Frailty and pain, human studies and animal models.

The hypothesis that pain can predispose to frailty development has been recently investigated in several clinical studies suggesting that frailty and pain may share some mechanisms. Both pain and frailty represent important clinical and social problems and both lack a successful treatment. This circumstance is mainly due to the absence of in-depth knowledge of their pathological mechanisms. Evidence of shared pathways between frailty and pain are preliminary. Indeed, many clinical studies are observational and the impact of pain treatment, and relative pain-relief, on frailty onset and progression has never been investigated. Furthermore, preclinical research on this topic has yet to be performed. Specific researches on the pain-frailty relation are needed. In this narrative review, we will attempt to point out the most relevant findings present in both clinical and preclinical literature on the topic, with particular attention to genetics, epigenetics and inflammation, in order to underline the existing gaps and the potential future interventional strategies. The use of pain and frailty animal models discussed in this review might contribute to research in this area.

Effect of Tapentadol on Splenic Cytokine Production in Mice.

BACKGROUND: Opioid drugs affect immunity, but not all opioid drugs share the same immunomodulatory properties. Tapentadol is an analgesic drug with a dual synergistic mechanism of action: µ-opioid receptor agonism and noradrenaline reuptake inhibition. Weaker µ-opioid receptor agonism combined with noradrenaline reuptake inhibition results in potent analgesia with reduced opioid side effects. We evaluated the impact of tapentadol on splenic cytokine in normal and in hyperalgesia/allodynia mice, comparing it with morphine and reboxetine, a noradrenaline reuptake inhibitor. METHODS: Tapentadol, reboxetine, and morphine were injected subcutaneously into naïve and mice that underwent sciatic nerve chronic constriction injury, and their effect on splenic cytokines (interferon-γ [IFN-γ], interleukin [IL]-2, IL-10, and IL-4) was measured by enzyme-linked immunosorbent assay after acute or chronic treatment. Nociceptive thresholds, thermal hyperalgesia, and allodynia also were assessed. Data were analyzed with 2-way analysis of variance (behavior) or 1-way analysis of variance (cytokines) followed by Bonferroni post hoc test. RESULTS: Primary outcomes of our study were the effects of drugs on splenic cytokines. Our data indicate that acute tapentadol did not modify cytokine production in comparison with animals that received saline, whereas morphine suppressed all the cytokines: saline versus morphine 10 mg/kg (mean difference [MD], 95% confidence interval [CI]: IFN-γ = 12,400 [7760, 17,040], P < .001; IL-2 = 216.2 [47.69, 384.7], P < .01; IL-10 = 868 [523.7, 1212], P < .001; and IL-4 = 17.26 [10.32, 24.20], P < .001). A significant difference also was present between morphine and tapentadol (morphine 10 mg/kg versus tapentadol 20 mg/kg: MD [95% CI]: IFN-γ = -11,600 [-16,240, -6960], P < .001; IL-2 = -334.2 [-502.7, -165.7], P < .001; IL-10 = -959 [-1303, -614.7], P < .001; IL-4 = -18.66 [-25.60, -11.72], P < .001). When chronically injected for 7 days, tapentadol and reboxetine did not significantly affect cytokines when compared with saline-treated animals. The immunoprofile of tapentadol was different from that of morphine also in mice that were in a condition of neuropathic pain. All cytokines appeared significantly decreased in mice that received a chronic constriction injury in comparison with sham animals but, after 7 days of treatment, with a similar antihyperalgesic profile, IL-10 and IL-4 were significantly increased in tapentadol and reboxetine animals in comparison with morphine mice (morphine versus tapentadol: MD [95% CI], IL-10 = -926.4 [-1664, -188.5], P < .01; IL-4 = -8.15 [-12.46, -3.84], P < .001). CONCLUSIONS: Acute and chronic tapentadol seem to be protective of splenic cytokines in contrast with morphine, which exerts a generalized suppression on all cytokines.

