Cannabidiol induces systemic analgesia through activation of the PI3Kγ/nNOS/NO/KATP signaling pathway in neuropathic mice. A KATP channel S-nitrosylation-dependent mechanism.

BACKGROUND: Cannabidiol (CBD) is the second most abundant pharmacologically active component present in Cannabis sp. Unlike Δ-9-tetrahydrocannabinol (THC), it has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential to treat anxiety and epilepsy. CBD has excellent anti-inflammatory potential and can be used to treat some types of inflammatory and neuropathic pain. In this context, the present study aimed to evaluate the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia. METHODS: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice. RESULTS: CBD produced dose-dependent antinociception after intraperitoneal injection. Selective inhibition of PI3Kγ dose-dependently reversed CBD-induced antinociception. Selective inhibition of nNOS enzymes reversed the antinociception induced by CBD, while selective inhibition of iNOS and eNOS did not alter this antinociception. However, the inhibition of cGMP production by guanylyl cyclase did not alter CBD-mediated antinociception, but selective blockade of ATP-sensitive K+ channels dose-dependently reversed CBD-induced antinociception. Inhibition of S-nitrosylation dose-dependently and completely reversed CBD-mediated antinociception. CONCLUSION: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of PI3Kγ as well as by nitric oxide and subsequent direct S-nitrosylation of KATP channels on peripheral nociceptors.

Participation of the cannabinoid system and the NO/cGMP/KATP pathway in serotonin-induced peripheral antinociception.

It has already been shown that serotonin can release endocannabinoids at the spinal cord level, culminating in inhibition of the dorsal horn. At the peripheral level, cannabinoid receptors modulate primary afferent neurons by inhibiting calcium conductance and increasing potassium conductance. Studies have shown that after the activation of opioid receptors and cannabinoids, there is also the activation of the NO/cGMP/KATP pathway, inducing cellular hyperpolarization. In this study, we evaluated the participation of the cannabinoid system with subsequent activation of the NO/cGMP/KATP pathway in the peripheral antinociceptive effect of serotonin. The paw pressure test of mice was used in animals that had their sensitivity to pain increased due to an intraplantar injection of PGE2 (2 µg). Serotonin (250 ng/paw), administered locally in the right hind paw, induced antinociceptive effect. CB1 and CB2 cannabinoid receptors antagonists, AM251 (20, 40 and 80 µg) and AM630 (25, 50 and 100 µg), respectively, reversed the serotonin-induced antinociceptive effect. MAFP (0.5 µg), an inhibitor of the FAAH enzyme that degrades anandamide, and JZL184 (3.75 µg), an inhibitor of the enzyme MAGL that degrades 2-AG, as well as the VDM11 (2.5 µg) inhibitor of anandamide reuptake, potentiated the antinociceptive effect induced by a low dose (62. 5 ng) of serotonin. In the evaluation of the participation of the NO/cGMP/KATP pathway, the antinociceptive effect of serotonin was reversed by the administration of the non-selective inhibitor of NOS isoforms L-NOarg (12.5, 25 and 50 µg) and by the selective inhibitor for the neuronal isoform LNPA (24 µg), as well as by the soluble guanylate cyclase inhibitor ODQ (25, 50 and 100 µg). Among potassium channel blockers, only Glibenclamide (20, 40 and 80 µg), an ATP-sensitive potassium channel blocker, reversed the effect of serotonin. In addition, intraplantar administration of serotonin (250 ng) was shown to induce a significant increase in nitrite levels in the homogenate of the plantar surface of the paw of mice. Taken together, these data suggest that the antinociceptive effect of serotonin occurs by activation of the cannabinoid system with subsequent activation of the NO/cGMP/KATP pathway.

Peripherally injected canabidiol reduces neuropathic pain in mice: Role of the 5-HT1A and TRPV1 receptors.

Cannabidiol (CBD) is the most abundant non-psychoactive component found in plants of the genus Cannabis. Its analgesic effect for the treatment of neuropathy has been widely studied. However, little is known about its effects in the acute treatment when Cannabidiol is administered peripherally. Because of that, this research was aimed to evaluate the antinociceptive effects of the CBD when administered peripherally for the treatment of acute neuropathic pain and check the involvement of the 5-HT1A and the TRPV1 receptors in this event. Neuropathic pain was induced with the constriction of the sciatic nerve while the nociceptive threshold was measured using the pressure test of the mouse paw. The technique used proved to be efficient to induce neuropathy, and the CBD (5, 10 and 30 µg/paw) induced the antinociception in a dosage-dependent manner. The dosage used that induced a more potent effect (30 µg/paw), did not induce a systemic response, as demonstrated by both the motor coordination assessment test (RotaRod) and the antinociceptive effect restricted to the paw treated with CBD. The administration of NAN-190 (10 µg/paw), a selective 5-HT1A receptor antagonist, and SB-366791 (16 µg/paw), a selective TRPV1 antagonist, partially reversed the CBD-induced antinociception. The results of the research suggest that the CBD produces the peripheral antinociception during the acute treatment of the neuropathic pain and it partially involved the participation of the 5-HT1A and TRPV1 receptors.

