Dietary supplementation of gingerols- and shogaols-enriched ginger root extract attenuate pain-associated behaviors while modulating gut microbiota and metabolites in rats with spinal nerve ligation.

Neuroinflammation is a central factor in neuropathic pain (NP). Ginger is a promising bioactive compound in NP management due to its anti-inflammatory property. Emerging evidence suggests that gut microbiome and gut-derived metabolites play a key role in NP. We evaluated the effects of two ginger root extracts rich in gingerols (GEG) and shogaols (SEG) on pain sensitivity, anxiety-like behaviors, circulating cell-free mitochondrial DNA (ccf-mtDNA), gut microbiome composition, and fecal metabolites in rats with NP. Sixteen male rats were divided into four groups: sham, spinal nerve ligation (SNL), SNL+0.75%GEG in diet, and SNL+0.75%SEG in diet groups for 30 days. Compared to SNL group, both SNL+GEG and SNL+SEG groups showed a significant reduction in pain- and anxiety-like behaviors, and ccf-mtDNA level. Relative to the SNL group, both SNL+GEG and SNL+SEG groups increased the relative abundance of Lactococcus, Sellimonas, Blautia, Erysipelatoclostridiaceae, and Anaerovoracaceae, but decreased that of Prevotellaceae UCG-001, Rikenellaceae RC9 gut group, Mucispirillum and Desulfovibrio, Desulfovibrio, Anaerofilum, Eubacterium siraeum group, RF39, UCG-005, Lachnospiraceae NK4A136 group, Acetatifactor, Eubacterium ruminantium group, Clostridia UCG-014, and an uncultured Anaerovoracaceae. GEG and SEG had differential effects on gut-derived metabolites. Compared to SNL group, SNL+GEG group had higher level of 1'-acetoxychavicol acetate, (4E)-1,7-Bis(4-hydroxyphenyl)-4-hepten-3-one, NP-000629, 7,8-Dimethoxy-3-(2-methyl-3-buten-2-yl)-2H-chromen-2-one, 3-{[4-(2-Pyrimidinyl)piperazino]carbonyl}-2-pyrazinecarboxylic acid, 920863, and (1R,3R,7R,13S)-13-Methyl-6-methylene-4,14,16-trioxatetracyclo[11.2.1.0∼1,10∼.0∼3,7∼]hexadec-9-en-5-one, while SNL+SEG group had higher level for (±)-5-[(tert-Butylamino)-2'-hydroxypropoxy]-1_2_3_4-tetrahydro-1-naphthol and dehydroepiandrosteronesulfate. In conclusion, ginger is a promising functional food in the management of NP, and further investigations are necessary to assess the role of ginger on gut-brain axis in pain management.

Limonene, a food additive, and its active metabolite perillyl alcohol improve regeneration and attenuate neuropathic pain after peripheral nerve injury: Evidence for IL-1ß, TNF-α, GAP, NGF and ERK involvement.

BACKGROUND: Limonene (LIM) and its main metabolite perillyl alcohol (POH) are ingredients found in food with promising chemical entities due to their pharmacological profile. In this study, we hypothesized that LIM and POH are two molecules capable of accelerating the regenerative process and alleviating neuropathic pain. METHODS: Animals were treated daily (LIM, POH and saline) for 28 days and during this period evaluated for mechanical hyperalgesia, astrocyte participation by immunofluorescence for GFAP, and ELISA was used to quantify IL-1ß and TNF-α in the spinal cord. Western blot analysis of the following proteins was also performed: GFAP, GAP-43, NGF and ERK. For motor deficit analysis, tests were performed to assess hind paw muscle strength and footprints through gait (SFI). RESULTS: Both POH and LIM accelerated the regenerative process and improved motor deficits comparing to positive control; however, POH was more effective, particularly between the 2nd and 3rd week after the nerve injury, increasing GAP-43, NGF and the phosphorylated ERK immunocontent. Moreover, POH and LIM were able to reduce hyperalgesia and astrocytosis. CONCLUSIONS: Both substances, LIM and POH, improved the regeneration process and sensory and motor function recovery in the PNI model in mice by mitigating the inflammatory reactions and up-regulating the neurotrophic process.