Olive oil-enriched diet reduces brain oxidative damages and ameliorates neurotrophic factor gene expression in different life stages of rats.

Our aim was to assess the influence of maternal diet rich in monounsaturated fatty acids on oxidative and molecular parameters in brains of mouse pups as well as their body weight during their lifetime. Female rats received a diet containing 20% of olive oil-enriched diet (OOED) and a standard diet control diet (CD) in different periods: pregnancy, lactation and after weaning until pups' adulthood. On the last prenatal day (Group 1), embryos from OOED group showed smaller body weight, brain weight and lower levels of sulphydryl groups glutathione reduced (GSH) in the brain. On postnatal delay-21 (PND21) (Group 2), pups from OOED group showed higher body weight and brain weight, reduced brain weight/body weight ratio and lower brain lipid peroxidation (LP). On PND70 (Group 3), pups from OOED group showed lower brain LP and higher levels of GSH in prefrontal cortex and lower brain levels of reactive species in the hippocampus. Interestingly, the group of animals whose diet was modified from OOED to CD on PND21 showed greater weight gain compared to the group that remained in the same original diet (OOED) until adulthood. Furthermore, OOED consumption during pregnancy and lactation significantly increased BDNF only, as well as its main transcripts exon IV and VI mRNA levels in the prefrontal cortex. In addition, OOED significantly up-regulated FGF-2 mRNA levels in the prefrontal cortex. These findings open a pioneering line of investigation about dietary adjunctive therapeutic strategies and the potential of healthy dietary habits to prevent neonatal conditions and their influence on adulthood.

Adult stem cell as new advanced therapy for experimental neuropathic pain treatment.

Neuropathic pain (NP) is a highly invalidating disease resulting as consequence of a lesion or disease affecting the somatosensory system. All the pharmacological treatments today in use give a long lasting pain relief only in a limited percentage of patients before pain reappears making NP an incurable disease. New approaches are therefore needed and research is testing stem cell usage. Several papers have been written on experimental neuropathic pain treatment using stem cells of different origin and species to treat experimental NP. The original idea was based on the capacity of stem cell to offer a totipotent cellular source for replacing injured neural cells and for delivering trophic factors to lesion site; soon the researchers agreed that the capacity of stem cells to contrast NP was not dependent upon their regenerative effect but was mostly linked to a bidirectional interaction between the stem cell and damaged microenvironment resident cells. In this paper we review the preclinical studies produced in the last years assessing the effects induced by several stem cells in different models of neuropathic pain. The overall positive results obtained on pain remission by using stem cells that are safe, of easy isolation, and which may allow an autologous transplant in patients may be encouraging for moving from bench to bedside, although there are several issues that still need to be solved.

Systemic administration of human adipose-derived stem cells reverts nociceptive hypersensitivity in an experimental model of neuropathy.

Over the last decade, it has been proved that mesenchymal stem cells (MSCs) elicit anti-inflammatory effects. MSCs from adipose tissue (hASCs) differentiate into cells of the mesodermal lineage and transdifferentiate into ectodermal-origin cells. Although there are various etiologies to chronic pain, one common feature is that painful states are associated with increased inflammation. We believe in hASCs as a therapeutic tool also in pathologies involving neuroinflammation and neuronal tissue damage. We have investigated the effect of hASCs injected in a model of neuropathic pain [(mouse sciatic nerve chronic constriction injury (CCI)]. hASCs from 5 donors were characterized, and no major differences were depicted. hASCs were cryopreserved and grown on demand. About 1×10(6), 3×10(6), and 6×10(6) hASCs were intravenously injected into normal immunocompetent mice. No mouse died, and no macroscopic toxicity or behavioral changes were observed, confirming the safety of hASCs. hASCs, intravenously (i.v.) injected into C57BL/6 mice when the neuropathic pain was already established, induced a significant reduction in mechanical allodynia and a complete reversion of thermal hyperalgesia in a dose-response fashion, already 1 day after administration. Moreover, the hASCs effect can be boosted by repeated administrations, allowing a prolonged therapeutic effect. Treatment decreased the level of the CCI-induced proinflammatory cytokine interleukin (IL)-1ß and activated the anti-inflammatory cytokine IL-10 in the lesioned nerve. hASCs treatment also restored normal inducible nitric oxide synthase expression in the spinal cord of CCI animals. Our data suggest that hASCs are worthy of further studies as an anti-inflammatory therapy in the treatment of neuropathic pain or chronic inflammatory diseases.

