Environmental factors and their impact on chronic pain development and maintenance

It is more than recognized and accepted that the environment affects the physiological responses of all living things, from bacteria to superior vertebrates, constituting an important factor in the evolution of all species. Environmental influences range from natural processes such as sunlight, seasons of the year, and rest to complex processes like stress and other mood disorders, infections, and air pollution, being all of them influenced by how each creature deals with them. In this chapter, it will be discussed how some of the environmental elements affect directly or indirectly neuropathic pain, a type of chronic pain caused by a lesion or disease of the somatosensory nervous system. For that, it was considered the edge of knowledge in translational research, thus including data from human and experimental animals as well as the applicability of such findings.

Cytotoxic effect of crotoxin on cancer cells and its antitumoral effects correlated to tumor microenvironment: A review

Cancer is the second leading cause of death worldwide, and despite the effort of standard treatments, the search for new tools against this disease is necessary. Importantly, it is known that the tumor microenvironment plays a crucial role in tumor initiation, progression, and response to therapies. Therefore, studies of potential drugs that act on these components are as critical as studies regarding antiproliferative substances. Through the years, studies of several natural products, including animal toxins, have been conducted to guide the development of medical compounds. In this review, we present the remarkable antitumor activities of crotoxin, a toxin from the rattlesnake Crotalus durissus terrificus, highlighting its effects on cancer cells and in the modulation of relevant elements in the tumor microenvironment as well as the clinical trials conducted with this compound. In summary, crotoxin acts through several mechanisms of action, such as activation of apoptosis, induction of cell cycle arrest, inhibition of metastasis, and decrease of tumor growth, in different tumor types. Crotoxin also modulates tumor-associated fibroblasts, endothelial cells, and immune cells, which contribute to its antitumoral effects. In addition, preliminary clinical studies confirm the promising results of crotoxin and support its potential future use as an anticancer drug.

Crotalphine modulates microglia M1/M2 phenotypes and induces spinal analgesia mediated by opioid-cannabinoid systems

Pain is a worldwide public health problem and its treatment is still a challenge since clinically available drugs do not completely reverse chronic painful states or induce undesirable effects. Crotalphine is a 14 amino acids synthetic peptide that induces a potent and long-lasting analgesic effect on acute and chronic pain models, peripherally mediated by the endogenous release of dynorphin A and the desensitization of the transient receptor potential ankyrin 1 (TRPA1) receptor. However, the effects of crotalphine on the central nervous system (CNS) and the signaling pathway have not been investigated. Thus, the central effect of crotalphine was evaluated on the partial sciatic nerve ligation (PSNL)-induced chronic neuropathic pain model. Crotalphine (100 µg/kg, p.o.)-induced analgesia on the 14th day after surgery lasting up to 24 h after administration. This effect was prevented by intrathecal administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists. Besides that, crotalphine-induced analgesia was reversed by CTOP, nor-BNI, and naltrindole, antagonists of mu, kappa, and delta-opioid receptors, respectively, and also by the specific antibodies for β-endorphin, dynorphin-A, and met-enkephalin. Likewise, the analgesic effect of crotalphine was blocked by the intrathecal administration of minocycline, an inhibitor of microglial activation and proliferation. Additionally, crotalphine decreased the PSNL-induced IL-6 release in the spinal cord. Importantly, in vitro, crotalphine inhibited LPS-induced CD86 expression and upregulated CD206 expression in BV-2 cells, demonstrating a polarization of microglial cells towards the M2 phenotype. These results demonstrated that crotalphine, besides activating opioid and cannabinoid analgesic systems, impairs central neuroinflammation, confirming the neuromodulatory mechanism involved in the crotalphine analgesic effect.

Pain and cellular migration induced by Bothrops jararaca venom in mice selected for an acute inflammatory response: involvement of mast cells

Bothrops jararaca venom (BjV) can induce mast cell degranulation. In order to investigate the role of mast cells and the interference of the host genetic background in the inflammation induced by BjV, we have used mouse strains selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory response (AIR). Mice were pretreated with an inhibitor of mast cell degranulation, cromolyn (CROM), and injected in footpads or intraperitoneally (i.p.) with BjV. Pain was measured with von Frey hairs, cell migration in the peritoneum by flow cytometry, and reactive oxygen species (ROS) production by chemiluminescence assays. The nociceptive response to BjV was higher in AIRmax than AIRmin mice; however, this difference was abolished by pretreatment with CROM. BjV induced peritoneal neutrophil (CD11b+ GR-1+) infiltration and ROS secretion in AIRmax mice only, which were partially inhibited by CROM. Our findings evidence a role for mast cells in pain, neutrophil migration, and ROS production triggered by BjV in AIRmax mice that are more susceptible to the action of BjV.

