNBS). After colitis establishment (24 h), mice were treated with SB225002. At later time-points, up to 72 h, mice were monitored for body weight loss and overall mortality. At the time of sacrifice, colonic tissues were scored for macro- and microscopic damage, and cytokine levels, myeloperoxidase (MPO) activity, and protein expression were analyzed. TNBS administration induced macro- and microscopic damage in colon tissue, leading in most cases to animal death. Curative treatment with SB225002 significantly reduced all of the parameters analyzed, leading to an improvement of inflammatory signs. SB225002 reduced neutrophil influx, MPO activity, IL-1beta, MIP-2, and keratinocyte-derived chemokine (KC) levels and the expression of vascular endothelial growth factor, inducible NO synthase, and cyclooxygenase-2 proteins into the colon tissue. Levels of IL-4 and IL-10 were increased significantly in the colons of animals treated with SB225002. Additionally, curative treatment with mouse anti-KC significantly reduced MPO activity and colonic damage. These results taken together demonstrate that a selective blockade of CXCR2 consistently reduced TNBS-induced colitis, suggesting that the use of SB225002 is a potential therapeutic approach for the treatment of IBD and other related inflammatory disorders.