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.

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.

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.

Distinct environmental enrichment protocols reduce anxiety but differentially modulate pain sensitivity in rats.

Environmental enrichment (EE) can alter anxiety as well as perception of nociceptive stimuli, suggesting a relationship between well-being and analgesia. Considering that, we aimed to evaluate the influence of different EE types on anxiety and peripheral pain sensitivity of male Wistar rats. Animals were submitted to two different types of EE: On the first one, animals were housed in standard size cages after weaning and received three different objects, one type per week, on a regular basis (simple EE - sEE). On the second one, animals were born in an already enriched environment and, after five weeks, were housed in larger cages and received five different objects, three of each type per week, on a regular basis (improved EE - iEE). Control group remained in standard cages and did not receive objects. Within 7 weeks of life, anxiety and thermal sensibility were evaluated using elevated plus maze and tail flick tests, respectively. Mechanical hyperalgesia was analyzed in the presence of acute and chronic noxious stimuli by paw pressure test. Both EE protocols tested were effective in diminish anxiety but they did not alter thermal sensibility. On the other hand, sEE protocol did not alter acute and chronic induced mechanical hypersensitivity, whereas iEE completely abolished such pain behavior, even without exercise wheel as part of the enrichment. Our results show that specific parameters (anxiety and pain sensitivity) can be differentially modulated depending on EE protocol used, making possible the implementation of welfare to experimental animals in pain research.

Local inflammatory reaction induced by Scolopendra viridicornis centipede venom in mice.

Centipede envenomation is generally mild, and human victims usually manifest burning pain, erythema and edema. Despite the abundance and ubiquity of these animals, centipede venom has been poorly characterized in literature. For this reason, the aim of this work was to investigate local inflammatory features induced by Scolopendra viridicornis centipede envenomation in mice, evaluating edema formation, leukocyte infiltration, production of inflammatory mediators, and also performing histological analysis. The highest edematogenic activity induced by the venom, determined by plethysmometry, was noticed 0.5 h after injection in mice footpad. At 24 h, edema was still detected in animals that received 15 and 60 µg of venom, and at 48 h, only in animals injected with 60 µg of venom. In relation to leukocyte count, S. viridicornis venom induced cell recruitment, mainly neutrophils and monocytes/macrophages, in all doses and time periods analyzed in comparison with PBS-injected mice. An increase in lymphocytes was detected especially between 1 and 24 h at 60 µg dose. Besides, eosinophil recruitment was observed mainly for 15 and 60 µg doses in early time periods. Edema formation and cell recruitment were also confirmed by histological analysis. Moreover, S. viridicornis venom stimulated the release of IL-6, MCP-1, KC, and IL-1ß. Conversely, S. viridicornis venom did not induce the release of detectable levels of TNF-α. We demonstrated that the edematogenic activity induced by S. viridicornis venom was of rapid onset, and the venom stimulated secretion of pro-inflammatory mediators which contribute to the inflammatory reaction induced by S. viridicornis venom in an experimental model.