[Subcutaneous botulinum toxin in the treatment of peripheral neuropathic pain]. / Toxina botulínica subcutánea en el tratamiento del dolor neuropático periférico.

Neuropathic pain impairs quality of life in affected individuals and poses a challenge to clinicians due to the complexity of its treatment and frequent therapeutic failures. We present 4clinical cases of chronic neuropathic pain (LANSS ≥ 19), refractory to conservative treatment (meralgia paraesthetica, post-surgical pain and 2surgical scars). Subcutaneous botulinum toxin type A was infiltrated periodically over the painful area. All patients experienced subjective improvement in pain and improvement measured by the visual analogic scale. Pain relief started at 5-21 days and continued up to 1.5-3 months, and up to 9 months in one patient. Pain that reappeared was of lower intensity in 3patients and was reduced in area in 2patients.

Effects of a nutraceutical combination in patients with chronic lumbosacral radicular pain.

Drugs used for the treatment of chronic lumbosacral radicular pain (LRP) may have frequent adverse effects leading to medication withdrawal. The use of add-on nutraceuticals, which have no side effects, may therefore play a role in LRP treatment. We performed a six-week, single-center, open label prospective uncontrolled clinical study to evaluate the effect of a nutraceutical combination (Noxiall®) used as an add-on therapy in patients with chronic LRP. Fifteen patients were treated with Noxiall® twice a day for 10 consecutive days, followed by once-daily administration up to the end of the six-week treatment. The participants were evaluated at two visits (before-after), when primary and secondary outcomes were assessed. We found a significant reduction in pain severity post-treatment, as assessed using a numerical rating scale (p= 0.03), and a significant reduction in painkiller intake (p=0.03). Nutraceuticals could be a complementary therapy for chronic LRP.

Gluten neuropathy: prevalence of neuropathic pain and the role of gluten-free diet.

BACKGROUND AND AIM: Peripheral neuropathy is a common extraintestinal manifestation of gluten sensitivity (gluten neuropathy). We aimed to establish the prevalence of neuropathic pain in patients with otherwise idiopathic PN and gluten sensitivity (positive antigliadin, endomysial, and/or transglutaminase antibodies, with or without enteropathy) and to describe any contributory factors. METHODS: All consecutive patients with gluten neuropathy (GN) attending a specialist gluten/neurology clinic were invited to participate. Pain was assessed via the DN4 questionnaire and the visual analog scale. Overall Neuropathy Limitations Scale was used to assess the severity of neuropathy. The Mental Health Index (MHI-5) was used to measure participants' general mental health status. RESULTS: In total, 60 patients (76.7% males, mean age 69.9 ± 10.1 years) with GN were recruited. Neuropathic pain was present in 33 patients (55.0%). Comparison between groups of painful and not painful GN did not show significant differences regarding age, gender, neuropathy severity and neuropathy type. Patients with painless GN were more likely to be on a strict gluten-free diet (55.6 versus 21.2%, p = 0.006). Patients with painful GN presented with significantly worse MHI-5 score (75.9 ± 13.8 versus 87.4 ± 8.1, p < 0.001). Multivariate analysis showed that, after adjusting for age, gender and MHI-5, strict gluten-free diet was associated with lowering the odds of peripheral neuropathic pain by 88.7% (95% CI 47.2-97.6%, p = 0.006). CONCLUSION: Neuropathic pain is very prevalent in GN and is associated with poorer mental health status. Strict gluten-free diet might be protective as it is associated with a significant reduction of the odds of peripheral neuropathic pain associated to GN.

Preventive and alleviative effects of the dual enkephalinase inhibitor (Denki) PL265 in a murine model of neuropathic pain.

