Natural polyphenolic coffee extract administration relieves chronic nociplastic pain in a reserpine-induced fibromyalgia-like female mouse model.

INTRODUCTION: Nociplastic pain involves reflexive and nonreflexive pain responses and it is a core symptom of fibromyalgia (FM). The increasing prevalence of this health condition and the low rates of patients' quality of life, combined with the lack of suitable pharmacologic treatments, evidence the demand to research new alternatives. Polyphenols may be potential therapeutic candidates as they have been reported to exert pathological pain modulation in preclinical models. In that context, this work was aimed to study the antinociceptive effects of a polyphenolic extract obtained from decaffeinated ground roasted coffee, in the RIM6 FM-like mouse model. METHODS: To this end, RIM6 adult ICR-CD1 female mice were administered daily once a week with either 10 or 15 mg/kg of extract, and reflexive pain responses were evaluated for up to 3 weeks. At the end, the depressive-like behavior was assessed as a nonreflexive pain response, and spinal cord and serum samples were collected for immunohistochemical and toxicological analyses. RESULTS: These findings showed that the repeated administration of the coffee polyphenolic extract (CE) modulated reflexive pain responses, depressive-like behavior, and spinal cord gliosis in a dose-dependent manner, without signs of systemic toxicity. CONCLUSION: Thus, the CE may be a potential pharmacological treatment suitable to relieve nociplastic pain responses characteristic of FM.

Long-lasting reflexive and nonreflexive pain responses in two mouse models of fibromyalgia-like condition.

Nociplastic pain arises from altered nociception despite no clear evidence of tissue or somatosensory system damage, and fibromyalgia syndrome can be highlighted as a prototype of this chronic pain subtype. Currently, there is a lack of effective treatments to alleviate both reflexive and nonreflexive pain responses associated with fibromyalgia condition, and suitable preclinical models are needed to assess new pharmacological strategies. In this context, although in recent years some remarkable animal models have been developed to mimic the main characteristics of human fibromyalgia, most of them show pain responses in the short term. Considering the chronicity of this condition, the present work aimed to develop two mouse models showing long-lasting reflexive and nonreflexive pain responses after several reserpine (RIM) or intramuscular acid saline solution (ASI) injections. To our knowledge, this is the first study showing that RIM6 and ASI mouse models show reflexive and nonreflexive responses up to 5-6 weeks, accompanied by either astro- or microgliosis in the spinal cord as pivotal physiopathology processes related to such condition development. In addition, acute treatment with pregabalin resulted in reflexive pain response alleviation in both the RIM6 and ASI models. Consequently, both may be considered suitable experimental models of fibromyalgia-like condition, especially RIM6.

Physiological Changes and Pathological Pain Associated with Sedentary Lifestyle-Induced Body Systems Fat Accumulation and Their Modulation by Physical Exercise.

A sedentary lifestyle is associated with overweight/obesity, which involves excessive fat body accumulation, triggering structural and functional changes in tissues, organs, and body systems. Research shows that this fat accumulation is responsible for several comorbidities, including cardiovascular, gastrointestinal, and metabolic dysfunctions, as well as pathological pain behaviors. These health concerns are related to the crosstalk between adipose tissue and body systems, leading to pathophysiological changes to the latter. To deal with these health issues, it has been suggested that physical exercise may reverse part of these obesity-related pathologies by modulating the cross talk between the adipose tissue and body systems. In this context, this review was carried out to provide knowledge about (i) the structural and functional changes in tissues, organs, and body systems from accumulation of fat in obesity, emphasizing the crosstalk between fat and body tissues; (ii) the crosstalk between fat and body tissues triggering pain; and (iii) the effects of physical exercise on body tissues and organs in obese and non-obese subjects, and their impact on pathological pain. This information may help one to better understand this crosstalk and the factors involved, and it could be useful in designing more specific training interventions (according to the nature of the comorbidity).

Graded photochemical spinal cord injury results in chronic hyperalgesia and depression-like behaviour but no anxiety exacerbation in female BALB/c mice.

Neuropathic pain (NP) is present in 40-to-50% of spinal cord injured patients. It tends to chronicity and correlates with lower quality-of-life. Moreover, the role of NP in the eventual exacerbation of anxiety- and depression-like behaviours during its development and chronification in genetically susceptible individuals remains unclear. Thus, although solely few animal models are available, new specific models are needed to complete the array of chances to assay new therapeutic strategies with the aim of treating chronic NT and its associated mood disorders. The present study was conceived to evaluate hyperalgesic responses and anxiety- and depression-like behaviours after graded photochemical spinal cord injury (SCI) up to chronic phase. BALB/c strain was used: it expresses a phenotype characterized by high innate anxiety levels, allowing to elucidate whether NP may exacerbate mood disorders at SCI chronic phase. After different photoinduction-times on exposed spinal cord, the mice developed a graded chronic hyperalgesia with minor to non-existent motor dysfunction. Behavioural data suggest that whilst hyperalgesia associated to SCI does not exacerbate BALB/c anxiety-like behaviours, it may result in depression-like behaviour at SCI chronic phase. Our study demonstrates that chronic central hyperalgesia may exacerbate despair-like behaviour at the SCI chronic phase in a mouse model of high anxiety-related behaviour. This implies that photochemical-SCI may be a suitable model to study the comorbidity between chronic NP and mood disorders.

Neuroplasticity of Supraspinal Structures Associated with Pathological Pain.