Involvement of the Hsp70/TLR4/IL-6 and TNF-a pathways in delayed-onset muscle soreness

Delayed-onset muscle soreness (DOMS) is a very common condition in athletes and individuals not accustomed to physical activity that occurs after moderate/high-intensity exercise sessions. Activation of microglial Toll-like receptor 4 (TLR4) in the spinal cord has been described to be important for the induction and maintenance of persistent pain. Based on that, we hypothesize that 70 kilodalton heat shock protein (Hsp70), a mediator released by exercise, could activate microglial TLR4 in the spinal cord, releasing proinflammatory cytokines and contributing to the start of DOMS. In fact, we found that the knockout of TLR4, myeloid differentiation primary response 88 (MyD88), interleukin-6 (IL-6), or both TNF-a receptor 1 (TNFR1) and TNF-a receptor 2 (TNFR2) in mice prevented the development of DOMS following acute aerobic exercise in contrast to the findings in male C57BL/6 wild-type (WT) mice. Furthermore, DOMS in exercised WT mice was also prevented after pretreatment with microglia inhibitor, TLR4 antagonist and anti-Hsp70 antibody. During exercise-induced DOMS, Hsp70 mRNA, TLR4 mRNA and protein levels, as well as Iba-1 (a microglial marker), IL-6 and TNF-a protein levels, were increased in the muscle and/or spinal cord. Together, these findings suggest that Hsp70 released during exercise-induced DOMS activates the microglial TLR4/IL-6/TNF-a pathway in the spinal cord. Thus, the blockade of TLR4 activation may be a new strategy to prevent the development of DOMS before intense exercise.

Early exposure to environmental enrichment protects male rats against neuropathic pain development after nerve injury

Because environmental elements modify chronic pain development and endogenous mechanisms of pain control are still a great therapeutic source, we investigated the effects of an early exposure to environmental enrichment (EE) in a translational model of neuropathic pain. Young male rats born and bred in an enriched environment, which did not count on running wheel, underwent chronic constriction injury (CCI) of sciatic nerve. EE abolished neuropathic pain behavior 14?days after CCI. Opioid receptors' antagonism reversed EE-analgesic effect. ß-endorphin and met-enkephalin serum levels were increased only in EE-CCI group. Blockade of glucocorticoid receptors did not alter EE-analgesic effect, although corticosterone circulating levels were increased in EE animals. In the spinal cord, EE controlled CCI-induced serotonin increase. In DRG, EE blunted the expression of ATF-3 after CCI. Surprisingly, EE-CCI group showed a remarkable preservation of sciatic nerve fibers compared to NE-CCI group. This work demonstrated global effects induced by an EE protocol that explain, in part, the protective role of EE upon chronic noxious stimulation, reinforcing the importance of endogenous mechanisms in the prevention of chronic pain development.

NFKF is a synthetic fragment derived from rat hemopressin that protects mice from neurodegeneration

Previous studies suggested the pharmacological potential of rat hemopressin (PVNFKFLSH) and its shorter synthetic peptide NFKF, to protect from pilocarpine-induced seizures in mice. Orally administered NFKF was shown to be hundred times more potent than cannabidiol in delaying the first seizure induced by pilocarpine in mice. Here, using an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis we have shown that C57BL/6J mice orally administrated with NFKF (500µg/kg) presented better EAE clinical scores and improved locomotor activity compared to saline administrated control mice. NFKF blocked the production of IL-1beta and IL-6, and has high scores binding cannabinoid type 2 receptors. Therefore, NFKF is an exciting new possibility to neurodegenerative diseases therapeutics.