Neuropathic pain remains difficult to treat due to the involvement of various pathophysiological mechanisms in its pathogeny. Among the different opioidergic systems the enkephalinergic one is primarily recruited via activation of delta opioid receptor (DOP) in chronic pain and of mu opioid receptor (MOP) in acute pain. To investigate the role of their endogenous ligands Met and Leu-enkephalin in neuropathic pain control, a dual inhibitor of their degrading enzymes, PL265, which acts restrictively at the level of peripheral nociceptors, was administered per os to assess its efficacy in pain prevention and alleviation using a partial sciatic nerve ligation model (PSNL) in mice. We demonstrated here that the pre-injury oral administration of PL265 (50mg/kg) during the 9 days of neuropathy development reduces thermal hyperalgesia and mechanical allodynia for two weeks after the end of treatment. The repeated administration (50mg/kg daily, during 10 days) does not induce tolerance. Therefore, protecting the enkephalins released at the peripheral level during neuropathic pain with oral PL265 seems to be a promising approach to prevent and alleviate the painful symptoms of neuropathic pain in humans without the unwanted effects of exogenous opiates such as morphine.

Targeting inflammation as a treatment modality for neuropathic pain in spinal cord injury: a randomized clinical trial.

BACKGROUND: The purpose of the present study was to examine the effectiveness of an anti-inflammatory intervention as a treatment for neuropathic pain following spinal cord injury (SCI). METHODS: This randomized, parallel-group, controlled clinical trial (NCT02099890) examined 20 participants with varying levels and severities of SCI, randomized (3:2) to either a 12-week anti-inflammatory diet, or control group. Outcome measures consisted of self-determined indices of pain as assessed using the neuropathic pain questionnaire (NPQ) and markers of inflammation as assessed by various pro- and anti-inflammatory cytokines, as well as the eicosanoids PGE2 and LTB4. RESULTS: A significant group × time interaction was found for sensory pain scores (p < 0.01). A Mann-Whitney test revealed that the change scores (3-month baseline) were significantly different between groups for IFN-y (U = 13.0, p = 0.01), IL-1ß (U = 14.0, p = 0.01), and IL-2 (U = 12.0, p = 0.01). A Friedman test revealed the treatment group had a significant reduction in IFN-y (x (2) = 8.67, p = 0.01), IL-1ß (x (2) = 17.78, p < 0.01), IL-6 (x (2) = 6.17, p < 0.05), while the control group showed no significant change in any inflammatory mediator. A stepwise backward elimination multiple regression analysis showed that the change in sensory neuropathic pain was a function of the change in the proinflammatory cytokines IL-2 and IFN-y, as well as the eicosanoid PGE2 (R = 0.689, R (2) = 0.474). CONCLUSIONS: Overall, the results of the study demonstrate the efficacy of targeting inflammation as a means of treating neuropathic pain in SCI, with a potential mechanism relating to the reduction in proinflammatory cytokines and PGE2. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02099890.

Neuralgia del nervio pudendo posparto / Pudendal nerve entrapment syndrome after delivery

Describimos 2 casos clínicos de dolor neuropático en la región perineal tras un parto vaginal. Después del examen físico y las pruebas de imagen, ambos casos se diagnosticaron de síndrome de atrapamiento del nervio pudendo. El primer caso se resolvió tras el desbridamiento de un hematoma en el canal de Alcock. El segundo caso se resolvió mediante fisioterapia. Es importante conocer el síndrome para ofrecer un tratamiento lo menos invasivo posible (AU)

We describe two patients with post-vaginal birth neuropathic-type pain in the perineal region. Pudendal nerve entrapment syndrome was diagnosed on the basis of a physical examination and imaging tests. The first case was resolved by debridement of a hematoma in Alcock's canal. The second case was resolved by physical therapy. Familiarity with this syndrome is important to be able to offer the least invasive treatment possible (AU)

Commiphora mukul attenuates peripheral neuropathic pain induced by chronic constriction injury of sciatic nerve in rats.