Neuroimmune circuits involved in ß-lactoglobulin-induced food allergy.

Several antigens can act as allergens eliciting IgE-mediated food allergy reactions when fed to sensitized animals. One of them is ovalbumin (OVA) which is the main allergen in egg white. Allergic mice develop aversion to OVA consumption. This aversive behavior is associated with anxiety, and it can be transferred to non-sensitized mice by injection of serum of allergic mice. However, it is yet to be determined whether altered behavior is a general component of food allergy or whether it is specific for some types of allergens. Cow's milk allergy is the most prevalent food allergy that usually begins early in life and ß-lactoglobulin (BLG) is the milk component with the highest allergenicity. In this study, we investigated behavioral and neuroimmune circuits triggered by allergic sensitization to BLG. A neuroimmune conflict between aversion and reward was observed in a model of food allergy induced by BLG intake. Mice sensitized to BLG did not present aversive behavior when BLG was used for sensitization and oral challenge. Mice allergic to BLG preferred to drink the allergen-containing solution over water even though they had high levels of specific IgE, inflammatory cells in the intestinal mucosa and significant weight loss. When sensitized to OVA and challenged with the same antigen, mice had increased levels of neuron activation in the amygdala, a brain area related to anxiety. On the other hand, when mice were sensitized to OVA and received a mixture of BLG and OVA in the oral challenge, mice preferred to drink this mixture, despite their aversion to OVA, which was associated with neuron activation in the nucleus accumbens, an area related to reward behavior. Thus, the aversive behavior observed in food allergy to OVA does not apply to all antigens and some allergens may activate the brain reward system rather than anxiety and aversion. Our study provides novel insights into the neuroimmune conflicts regarding preference and avoidance to a common antigen associated with food allergy.

Curcumin induces peripheral antinociception by opioidergic and cannabinoidergic mechanism: Pharmacological evidence.

BACKGROUND: Curcumin is one of the compounds present in plants of the genus Curcuma sp., being very used not only as condiment but also with medicinal purposes. As an analgesic, papers highlight the efficacy of curcumin in the treatment of various types of pain. AIMS: In this study we evaluated the peripheral antinociceptive effect of curcumin and by which mechanisms this effect is induced. MAIN METHODS: The mice paw pressure test was used on animals which had increased pain sensitivity by intraplantar injection of carrageenan. All the drugs were administered in the right hind paw. KEY FINDINGS: Curcumin was administered to the right hind paw animals induced antinociceptive effect. Non -selective antagonist of opioid receptors naloxone reverted the antinociceptive effect induced by curcumin. Selective antagonists for µ, δ and κ opioid receptors clocinnamox, naltrindole and nor- binaltorphimine, respectively, reverted the antinociceptive effect induced by curcumin. Bestatin, enkephalinases inhibitor that degrade peptides opioids, did not change the nociceptive response. Selective antagonists for CB1 and CB2 cannabinoid receptors, AM251 and AM630, respectively, reversed the antinociceptive effect induced by curcumin. The MAFP inhibitor of the enzyme FAAH which breaks down anandamide, JZL184, enzyme inhibitor MAGL which breaks down the 2-AG, as well as the VDM11 anandamide reuptake inhibitor potentiated the antinociceptive effect of curcumin. SIGNIFICANCE: These results suggest that curcumin possibly peripheral antinociception induced by opioid and cannabinoid systems activation and possibly for endocannabinoids and opioids release.

