Abstract
The present study demonstrates that synaptamide (N-docosahexaenoylethanolamine), an endogenous metabolite of docosahexaenoic acid, when administered subcutaneously (4 mg/kg/day, 14 days), exhibits analgesic activity and promotes cognitive recovery in the rat sciatic nerve chronic constriction injury (CCI) model. We analyzed the dynamics of GFAP-positive astroglia and S100β-positive astroglia activity, the expression of nerve growth factor (NGF), and two subunits of the NMDA receptor (NMDAR1 and NMDAR2A) in the hippocampi of the experimental animals. Hippocampal neurogenesis was evaluated by immunohistochemical detection of DCX. Analysis of N-acylethanolamines in plasma and in the brain was performed using the liquid chromatography-mass spectrometry technique. In vitro and in vivo experiments show that synaptamide (1) reduces cold allodynia, (2) improves working memory and locomotor activity, (3) stabilizes neurogenesis and astroglial activity, (4) enhances the expression of NGF and NMDAR1, (5) increases the concentration of Ca2+ in astrocytes, and (6) increases the production of N-acylethanolamines. The results of the present study demonstrate that synaptamide affects the activity of hippocampal astroglia, resulting in faster recovery after CCI.
Highlights
Neuropathic pain is a chronic pain condition resulting from dysfunction of the somatosensory nervous system
Peripheral neuropathic pain can develop after peripheral nerve injury, which is common in patients with cancer, chronic diabetes, traumatic spinal cord injury, multiple sclerosis, and after certain surgical procedures [1]
It has been previously shown that the inhibition of glial fibrillary acidic protein (GFAP) expression and astrogliosis after nerve injury correlates with a decrease in the severity of neuropathic pain syndrome [8]
Summary
Neuropathic pain is a chronic pain condition resulting from dysfunction of the somatosensory nervous system. A number of studies, including our recent research, show that chronic peripheral pain can cause changes in the plasticity of the hippocampus, such as impaired neurogenesis and neuroinflammation. These processes involve glial cells (micro- and astroglia), which are characterized by increased proliferation, hypertrophy, and an increased production of pro-inflammatory cytokines [5,6]. The important role of astrocytes in the pathogenesis of pain, especially neuropathic pain after peripheral nervous system damage, has been shown. Chronic pain is accompanied by astrogliosis, a reactive response of astrocytes characterized by morphological, molecular, and functional changes. One of the most important is nerve growth factor (NGF), which plays a key role in the survival and functioning of sensory and sympathetic neurons in the peripheral nervous system, as well as cholinergic neurons in the basal forebrain in the CNS [9]
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