Crotalphine attenuates pain and neuroinflammation induced by experimental autoimmune encephalomyelitis in mice

Multiple sclerosis (MS) is a demyelinating disease of inflammatory and autoimmune origin, which induces sensory and progressive motor impairments, including pain. Cells of the immune system actively participate in the pathogenesis and progression of MS by inducing neuroinflammation, tissue damage, and demyelination. Crotalphine (CRO), a structural analogue to a peptide firstly identified in Crotalus durissus terrificus snake venom, induces analgesia by endogenous opioid release and type 2 cannabinoid receptor (CB2) activation. Since CB2 activation downregulates neuroinflammation and ameliorates symptoms in mice models of MS, it was presently investigated whether CRO has a beneficial effect in the experimental autoimmune encephalomyelitis (EAE). CRO was administered on the 5th day after immunization, in a single dose, or five doses starting at the peak of disease. CRO partially reverted EAE-induced mechanical hyperalgesia and decreased the severity of the clinical signs. In addition, CRO decreases the inflammatory infiltrate and glial cells activation followed by TNF-α and IL-17 downregulation in the spinal cord. Peripherally, CRO recovers the EAE-induced impairment in myelin thickness in the sciatic nerve. Therefore, CRO interferes with central and peripheral neuroinflammation, opening perspectives to MS control.

Crotoxin conjugated to SBA-15 nanostructured mesoporous silica induces long-last analgesic effect in the neuropathic pain model in mice

Neuropathic pain is a disease caused by structural and functional plasticity in central and peripheral sensory pathways that produce alterations in nociceptive processing. Currently, pharmacological treatment for this condition remains a challenge. Crotoxin (CTX), the main neurotoxin of Crotalus durissus terrificus rattlesnake venom, has well described prolonged anti-inflammatory and antinociceptive activities. In spite of its potential benefits, the toxicity of CTX remains a limiting factor for its use. SBA-15 is an inert nanostructured mesoporous silica that, when used as a vehicle, may reduce toxicity and potentiate the activity of different compounds. Based on this, we propose to conjugate crotoxin with SBA-15 (CTX:SBA-15) in order to investigate if when adsorbed to silica, CTX would have its toxicity reduced and its analgesic effect enhanced in neuropathic pain induced by the partial sciatic nerve ligation (PSNL) model. SBA-15 enabled an increase of 35% of CTX dosage. Treatment with CTX:SBA-15 induced a long-lasting reduction of mechanical hypernociception, without modifying the previously known pathways involved in antinociception. Moreover, CTX:SBA-15 reduced IL-6 and increased IL-10 levels in the spinal cord. Surprisingly, the antinociceptive effect of CTX:SBA-15 was also observed after oral administration. These data indicate the potential use of the CTX:SBA-15 complex for neuropathic pain control and corroborates the protective potential of SBA-15

Non-peptidergic nociceptive neurons are essential for mechanical inflammatory hypersensitivity in mice

Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.

Involvement of the Hsp70/TLR4/IL-6 and TNF-α pathways in delayed-onset muscle soreness

Delayed-onset muscle soreness (DOMS) is a very common condition in athletes and individuals not accustomed to physical activity that occurs after moderate/high-intensity exercise sessions. Activation of microglial Toll-like receptor 4 (TLR4) in the spinal cord has been described to be important for the induction and maintenance of persistent pain. Based on that, we hypothesize that 70 kilodalton heat shock protein (Hsp70), a mediator released by exercise, could activate microglial TLR4 in the spinal cord, releasing proinflammatory cytokines and contributing to the start of DOMS. In fact, we found that the knockout of TLR4, myeloid differentiation primary response 88 (MyD88), interleukin-6 (IL-6), or both TNF-a receptor 1 (TNFR1) and TNF-a receptor 2 (TNFR2) in mice prevented the development of DOMS following acute aerobic exercise in contrast to the findings in male C57BL/6 wild-type (WT) mice. Furthermore, DOMS in exercised WT mice was also prevented after pretreatment with microglia inhibitor, TLR4 antagonist and anti-Hsp70 antibody. During exercise-induced DOMS, Hsp70 mRNA, TLR4 mRNA and protein levels, as well as Iba-1 (a microglial marker), IL-6 and TNF-a protein levels, were increased in the muscle and/or spinal cord. Together, these findings suggest that Hsp70 released during exercise-induced DOMS activates the microglial TLR4/IL-6/TNF-a pathway in the spinal cord. Thus, the blockade of TLR4 activation may be a new strategy to prevent the development of DOMS before intense exercise.