Tratamento do nevo de Ota em ocidentais de fototipos altos / Treatment of Nevus of Ota in patients from Western populations with high phototypes

Introdução: O nevo de Ota é nevo melanocítico dérmico localizado na pele inervada pelos segundo e terceiro ramos do nervo facial. Ocorre principalmente em asiáticos. Nosso objetivo foi avaliar a resposta terapêutica em nossa população, em que são comuns os fototipos altos e características distintas das já estudadas. Métodos: estudo retrospectivo a partir da análise dos prontuários, busca ativa dos pacientes e aplicação de questionário. Todos foram tratados com o Q-Switched Nd:YAG laser 1064 associado ou não a ponteira de 532nm, com intervalo entre cada sessão variando de um a quatro meses, duração de pulso de 10ns, spot size de 3mm, frequência de um a 3Hz e fluência de 2-12J/cm2. Resultados: de acordo com a avaliação dos médicos pesquisadores, dos sete pacientes analisados, três tiveram melhora excelente (superior a 75%), dois tiveram resposta boa (entre 51 e 75%) e um resposta moderada (entre 25 e 50%). O grau de satisfação do paciente mostrou que quatro pacientes relataram estar muito satisfeitos e três satisfeitos. Os melhores resultados foram observados em pacientes com fototipos até IV e após sete sessões. Conclusões: os QS lasers se mostraram ferramenta útil na abordagem de pacientes com nevo de Ota e fototipos elevados.

Introduction: Nevus of Ota is a dermal melanocytic nevus located in the skin area that is innervated by the second and third branches of the facial nerve. It occurs mainly in patients of Asian ethnic background. The present study was aimed at evaluating the therapeutic response in the Western population, where higher skin types and characteristics diverse from those that have already been studied are common. Methods: A retrospective study based on the analysis of medical records, an active search of patients and the application of a questionnaire. All study patients were treated with 1,064 nm Q-Switched Nd:YAG laser, with or without a 532 nm tip, with 1 to 4-month intervals between sessions, 10ns pulse duration, 3mm spot size, 1 to 3 Hz frequencies and 2 to 12 J/cm2fluences. Results: According to the research physicians' evaluation, from the seven assessed patients, three had excellent improvement (greater than 75%), two had good response (51-75%) and one had moderate response (25-50%). The analysis of the degree of patient satisfaction showed that four patients reported being very satisfied and three, satisfied. The best results were observed in patients with phototypes up to grade IV and after having undergone seven sessions. Conclusions: QS lasers have proven a useful tool for treating patients with Nevus of Ota and high skin phototypes.

Dermoscopy features for the diagnosis of furuncular myiasis.

We describe a 56-year-old Brazilian woman presenting three nodular lesions on the scalp. Dermoscopy of all lesions showed a creamy-white body with central bird's feet-like structures surrounded by a thorn crown, corresponding to the posterior segment of the Dermatobia hominis larvae. These novel dermoscopic features allowed us to easily diagnose furuncular myiasis.

Dermoscopy features for the diagnosis of furuncular myiasis / Características dermatoscópicas para diagnosticar miíase furunculóide

We describe a 56-year-old Brazilian woman presenting three nodular lesions on the scalp. Dermoscopy of all lesions showed a creamy-white body with central bird's feet-like structures surrounded by a thorn crown, corresponding to the posterior segment of the Dermatobia hominis larvae. These novel dermoscopic features allowed us to easily diagnose furuncular myiasis.

Descrevemos o caso de uma paciente brasileira de 56 anos de idade do sexo feminino que apresentou três lesões nodulares no couro cabeludo. A dermatoscopia das lesões mostrou um corpo branco-amarelado com uma estrutura central similar a pés de pássaro, circundado por uma coroa de espinhos, correspondendo ao segmento posterior das larvas de Dermatobia hominis. Estas novas características dermatoscópicas nos permitiram diagnosticar facilmente miíase furuncular.

Atendimento odontológico ao paciente diabético tipo 1: [revisão] / Dental care for type 1 diabetic patients: [review]

Diabetes mellitus (DM) é uma desordem metabólica caracterizada por uma alteração nos níveis de insulina. Há dois tipos principais de DM: tipo 1, onde há deficiência total de secreção de insulina, e tipo 2, onde há uma inadequada secreção compensatória. Dentre as alterações bucais destes pacientes estão: baixo fluxo salivar e aumento de seu pH e viscosidade, que são fatores de risco para cárie. A presente revisão da literatura tem por objetivo fornecer maiores informações sobre esta síndrome, assim, como orientar o clínico como proceder com estes pacientes.

Diabetes mellitus (DM) is a metabolic disorder characterized by deficient management of insulin. Two main types of DM exist: type 1, a total deficiency in insulin secretion, and type 2, a combination of resistance to insulin action and inadequate compensatory insulin secretion. Amongst the buccal alterations of these patients, there are reduction of the flow and increase of the saliva's acidity and viscosity, risk factors for caries. This review intends to provide not only general information about this syndrome, but also orientations how to preceed with these patients.