| Summary: | 博士 === 國防醫學院 === 醫學科學研究所 === 101 === ABSTRACT
Neuropathic pain is resulted from damage to, or dysfunction of, the peripheral or central nervous system. Thermal hyperalgesia and tactile allodynia are well-documented symptoms of neuropathic pain in both clinical setting and animal models. Although neuropathic pain responds to opioids, the results are unsatisfactory and adjuvant drugs are often needed. Naloxone had been demonstrated to have dual effects. At classic doses, naloxone causes antagonism of opioid effects, while, at ultra-low doses, it potentiates the antinociceptive effect of morphine. In our serial studies, we tried to elucidate the mechanism of the augmentation by ultra-low dose naloxone on morphine antinociception in partial sciatic nerve transected (PST) rats.
The PST rat model induces nerve lesions without introducing foreign material; it shows reduction in thermal and tactile thresholds, and allows examination of drugs on animal nociceptive behaviours after endoneurial injury. After peripheral nerve injury, inflammatory mediators such as proinflammatory cytokines, chemokines, histamine, prostaglandins, bradykinin, and nerve growth factors are released from injured nerve fibers and adjacent immune cells. These mediators can directly act on dorsal root ganglia (DRG) neuronal cell bodies and axons, and lead to peripheral sensitization. Proinflammatory cytokine tumor necrosis factor-α (TNF-α) rapidly elicits central sensitization and pain via direct activation of neurons. Moreover, neuropathic pain is associated with enhanced synaptic excitatory signal transduction in the spinal cord dorsal horn; it explains the observed thermal hyperalgesia and tactile allodynia. Increasing of TNF-α expression in DRG and spinal cord has been demonstrated. TNF-α, via tumor necrosis factor receptor (TNFR), modulates spinal synaptic transmission and plays a critical role in both induction and maintenance of neuropathic pain. Ultra-low dose (ng) naloxone in combination with morphine administration significantly suppressed the expression of TNF-α and TNFR1 in PST rats and enhanced the antiinflammatory effect of morphine.
As known, glial glutamate transporters (GTs) are responsible for the regulation of excitatory synaptic transmission by controlling the synaptic glutamate concentration. Wrapping of neurons by astroglia plays a significant role in regulating glutamatergic neurotransmission, which controls synaptic glutamate clearance by GTs. Excessive glutamate increases excitatory signal transmission, via NMDA (N-methyl-D-aspartic acid) and AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole- propionate) receptors, to post-synaptic neurons. Downregulation of spinal GTs contributes to various abnormal pain states, such as neuropathic pain and morphine tolerance. Intrathecal ultra-low dose naloxone potentiates the antinociceptive effect of morphine by enhancing the reuptake of excitatory amino acids (EAAs) from synaptic cleft in the spinal cord of partial sciatic nerve transected rats.
We had demonstrated that ultra-low dose naloxone plus morphine treatment restores the antinociceptive effect of morphine in PST rats and significantly suppresses the expression of TNF-α and TNFR1 in PST rats and enhances the antiinflammatory effect of morphine, and this is accompanied by restoration of GLAST and GLT-1 expression in astrocytes, which enhances EAAs reuptake and inhibits synaptic excitatory transmission. Clinical efforts to inhibit TNF-α and TNFR1 expression and increase astrocytic expression of GTs or prevent their downregulation could help to clear accumulated EAAs from synaptic cleft and minimize synaptic excitatory transmission, thus improving the analgesic effect of morphine for neuropathic pain. The present results open promising prospects on the development of new pharmacotherapeutic approach against neuropathic pain.
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