Early exposure to environmental enrichment protects male rats against neuropathic pain development after nerve injury

Because environmental elements modify chronic pain development and endogenous mechanisms of pain control are still a great therapeutic source, we investigated the effects of an early exposure to environmental enrichment (EE) in a translational model of neuropathic pain. Young male rats born and bred in an enriched environment, which did not count on running wheel, underwent chronic constriction injury (CCI) of sciatic nerve. EE abolished neuropathic pain behavior 14?days after CCI. Opioid receptors' antagonism reversed EE-analgesic effect. ß-endorphin and met-enkephalin serum levels were increased only in EE-CCI group. Blockade of glucocorticoid receptors did not alter EE-analgesic effect, although corticosterone circulating levels were increased in EE animals. In the spinal cord, EE controlled CCI-induced serotonin increase. In DRG, EE blunted the expression of ATF-3 after CCI. Surprisingly, EE-CCI group showed a remarkable preservation of sciatic nerve fibers compared to NE-CCI group. This work demonstrated global effects induced by an EE protocol that explain, in part, the protective role of EE upon chronic noxious stimulation, reinforcing the importance of endogenous mechanisms in the prevention of chronic pain development.

NFKF is a synthetic fragment derived from rat hemopressin that protects mice from neurodegeneration

Previous studies suggested the pharmacological potential of rat hemopressin (PVNFKFLSH) and its shorter synthetic peptide NFKF, to protect from pilocarpine-induced seizures in mice. Orally administered NFKF was shown to be hundred times more potent than cannabidiol in delaying the first seizure induced by pilocarpine in mice. Here, using an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis we have shown that C57BL/6J mice orally administrated with NFKF (500µg/kg) presented better EAE clinical scores and improved locomotor activity compared to saline administrated control mice. NFKF blocked the production of IL-1beta and IL-6, and has high scores binding cannabinoid type 2 receptors. Therefore, NFKF is an exciting new possibility to neurodegenerative diseases therapeutics.

The crotoxin: SBA-15 complex down-regulates the Incidence and Intensity of experimental autoimmune encephalomyelitis through peripheral and central actions

Crotoxin (CTX), the main neurotoxin from Crotalus durissus terrificus snake venom, has anti-inflammatory, immunomodulatory and antinociceptive activities. However, the CTX-induced toxicity may compromise its use. Under this scenario, the use of nanoparticle such as nanostructured mesoporous silica (SBA-15) as a carrier might become a feasible approach to improve CTX safety. Here, we determined the benefits of SBA-15 on CTX-related neuroinflammatory and immunomodulatory properties during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis that replicates several histopathological and immunological features observed in humans. We showed that a single administration of CTX:SBA-15 (54 μg/kg) was more effective in reducing pain and ameliorated the clinical score (motor impairment) in EAE animals compared to the CTX-treated EAE group; therefore, improving the disease outcome. Of interest, CTX:SBA-15, but not unconjugated CTX, prevented EAE-induced atrophy and loss of muscle function. Further supporting an immune mechanism, CTX:SBA-15 treatment reduced both recruitment and proliferation of peripheral Th17 cells as well as diminished IL-17 expression and glial cells activation in the spinal cord in EAE animals when compared with CTX-treated EAE group. Finally, CTX:SBA-15, but not unconjugated CTX, prevented the EAE-induced cell infiltration in the CNS. These results provide evidence that SBA-15 maximizes the immunomodulatory and anti-inflammatory effects of CTX in an EAE model; therefore, suggesting that SBA-15 has the potential to improve CTX effectiveness in the treatment of MS.

Crotoxin conjugated to SBA-15 nanostructured mesoporous silica induces long-last analgesic effect in the neuropathic pain model in mice

Neuropathic pain is a disease caused by structural and functional plasticity in central and peripheral sensory pathways that produce alterations in nociceptive processing. Currently, pharmacological treatment for this condition remains a challenge. Crotoxin (CTX), the main neurotoxin of Crotalus durissus terrificus rattlesnake venom, has well described prolonged anti-inflammatory and antinociceptive activities. In spite of its potential benefits, the toxicity of CTX remains a limiting factor for its use. SBA-15 is an inert nanostructured mesoporous silica that, when used as a vehicle, may reduce toxicity and potentiate the activity of different compounds. Based on this, we propose to conjugate crotoxin with SBA-15 (CTX:SBA-15) in order to investigate if when adsorbed to silica, CTX would have its toxicity reduced and its analgesic effect enhanced in neuropathic pain induced by the partial sciatic nerve ligation (PSNL) model. SBA-15 enabled an increase of 35% of CTX dosage. Treatment with CTX:SBA-15 induced a long-lasting reduction of mechanical hypernociception, without modifying the previously known pathways involved in antinociception. Moreover, CTX:SBA-15 reduced IL-6 and increased IL-10 levels in the spinal cord. Surprisingly, the antinociceptive effect of CTX:SBA-15 was also observed after oral administration. These data indicate the potential use of the CTX:SBA-15 complex for neuropathic pain control and corroborates the protective potential of SBA-15

