| Neuropathic pain is caused by a primary lesion or disease of the nervous system, and characterized by spontaneous pain, paresthesia, and allodynia.At present, there is no reliable way to treat neuropathic pain due largely to lacking of the knowledge that we need to understand about the pathogenesis of neuropathic pain. It has been known that central sensitization in the spinal cord plays an important role in the formation of neuropathic pain. Central sensitization is the enhancement of synaptic transmission performance in the spinal cord neural network and able to magnify the signals of external pain stimuli leading to increase in excitatory neurotransmitters release between synapses, enhanced opening of ion channels on the chemical synapses, changes in synapse structure, and reduced activity of inhibitory interneurons.The formation of neuropathic pain and the learning and memory process often sharea similar neural network structure as both central sensitization in the spinal cord and learning-memory of brain can cause changes in the plasticity of neural network structure. There has been report showing that the long-term potentiation (LTP), a basic form of learning-memory in the brain, would be induced in the spinal dorsal horn C-fiber in response to occurrence of neuropathic pain., New learning and memory consolidation requires the synthesis of new proteins in relevant regions of the brain. Blockage of the protein synthesis would disrupt the reconsolidation of new memory. There were also studies finding that the injection of capsaicin into the paws of rat could form short-term inflammatory pain and, if this stimulus continued, eventually develop into allodynia in rat. If re-activating the central sensitization in the spinal cord by the same stimulation while injecting a protein synthesis inhibitor, the hyperalgesia would be significantly reduced in rat. These observations suggest a spinal analog of memory reconsolidation that could be considered to be a therapeutic approach towards cure of neuropathic pain by eliminating pain memory similar to the erasure of fear memory..Previous studies in our laboratory found that the intraperitoneal injection of (-)-mefloquine, an electrical synapse blocker, can prevent the occurrence of, but not cure neuropathic pain, presumably through inhibitory effect on the neural excitability prior to pain formation, in a neuropathic pain (chronic constriction injury, CCI) rat model. The present study was conducted to test the hypothesis as to whether the mechanism underlying the therapeutic action of (-)-mefloquine on CCI-induced neuropathic pain would be linked to the retrieval/reconsolidation stages of memory formation process.Firstly, we constructed such a rat model with spinal analogue of retrieval/reconsolidation memory by applying the second, at day 5 or 10 next to the first, CCI operation (dual-CCI). The dual-CCI rats were then systematically examined for their physiological status in terms of the body weight, food-intake, locomotor activity as well as the mechanical/thermal pain thresholds, and no significant differences were found in these rats compared to those of single-CCI rats, indicating that dual-CCI rats could be considered to be a reliable neuropathic pain model.Secondly, to investigate the therapeutic efficacy for neuropathic pain of (-)-mefloquine, the time for the second CCI operation was designed on day 5 (dual-CCI-d5) or day 10 (dual-CCI-d10) after the first CCI, which would presumably stimulate a retrieval of the consolidated pain memory in the single-CCI rats. Three protocols for the time-window of (-)-mefloquine administration were designed with the rationale that (-)-mefloquine administrated within the time-windows could just play an interfering role in preventing the second CCI-stimulated retrieval of pain memory from entering into the reconsolidation process. In protocol 1, the drug was i.p. injected once daily (15mg/kg) for consecutive 5 days immediately following the second CCI operation (dual-CCI-d5). For protocols 2 and 3, (-)-mefloquine was i.p. dosed once daily (15mg/kg) for consecutive 3 days before the second CCI (dual-CCI-d10) and 5 days after the second CCI (dual-CCI-d10), respectively. The anti-pain efficacy in the dual-CCI rats was examined behaviorally. The results showed that (-)-mefloquine treatment using protocol 1 in the dual-CCI-d5 rats could significantly increase both the mechanical and thermal pain thresholds as compared with those in the vehicle and single-CCI rats. In the dual-CCI-d10 rats, (-)-mefloquine dosing, whatever for 3 days before or 5 days after the second CCI, could effectively elevate the thermal, though not the mechanical, pain threshold compared to those in the vehicle and single-CCI rats. These data suggest that 1) (-)-mefloquine could rescue the dual-CCI model of neuropathic pain; 2) the second CCI might act as a stimulus in stimulating retrieval of the pain memory formed during the first CCI, and 3) (-)-mefloquine actioning within the time-window between the retrieval and reconsolidation of the pain memory might be critical for its therapeutic efficacy against the neuropathic pain. Further studies in terms of molecular and electrophysiological mechanism underlying the link between the (-)-mefloquine action and the processing of memory in neuropathic pain are necessary.Thirdly, in addition to the pharmacodynamics of (-)-mefloquine in neuropathic pain, the acute toxic effects of 5-day consecutive administration of (-)-mefloquine (i.p., 15mg/kg daily) on physiological and biochemical status, memory and emotion, and the central distribution following 5-day consecutive administration of this drug (i.p., 15mg/kg) were investigated, respectively, in the dual-and single-CCI rats. The results showed that 5-day consecutive i.p. injections of (-)-mefloquine had generally no significant side-effect on the biochemical parameters and memorial function, while affecting the body-weight and particularly the food-intake (merely observable over the dosing period), in the dual-CCI rats as compared with that of the single-CCI rats. Interestingly, in addition to the therapeutic role on neuropathic pain, (-)-mefloquine was behaviorally shown to be effective in ameliorating anxiety and depression in the rats with neuropathic pain. The central distribution of (-)-mefloquine was analyzed using LC-MS method. The data showed that, even on day 7 or 10 after 5-day consecutive injections of the drug (i.p.,15mg/kg daily), the concentration of (-)-mefloquine in the spinal cord was still the highest amongst those in the hippocampus and anterior cingulate cortex (ACC), suggesting that the spinal cord is most likely to be the main target region of (-)-mefloquine, and in this regards, the second CCI applied to the single-CCI rats in the present study might be considered to action mostly likely as a spinal analogue of retrieval/reconsolidation memory.Fourthly, to explore the possible molecular explanations for the link between the (-)-mefloquine action and the retrieval/reconsolidation stages of memory formation process in the dual-CCI model of neuropathic pain, we preliminarily examined the changes of several components important for synaptic plasticity, e.g., p-ERK1/2, PKC and NR2B, in the selected brain regions including hippocampus, ACC and spinal cord. The data revealed that the expressions of p-ERK1/2, PKC8 and NR2B were elevated to a varied extent in these brain regions examined, but predominantly in the spinal cord, of the dual-CCI rats without (-)-mefloquine treatment. Following (-)-mefloquine treatment, however, the expressions of these proteins, especially of NR2B, were decreased in the spinal cord of the dual-CCI rats. By contrast, in ACC only p-ERK1/2, and in hippocampus none of these proteins, were obviously down-regulated in the dual-CCI rats treated with (-)-mefloquine. The results further provide molecular evidence supporting that the therapeutic efficacy of (-)-mefloquine against CCI neuropathic pain could be linked to the second CCI-induced spinal analogue of retrieval/reconsolidation memory. |
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