Peripheral nerve and spinal cord injuries, along with other painful syndromes such as fibromyalgia, diabetic neuropathy, chemotherapeutic neuropathy, trigeminal neuralgia, complex regional pain syndrome, and/or irritable bowel syndrome, cause several neuroplasticity changes in the nervous system along its entire axis affecting the different neuronal nuclei. This paper reviews these changes, focusing on the supraspinal structures that are involved in the modulation and processing of pain, including the periaqueductal gray matter, red nucleus, locus coeruleus, rostral ventromedial medulla, thalamus, hypothalamus, basal ganglia, cerebellum, habenula, primary, and secondary somatosensory cortex, motor cortex, mammillary bodies, hippocampus, septum, amygdala, cingulated, and prefrontal cortex. Hyperexcitability caused by the modification of postsynaptic receptor expression, central sensitization, and potentiation of presynaptic delivery of neurotransmitters, as well as the reduction of inhibitory inputs, changes in dendritic spine, neural circuit remodeling, alteration of gray matter, and upregulation of proinflammatory mediators (e.g., cytokines) by reactivation of astrocytes and microglial cells are the main functional, structural, and molecular neuroplasticity changes observed in the above supraspinal structures, associated with pathological pain. Studying these changes in greater depth may lead to the implementation and improvement of new therapeutic strategies against pathological pain. Anat Rec, 300:1481-1501, 2017. © 2017 Wiley Periodicals, Inc.

(-)-Epigallocatechin-3-Gallate Antihyperalgesic Effect Associates With Reduced CX3CL1 Chemokine Expression in Spinal Cord.

(-)-Epigallocatechin-3-gallate (EGCG) is a major polyphenol in green tea with beneficial effects on the neuropathic pain alleviation in animal models. Because chemokine fractalkine (CX3CL1) has been suggested as an important signal during neuropathic pain development, this study aimed to investigate whether CX3CL1 expression may be modulated by EGCG treatment reducing hyperalgesia in chronic constriction injured mice. To this end, Balb/c mice were subjected to a chronic constriction injury of sciatic nerve (CCI) and treated with EGCG or vehicle once a day during the first week following surgery. Thermal hyperalgesia was tested at 7 and 14 days post-surgery, and the expression of CX3CL1 and its mRNA were analyzed in spinal cord at the end of the experimental period. Results revealed that EGCG treatment significantly reduced thermal hyperalgesia in CCI-injured mice at short time, and this antihyperalgesic effect was associated with a down-regulation of CX3CL1 protein expression in the spinal cord. On the other hand, EGCG treatment did not affect the CX3CL1 transcription. Overall, our results suggest a new role of EGCG-treatment in an experimental model of neuropathic pain as a mediator of nociceptive signaling cross talk between neurons and glial cells in the dorsal horn of the spinal cord. Copyright © 2016 John Wiley & Sons, Ltd.

Intrathecal administration of IGF-I by AAVrh10 improves sensory and motor deficits in a mouse model of diabetic neuropathy.

Different adeno-associated virus (AAV) serotypes efficiently transduce neurons from central and peripheral nervous systems through various administration routes. Direct administration of the vectors to the cerebrospinal fluid (CSF) could be an efficient and safe strategy. Here, we show that lumbar puncture of a nonhuman AAV leads to wide and stable distribution of the vector along the spinal cord in adult mice. AAVrh10 efficiently and specifically infects neurons, both in dorsal root ganglia (60% total sensory neurons) and in the spinal cord (up to one-third of α-motor neurons). As a proof of concept, we demonstrate the efficacy of AAVrh10 in a mouse model of diabetic neuropathy, in which intrathecal delivery of the vector coding for insulin-like growth factor (IGF-I) favored the release of the therapeutic protein into the CSF through its expression by sensory and motor neurons. IGF-I-treated diabetic animals showed increased vascular endothelial growth factor expression, activation of Akt/PI3K pathway, and stimulated nerve regeneration and myelination in injured limbs. Moreover, we achieved restoration of nerve conduction velocities in both sensory and motor nerves by AAVrh10, whereas we reached only sensory nerve improvement with AAV1. Our results indicate that intrathecal injection of AAVrh10 is a promising tool to design gene therapy approaches for sensorimotor diseases.

Comparative study of peripheral neuropathy and nerve regeneration in NOD and ICR diabetic mice.

The non-obese diabetic (NOD) mouse was suggested as an adequate model for diabetic autonomic neuropathy. We evaluated sensory-motor neuropathy and nerve regeneration following sciatic nerve crush in NOD males rendered diabetic by multiple low doses of streptozotocin, in comparison with similarly treated Institute for Cancer Research (ICR) mice, a widely used model for type I diabetes. Neurophysiological values for both strains showed a decline in motor and sensory nerve conduction velocity at 7 and 8 weeks after induction of diabetes in the intact hindlimb. However, amplitudes of compound muscle and sensory action potentials (CMAPs and CNAPs) were significantly reduced in NOD but not in ICR diabetic mice. Morphometrical analysis showed myelinated fiber loss in highly hyperglycemic NOD mice, but no significant changes in fiber size. There was a reduction of intraepidermal nerve fibers, more pronounced in NOD than in ICR diabetic mice. Interestingly, aldose reductase and poly(ADP-ribose) polymerase (PARP) activities were increased already at 1 week of hyperglycemia, persisting until the end of the experiment in both strains. Muscle and nerve reinnervation was delayed in diabetic mice following sciatic nerve crush, being more marked in NOD mice. Thus, diabetes of mid-duration induces more severe peripheral neuropathy and slower nerve regeneration in NOD than in ICR mice.