Non-peptidergic nociceptive neurons are essential for mechanical inflammatory hypersensitivity in mice

Small nerve fibers that bind the isolectin B4 (IB4+ C-fibers) are a subpopulation of primary afferent neurons that are involved in nociceptive sensory transduction and do not express the neuropeptides substance P and calcitonin-gene related peptide (CGRP). Several studies have attempted to elucidate the functional role of IB4+-nociceptors in different models of pain. However, a functional characterization of the non-peptidergic nociceptors in mediating mechanical inflammatory hypersensitivity in mice is still lacking. To this end, in the present study, the neurotoxin IB4-Saporin (IB4-Sap) was employed to ablate non-peptidergic C-fibers. Firstly, we showed that intrathecal (i.t.) administration of IB4-Sap in mice depleted non-peptidergic C-fibers, since it decreased the expression of purinoceptor 3 (P2X3) and transient receptor potential cation channel subfamily V member 1 (TRPV1) in the dorsal root ganglia (DRGs) as well as IB4 labelling in the spinal cord. Non-peptidergic C-fibers depletion did not alter the mechanical nociceptive threshold, but it inhibited the mechanical inflammatory hypersensitivity induced by glial cell-derived neurotrophic factor (GDNF), but not nerve growth factor (NGF). Depletion of non-peptidergic C-fibers abrogated mechanical inflammatory hypersensitivity induced by carrageenan. Finally, it was found that the inflammatory mediators PGE2 and epinephrine produced a mechanical inflammatory hypersensitivity that was also blocked by depletion of non-peptidergic C-fibers. These data suggest that IB4-positive nociceptive nerve fibers are not involved in normal mechanical nociception but are sensitised by inflammatory stimuli and play a crucial role in mediating mechanical inflammatory hypersensitivity.

Advanced glycation endproducts produced by in vitro glycation of type I collagen modulate the functional and secretory behavior of dorsal root ganglion cells cultivated in two-dimensional system

Advanced glycation end-products (AGEs) are proteins/lipids that are glycated upon sugar exposure and are often increased during inflammatory diseases such as osteoarthritis and neurodegenerative disorders. Here, we developed an extracellular matrix (ECM) using glycated type I collagen (ECM-GC), which produced similar levels of AGEs to those detected in the sera of arthritic mice. In order to determine whether AGEs were sufficient to stimulate sensory neurons, dorsal root ganglia (DRGs) cells were cultured on ECM-GC or ECM-NC-coated plates. ECM-GC or ECM-NC were favorable for DRG cells expansion. However, ECM-GC cultivated neurons displayed thinner F-actin filaments, rounded morphology, and reduced neuron interconnection compared to ECM-NC. In addition, ECM-GC did not affect RAGE expression levels in the neurons, although induced rapid p38, MAPK and ERK activation. Finally, ECM-GC stimulated the secretion of nitrite and TNF-α by DRG cells. Taken together, our in vitro glycated ECM model suitably mimics the in vivo microenvironment of inflammatory disorders and provides new insights into the role of ECM impairment as a nociceptive stimulus.

Avaliação do efeito da crotoxina conjugada a sílica nanoestruturada SBA-15 na dor crônica: aspectos imunomodulatórios, anti-inflamatórios e antinociceptivos / Evaluating the effect of crotoxin conjugated nanostructured silica SBA-15 in chronic pain: immunomodulatory, antinociceptive and anti-inflammatory aspects

