Neuropathic pain is an intractable chronic pain condition. The efficacy of sodium channel inhibitors for treating neuropathic pain has been examined in the past decade.[5] Because current therapies for neuropathic pain are not suitable for some patients, the search for new pain medications and therapies must continue.[6]
In this study, we examined pain inhibitory effects of choline and parecoxib sodium in rats with neuropathic pain. We used the CCI model because it has been reported that this model may simulate some characteristics of neuropathic pain in humans, and CCI of the sciatic nerve induced rapid and significant mechanical and heat hypersensitivities in rats.[7] Similarly, our study showed that CCI rats began to develop pain hypersensitivity at 3 days after injury, and persisted through the study period. The affected hind limb (i.e., ipsilateral to the side of CCI) showed eversion, and were often lifted to avoid touching the ground. The paw withdrawal threshold to mechanical stimulation and paw withdrawal latency to heat stimulation were significantly decreased, as compared to that before the injury.
Parecoxib sodium is a highly selective COX-2 inhibitor. It inhibits the production of PGE2 and nitric oxide and regulates neurotransmission in the spinal cord dorsal horn.[8] Parecoxib sodium has been reported to reduce the accumulation of tumor necrosis factor -α (TNF-α) and neutrophils in inflammatory exudates (Add reference please). Compared to other commonly used NSAIDs (e.g., diclofenac and nimesulide), parecoxib sodium induces a quicker pain inhibition in humans.[9] Studies also showed that parecoxib sodium reduced pain and inflammatory responses in formalin and other inflammatory pain models.[10] Our study demonstrated that after 7 days of treatment with 6 mg/kg and 12 mg/kg parecoxib sodium, CCI rats showed significant reductions of mechanical and heat hypersensitivities, as compared to pre-drug condition. However, 3 mg/kg dose was not effective. Thus, moderate and high doses of parecoxib sodium reduced neuropathic mechanical and heat hypersensitivities, and these findings are consistent with a previous report.[11]
As a specific α7nAChR agonist, choline exerts anti-inflammatory and analgesic effects through activation of cholinergic anti-inflammatory pathway,[12] which was shown in several pain models and sepsis models.[13] In acetic acid torsion model, choline induced dose-dependent analgesic effects.[14] In current study, choline attenuated mechanical and heat hypersensitivity in CCI rats at 12 mg/kg and 24 mg/kg doses, but 6 mg/kg was not effective. Under chronic neuropathic pain condition, the decomposition and synthesis of ACh were reduced in the hypothalamus, causing a low level of cholinergic activity.[15] Our findings suggest that choline supplement may help to alleviate chronic pain after nerve injury.
In patients with diabetic neuropathy and postherpetic neuralgia, a previous study showed that morphine in combination with a low dose of gabapentin provided a better pain relief than morphine alone.[16] In current study, co-treatment of CCI rats with a low, sub-effective dose of choline (6 mg/kg) and parecoxib sodium (3 mg/kg) induced a significant pain inhibition, indicating that two drugs may exert an additive or synergistic pain inhibitory effect. Using low doses may limit the dose-limiting adverse effects for each drug .
After peripheral nerve injury, glial cells were activated and pro-inflammatory cytokines were released in the spinal cord.[17] HMGB1 is a late inflammatory factor. It can promote the release of pro-inflammatory factors and more HMGB1 from inflammatory cells, thus forming a positive feedback loop and aggravating inflammatory responses.[18] NF-κBp65 is an activated nuclear signal transduction protein, and mediates the production of inflammatory mediators.[19] Our study showed that the expressions of HMGB1 and NF-κBp65 were increased in DRGs after CCI, which may increase the inflammatory responses and pain.
Parecoxib sodium was shown to reduce the expression of HMGB1 in cerebral ischemia model, and hence it plays a neuroprotective role.[‘20] Choline-activated α7nAChR signaling pathway was suggested to be sensitive to control HMGB1 release.[21] In this study, although there was a trend that parecoxib sodium at 3 mg/kg dose reduced HMGB1 and NF-κBp65 levels, the difference was not statistically significant. Similarly, choline at 6 mg/kg dose did not significantly reduced the upregulated HMGB1 and NF-κBp65 expression in CCI rats. However, a combination of these drugs significantly reduced the expressions of HMGB1 and NF-κBp65, which was consistent with findings in our behavioral study. HMGB1 can bind and activate TLR4 receptors, and induces the production and release of inflammatory factors. NF-κB, as a major nuclear signal transduction protein that mediates the production of a variety of inflammatory mediators, is downstream of HMGB1/TLR4 pathway.[22–23]Therefore, these findings suggest that choline and parecoxib sodium may both inhibit HMGB1/TLR4/NF-κB signaling pathway, and may be used together for the treatment of neuropathic pain which remains a great clinical challenge.
Parecoxib sodium is frequently used in the clinic as an analgesic, but has dose-limiting side effects.[24]The cholinergic pathway may also be targeted for pain inhibition by inducing an anti-inflammatory effect.[25]Current findings suggest that combining choline and parecoxib sodium, which have different properties, may improve neuropathic pain inhibition and decrease the side effects of each drug by reducing the required dose. This notion needs to be further tested in future clinical studies.