RESUMO

Aristotelia chilensis or "maqui" is a tree native to Chile used in the folk medicine of the Mapuche people as an anti-inflammatory agent for the treatment of digestive ailments, fever, and skin lesions. Maqui fruits are black berries which are considered a "superfruit" with notable potential health benefits, promoted to be an antioxidant, cardioprotective, and anti-inflammatory. Maqui leaves contain non-iridoid monoterpene indole alkaloids which have previously been shown to act on nicotinic acetylcholine receptors, potassium channels, and calcium channels. Here, we isolated a new alkaloid from maqui leaves, now called makomakinol, together with the known alkaloids aristoteline, hobartine, and 3-formylindole. Moreover, the polyphenols quercetine, ethyl caffeate, and the terpenes, dihydro-ß-ionone and terpin hydrate, were also obtained. In light of the reported analgesic and anti-nociceptive properties of A. chilensis, in particular a crude mixture of alkaloids containing aristoteline and hobartinol (PMID 21585384), we therefore evaluated the activity of aristoteline and hobartine on NaV1.8, a key NaV isoform involved in nociception, using automated whole-cell patch-clamp electrophysiology. Aristoteline and hobartine both inhibited Nav1.8 with an IC50 of 68 ± 3 µM and 54 ± 1 µM, respectively. Hobartine caused a hyperpolarizing shift of the voltage-dependence of the activation, whereas aristoteline did not change the voltage-dependence of the activation or inactivation. The inhibitory activity of these alkaloids on NaV channels may contribute to the reported analgesic properties of Aristotelia chilensis used by the Mapuche people.

Assuntos

RESUMO

While current research highlights the role of Nav1. 8 sensory neurons from the peripheral nervous system, the anatomical and physiological characterization of encephalic Nav1.8 neurons remains unknown. Here, we use a Cre/fluorescent reporter mouse driven by the Nav1.8 gene promoter to reveal unexpected subpopulations of transiently-expressing Nav1.8 neurons within the limbic circuitry, a key mediator of the emotional component of pain. We observed that Nav1.8 neurons from the bed nuclei of the stria terminalis (BST), amygdala, and the periaqueductal gray (vPAG) are sensitive to noxious stimuli from an experimental model of chronic inflammatory pain. These findings identify a novel role for central Nav1.8 neurons in sensing nociception, which could be researched as a new approach to treating pain disorders.

RESUMO

Drimys winteri J.R.Forst. & G.Forst, a South American evergreen shrub that is used by the Mapuche people for treatment of several painful conditions, contains polygodial, a lipophilic drimane-type sesquiterpene dialdehyde with known activity at transient receptor potential channel family members including TRPA1 and TRPV1. We sought to assess the activity of polygodial at NaV1.7 and NaV1.8, two key isoforms of the voltage-gated sodium channel family involved in nociception. Polygodial was isolated from D. winteri by thin-layer chromatography and analysed structurally by 1 D and 2 D nuclear magnetic resonance (NMR) spectroscopy. Activity at heterologously expressed NaV1.7 and NaV1.8 was assessed using automated whole-cell patch-clamp electrophysiology. Here, we show that polygodial inhibits members of the voltage-gated sodium channel family, specifically NaV1.7 and NaV1.8, without changing the voltage-dependence of activation or inactivation. Activity of polygodial at voltage-gated sodium channels may contribute to the previously reported antinociceptive properties.

Assuntos

RESUMO

Recently the voltage-gated sodium (Nav) channels began to be studied as possible targets for analgesic drugs. In addition, specific Nav 1.8 blockers are currently being used to treat some types of chronic pain pathologies such as neuropathies and fibromyalgia. Nav 1.8+ fibers convey nociceptive information to brain structures belonging to the limbic system, which is involved in the pathophysiology of major depressive disorders. From this, using a model of chronic social defeat stress (SDS) and intrathecal injections of Nav 1.8 antisense, this study investigated the possible involvement of Nav 1.8+ nociceptive fibers in SDS- induced hyperalgesia in C57/BL mice. Our results showed that SDS induced a depressive-like behavior of social avoidance and increased the sensitivity to mechanical (electronic von Frey test) and chemical (capsaicin test) nociceptive stimuli. We also showed that intrathecal injection of Nav 1.8 antisense reversed the SDS-induced hyperalgesia as demonstrated by both, mechanical and chemical nociceptive tests. We confirmed the antisense efficacy and specificity in a separate no-defeated cohort through real-time PCR, which showed a significant reduction of Nav 1.8 mRNA and no reduction of Nav 1.7 and Nav 1.9 in the L4, L5 and L6 dorsal root ganglia (DRG). The present study advances the understanding of SDS-induced hyperalgesia, which seems to be dependent on Nav 1.8+ nociceptive fibers.

Assuntos

RESUMO

BACKGROUND: Experimental studies suggest that testosterone reduces the nociceptive response after inflammatory and neuropathic stimuli, however the underlying mechanisms have not been fully elucidated. The aims of this study were to evaluate the effect of peripheral blockade of testosterone on pain behaviour and on expression levels of the genes that encode the NaV1.7 and NaV1.8 channels, in dorsal root ganglia in an acute postoperative pain model, as well as the influence of androgen blockade on the expression of these genes. METHODS: Postoperative pain was induced by a plantar incision and the study group received flutamide to block testosterone receptor. The animals were submitted to behavioural evaluation preoperatively, 2 h after incision, and on the 1st, 2nd, 3rd and 7th postoperative days. Von Frey test was used to evaluate paw withdrawal threshold after mechanical stimuli and the guarding pain test to assess spontaneous pain. The expression of the genes encoding the sodium channels at the dorsal root ganglia was determined by real time quantitative polymerase chain reaction. RESULTS: Animals treated with flutamide presented lower paw withdrawal threshold at the 1st, 2nd, 3rd, and 7th postoperative days. The guarding pain test showed significant decrease in the flutamide group at 2 h and on the 3rd and 7th postoperative days. No difference was detected between the study and control groups for the gene expression. CONCLUSIONS: Our data suggest an antinociceptive effect of androgens following plantar incision. The expression of genes that encode voltage-gated sodium channels was not influenced by androgen blockade.

Assuntos

RESUMO

Lysophosphatidic acid or LPA is a phospholipid which has been extensively linked to the generation and maintenance of pain. Several ion channels have also been shown to participate in this pathological process but the link between LPA and these proteins in pain has just recently gained interest. In this respect, the field has advanced by determining the molecular mechanisms by which LPA promotes changes in the function of some ion channels. While some of the actions of LPA include modulation of signaling pathways associated to its specific receptors, other include a direct interaction with a region in the structure of ion channels to affect their gating properties. Here, we focus on the known effects of LPA on some transient receptor potential, sodium, potassium, and calcium channels. As the field moves forward, mechanisms are unveiled with the hope of understanding the underlying causes of pain in order to target these and control this pathophysiological state.