Chronic pain is among the most disabling and costly afflictions, has a negative effect on physical and psychological health, daily activities, employment and economic well-being, being recognised as an important healty public problematic. Chronic pain is characterized by sensorial alterations (hyperalgesia and allodynia) and other symptoms such as lethargy, depression and anxiety. These sickness behaviours with chronic pain are suggestive of a subjacent immune activity. The persistent pain is often associated with some other disease, such as multiple sclerosis [MS], an example of autoimmune disorder. MS is one of the most common neurological disorders diagnosed in young adults; this neuroinflammatory autoimmune disease have common symptoms such as, fatigue, visual impairment, sensory impairment, weakness, urinary dysfunction, spasticity, incoordination, cognitive dysfunction and pain. Despite the advances in research related to chronic pain and multiple sclerosis, the treatments still presenting great difficulties, since that the administration of pharmacos there is no complete reversal of symptoms or cure. Moreover, there are continual reports of patients suffering from their undesirable adverse effects. Therefore, it is necessary to study new drugs for the treatment of these pathologies. It is known that the crotoxin (CTX) despite the toxic effect, in low doses, presents immunomodulatory, anti-inflammatory, antitumor and antinociceptive effect, revealing its potential for the clinical treatment of several pathologies. It is also known that the nanostructured SBA-15 silica, a protective vehicle of biomolecules, may decrease toxicity and increase the immune response to distinct immunogens including vaccins. Thus, the objective of this study was to evaluate whether crotoxin, when conjugated to SBA-15, has its toxic effect reduced and its antinociceptive e immunomodulatory effect enhanced, evaluating its interference on the inflammatory response in the Partial Injury models of the Sciatic Nerve (PSNL) and Experimental Autoimmune Encephalomyelitis (EAE). The results show that the CTX:SBA-15 complex has analgesic effect in both models of chronic pain and reduces the incidence and intensity of clinical signs (motor defict) induced by the EAE model. Further, the treatment with the complex modulates neuroinflammation by reducing the expression of glial cell markers and the expression of proinflammatory cytokines in the CNS. Summarizing, the present work expands the knowledge of the effect of CTX, silica SBA-15 and complex CTX:SBA-15, showing that silica has a protective mechanism, which allows the use of oral CTX. Our data also significantly increase the possibilities of using silica, demonstrating its capacity as a protective vehicle for drugs.

A dor crônica quando comparada a outras doenças é uma das mais incapacitantes, apresentando efeito negativo sobre a saúde física e psicológica, atividades de vida diária, emprego e ao bem-estar econômico, gerando altos custos aos serviços de saúde, sendo considerado, portanto um problema de saúde pública. A dor crônica caracteriza-se por apresentar alterações sensoriais (hipernocicepção e alodinia) e outros sintomas como letargia, depressão e ansiedade, o que caracteriza uma resposta clássica de doença sistêmica e sugere atividade imune subjacente. Esta condição pode estar frequentemente associada a algumas outras doenças, como a esclerose múltipla [EM], exemplo de desordem de origem autoimune; essa é uma das doenças neurológicas mais comuns diagnosticada em jovens adultos, que desenvolvem doença autoimune neuroinflamatória. Os sintomas mais comuns incluem fadiga, déficit visual e sensorial, fraqueza, disfunções urinárias, espasticidade, problemas de coordenação motora e cognitivos, dor, entre outros. Apesar dos avanços das pesquisas relacionadas a estas doenças, o tratamento ainda apresenta grandes dificuldades, pois mesmo com a administração de fármacos não há reversão completa dos sintomas ou cura; além disso, são constantes os relatos de pacientes que sofrem com efeitos adversos indesejáveis decorrente das terapias. Assim, faz-se necessário o estudo de novas drogas para o tratamento desta doença. Sabe-se que a crotoxina (CTX) apesar do efeito tóxico, em baixas doses apresenta efeito imunomodulatório, antiinflamatório, antitumoral e antinociceptivo, revelando seu potencial para o tratamento clinico de diversas doenças. Por sua vez, a sílica nanoestruturada SBA-15 quando utilizada como veiculo protetor de biomoléculas pode diminuir a toxicidade e favorecer a resposta imunológica a diversos imunógenos, incluindo vacinas. Assim, o objetivo deste trabalho foi avaliar se a CTX, quando conjugada à sílica SBA-15, tem seu efeito tóxico diminuído e seu efeito antinociceptivo e imunomodulatório aumentado, avaliando ainda sua interferência sobre a inflamação nos modelos de Lesão Parcial do Nervo Isquiático (PSNL) e Encefalomielite Autoimune Experimental (EAE). Os resultados obtidos mostram que, o complexo CTX:SBA-15 apresenta efeito analgésico nos dois modelos de dor crônica e reduz a incidência e a intensidade dos sinais clínicos (defict motor) induzido pelo modelo de EAE. O tratamento com o complexo ainda, modula a neuroinflamaçao, reduzindo a expressão de marcadores de celulas gliais e a expressão de citocinas próinflamatótias no SNC. O presente trabalho amplia o conhecimento do efeito da CTX, da sílica SBA-15 e do complexo CTX:SBA-15, demonstrando ainda que a sílica apresenta mecanismo protetor, o que permite a utilização da CTX por via oral. Nossos dados ampliam, ainda, de maneira significativa, as possibilidades de uso da sílica, demonstrando sua capacidade como veículo protetor de fármacos.