OBJECTIVE: The management of neuropathic pain remains unsatisfactory till date, despite immense advances in the therapeutic strategies. Commiphora mukul (CM), also known as Commiphora wightii, is well known in the traditional Indian system of medicine, and has been used to treat ailments such as obesity, bone fractures, arthritis, inflammation, cardiovascular diseases, and lipid disorders. The present study was performed to investigate the effect of CM on peripheral neuropathic pain in rats. METHODS: Neuropathic pain was induced by the chronic constriction injury of the sciatic nerve. Following this, CM was orally administered for 2 weeks in doses of 50, 100, and 200 mg/kg, and pain assessment was performed by employing the behavioral tests for thermal hyperalgesia (hot-plate and tail-flick tests) and cold allodynia (acetone test). RESULTS: Following the induction of neuropathic pain, significant development of thermal hyperalgesia and cold allodynia was observed. The administration of CM (50 mg/kg) did not have any effect on the hot-plate and tail-flick tests, but significant anti-allodynic effect was observed in the acetone test. Furthermore, administration of CM (100 mg/kg) caused significant decrease in pain as observed on the tail-flick and acetone tests, but not in the hot-plate test. CM in a dose of 200 mg/kg significantly modulated neuropathic pain as observed from the increased hot-plate and tail-flick latencies, and decreased paw withdrawal duration (in acetone test). DISCUSSION: Therefore, the present study suggests that CM may be used in future as a treatment option for neuropathic pain.

Oral 2-hydroxyoleic acid inhibits reflex hypersensitivity and open-field-induced anxiety after spared nerve injury.

BACKGROUND: Recently, fatty acids have been shown to modulate sensory function in animal models of neuropathic pain. In this study, the antinociceptive effect of 2-hydroxyoleic acid (2-OHOA) was assessed following spared nerve injury (SNI) with reflex and cerebrally mediated behavioural responses. METHODS: Initial antinociceptive behavioural screening of daily administration of 2-OHOA (400 mg/kg, p.o.) was assessed in Wistar rats by measuring hindlimb reflex hypersensitivity to von Frey and thermal plate stimulation up to 7 days after SNI, while its modulatory effect on lumbar spinal dorsal horn microglia reactivity was assessed with OX-42 immunohistochemistry. In vitro the effect of 2-OHOA (120 µM) on cyclooxygenase protein expression (COX-2/COX-1 ratio) in lipopolysaccharide-activated macrophage cells was tested with Western blot analysis. Finally, the effects of 2-OHOA treatment on the place escape aversion paradigm (PEAP) and the open-field-induced anxiety test were tested at 21 days following nerve injury compared with vehicle-treated sham and pregabalin-SNI (30 mg/kg, p.o.) control groups. RESULTS: Oral 2-OHOA significantly reduced ipsilateral mechanical and thermal hypersensitivity up to 7 days after SNI. Additionally 2-OHOA decreased the COX-2/COX-1 ratio in lipopolysaccharide-activated macrophage cells and OX-42 expression within the ipsilateral lumbar spinal dorsal horn 7 days after SNI. 2-OHOA significantly restored inner-zone exploration in the open-field test compared with the vehicle-treated sham group at 21 days after SNI. CONCLUSIONS: Oral administration of the modified omega 9 fatty acid, 2-OHOA, mediates antinociception and prevents open-field-induced anxiety in the SNI model in Wistar rats, which is mediated by an inhibition of spinal dorsal horn microglia activation.

Methylglyoxal activates nociceptors through transient receptor potential channel A1 (TRPA1): a possible mechanism of metabolic neuropathies.

Neuropathic pain can develop as an agonizing sequela of diabetes mellitus and chronic uremia. A chemical link between both conditions of altered metabolism is the highly reactive compound methylglyoxal (MG), which accumulates in all cells, in particular neurons, and leaks into plasma as an index of the severity of the disorder. The electrophilic structure of this cytotoxic ketoaldehyde suggests TRPA1, a receptor channel deeply involved in inflammatory and neuropathic pain, as a molecular target. We demonstrate that extracellularly applied MG accesses specific intracellular binding sites of TRPA1, activating inward currents and calcium influx in transfected cells and sensory neurons, slowing conduction velocity in unmyelinated peripheral nerve fibers, and stimulating release of proinflammatory neuropeptides from and action potential firing in cutaneous nociceptors. Using a model peptide of the N terminus of human TRPA1, we demonstrate the formation of disulfide bonds based on MG-induced modification of cysteines as a novel mechanism. In conclusion, MG is proposed to be a candidate metabolite that causes neuropathic pain in metabolic disorders and thus is a promising target for medicinal chemistry.