The soy isoflavone genistein reverses oxidative and inflammatory state, neuropathic pain, neurotrophic and vasculature deficits in diabetes mouse model.

Treatment of diabetes complications remains a substantial challenge. The aim of this study was to explore the ability of the soy isoflavone genistein in attenuating the signs that follow diabetes onset: nociceptive hypersensitivity, oxidative and inflammatory state, nerve growth factor (NGF) decrease and vascular dysfunctions. Genistein (3 and 6 mg/kg) was administered to C57BL/6J streptozotocin diabetic mice from the 2nd till the 5th week after disease induction. The hind paw withdrawal threshold to mechanical stimulation (tactile allodynia) was evaluated by a von Frey filament. The oxidative stress was assessed measuring: reactive oxygen species by fluorimetric analysis, both the lipoperoxide content, as malondialdehyde, the antioxidant enzymatic activities spectrophotometrically and the glutathione content spectrofluorimetrically. Proinflammatory cytokines and NGF were measured in the sciatic nerve by enzyme-linked immunosorbent assay. Aortic inducible (iNOS) and endothelial nitric oxide synthase (eNOS) protein content was measured by western immunoblotting. Genistein relieved diabetic peripheral painful neuropathy, reverted the proinflammatory cytokine and reactive oxygen species overproduction, and restored the NGF content in diabetic sciatic nerve. Furthermore it restored the GSH content and the GSH and GSSG ratio, improved the antioxidant enzymes activities, decreased reactive oxygen species and lipoperoxide level in the brain and liver. Finally it restored the iNOS and eNOS content and the superoxide dismutase activity in thoracic aorta. Hyperglycaemia and weight decrease were not affected. Genistein is able to reverse a diabetes established condition of allodynia, oxidative stress and inflammation, ameliorates NGF content and the vascular dysfunction, thus suggesting its possible therapeutic use for diabetes complications.

Genistein, a natural phytoestrogen from soy, relieves neuropathic pain following chronic constriction sciatic nerve injury in mice: anti-inflammatory and antioxidant activity.

There is great interest in soy isoflavones as alternatives to endogenous estrogens not only in hormonal pathologies, but also in inflammatory, neurodegenerative diseases, and pain. We investigated the effect of the isoflavone genistein on neuropathic pain. Genistein binds estrogen receptors (ER) with higher affinity for the ERbeta particularly expressed in neuronal and immune cells. Neuropathy was induced in mice by means of chronic sciatic nerve constriction, and the subcutaneous administration of genistein from the third day after the lesion reversed pain hypersensitivity in a time- and dose-dependent manner. This effect may have been due to the activation of classical nuclear receptor and/or anti-oxidant, anti-inflammatory, and immunomodulating properties of genistein. The fact that a specific ERbeta antagonist prevented both its anti-allodynic and anti-hyperalgesic action, whereas a specific ERalpha antagonist was ineffective and a non-selective ER antagonist only reversed the anti-allodynic effect, suggests the involvement of ERbeta. Antioxidant effects are also involved as the anti-nociceptive dose reversed the increase in reactive oxygen species and malondialdehyde in injured paw tissues, and increased the activity of anti-oxidant enzymes. The phytoestrogen had immunomodulatory and anti-inflammatory activities as it reduced peripheral and central nuclear factor-kappaB, nitric oxide system and pro-inflammatory cytokine over-activation. Taken together, our results suggest that genistein could ameliorate painful neuropathy by multiple mechanisms.