Polyphenolic grape stalk and coffee extracts attenuate spinal cord injury-induced neuropathic pain development in ICR-CD1 female mice

Abstract

More than half of spinal cord injury (SCI) patients develop central neuropathic pain (CNP), which is largely refractory to current treatments. Considering the preclinical evidence showing that polyphenolic compounds may exert antinociceptive effects, the present work aimed to study preventive effects on SCI-induced CNP development by repeated administration of two vegetal polyphenolic extracts: grape stalk extract (GSE) and coffee extract (CE). Thermal hyperalgesia and mechanical allodynia were evaluated at 7, 14 and 21 days postinjury. Then, gliosis, ERK phosphorylation and the expression of CCL2 and CX3CL1 chemokines and their receptors, CCR2 and CX3CR1, were analyzed in the spinal cord. Gliosis and CX3CL1/CX3CR1 expression were also analyzed in the anterior cingulate cortex (ACC) and periaqueductal gray matter (PAG) since they are supraspinal structures involved in pain perception and modulation. GSE and CE treatments modulated pain behaviors accompanied by reduced gliosis in the spinal cord and both treatments modulated neuron-glia crosstalk-related biomolecules expression. Moreover, both extracts attenuated astrogliosis in the ACC and PAG as well as microgliosis in the ACC with an increased M2 subpopulation of microglial cells in the PAG. Finally, GSE and CE prevented CX3CL1/CX3CR1 upregulation in the PAG, and modulated their expression in ACC. These findings suggest that repeated administrations of either GSE or CE after SCI may be suitable pharmacologic strategies to attenuate SCI-induced CNP development by means of spinal and supraspinal neuroinflammation modulation.

Central Neuropathic Pain Development Modulation Using Coffee Extract Major Polyphenolic Compounds in Spinal-Cord-Injured Female Mice

“…CGA, neochlorogenic acid, 4-O-caffeoylquinic acid, coffee extract, or saline vehicle daily during the first week after injury. These polyphenols were chosen since they are the major ones present in natural coffee extract according to high-performance liquid chromatography high-resolution mass spectrometry (HPLC-HRMS) results [ 11 ]. Reflexive pain responses and locomotor activity were evaluated weekly up to 14 days post-injury.…”

“…After the back was shaved and disinfected with povidone iodide, dorsal laminectomy was performed to expose T8–T9 thoracic spinal cord segments. To induce mild spinal cord injury, a weight drop apparatus was used (2 g; 25 mm high) [ 10 , 11 , 16 , 17 ]. This spinal cord contusion is known to cause spinal cord injury but preserves the ventrolateral funicles bilaterally, which is where the ascending pain pathways project [ 11 ].…”

“…To induce mild spinal cord injury, a weight drop apparatus was used (2 g; 25 mm high) [ 10 , 11 , 16 , 17 ]. This spinal cord contusion is known to cause spinal cord injury but preserves the ventrolateral funicles bilaterally, which is where the ascending pain pathways project [ 11 ]. After closing the wound, the animals received (i.p.)…”

“…Per this hypothesis, our research group recently showed that natural coffee polyphenolic extract exerts preventive effects on the development of central neuropathic pain in wild-type CD-1 Swiss female mice in the acute phase of SCI. The effects of the repeated administration of coffee extract were associated with the modulation of central nervous system gliosis as well as the downregulation of chemokines and their receptors, which are known to be related to the development of pathological pain [ 11 ].…”

“…This is not the case for coffee extract, since a commercial powdered decaffeinated variety was used, with physiological serum as the extractor to be compatible with in vivo administration. In addition, the polyphenolic content was fully characterized by HPLC, and its repeated administration in mice has shown neither hepatoxicity nor nephrotoxicity [ 11 ]. However, while it is known that coffee extract consists of a mixture of several polyphenolic molecules, it is still unknown whether its beneficial effects on the development of central neuropathic pain are associated with the potential synergistic mechanisms of the polyphenolic content of the whole extract or, in contrast, with one of the major polyphenols within the solution.…”