In this report, our results indicated that perisciatic nerve administration of em l- /em CDL (1.5, 3, and 6?mg/kg) around the operated side of CCI rats also attenuated CCI-induced neuropathic pain in a dose-dependent manner and without tolerance. Perisciatic nerve administration of W.T. Wang, which was found to have favorable antinociceptive effects in acute and chronic pain in our previous work, and the mechanism of W.T. Wang, a traditional Chinese medicine, has been widely used clinically as an analgesic for hundreds of years. Several natural products from W.T. Wang have been demonstrated to have extensive pharmacological activities [28, 29]. In this statement, our results indicated that perisciatic nerve administration of em l- /em CDL PRPH2 (1.5, 3, and 6?mg/kg) around the operated side of CCI rats also attenuated CCI-induced neuropathic pain in a dose-dependent manner and without tolerance. Further results indicated that em l- /em CDL decreased the upregulated expression of mNGF and proNGF in the DRG and sciatic nerve of CCI rats and that the antinociceptive effect of em l- /em CDL was reversed by intraplantar administration of NGF to the hurt hind paw. Interesting, in the DRG, em l- /em CDL decreased NGF in small neurons and increased NGF in large and medium neurons. Small and medium cell body are nociceptors that transmit nociceptive stimuli, while medium and large cell body are nonnociceptive neurons [30]. NGF increases in small neurons, especially C fibers, with high TrkA intensity may promote neuropathic pain [31] by releasing SP and CGRP to promote central sensitization [32], indicating that em l- /em CDL not only decreases the expression of NGF to exert antinociception but also maintains the physical function mediated by NGF in CCI rats. Our previous research also found that em l- /em CDL shows affinity to both dopamine D1 receptors (D1DR) and dopamine D1 receptors (D2DR) with IC50 of 0.20?M and 0.86?M. And we found that em l- /em CDL could antagonize spinal D1DR and D2DR to attenuate chronic pain ( em the manuscript is being submitted /em ). In addition, em l- /em CDL was also found in our previous study to alleviate chronic pain through inhibiting spinal N-Methyl-D-Aspartate (NMDA) and metabotropic glutamate1/5 (mGlu1/5) receptors [10]. But in the periphery, em l- /em CDL was found showed great potential to suppress NGF, whether em l- /em CDL induced inhibition of NGF was mediated by dopamine receptors or glutamate receptors will need further exploration. And our future research will investigate the associations of dopamine receptors, glutamate receptors and NGF in the chronic pain. However, we also could Pim1/AKK1-IN-1 not disavow the synergistic effects of em l- /em CDL in multi-target approach, which might largely explain the strong observed effects Pim1/AKK1-IN-1 in attenuating chronic pain. NGF binding to its receptors was reported to activate MAPK family [33]. The MAPK family has three users, ERK, JNK, and p38, which promote the release of proinflammatory cytokines and are Pim1/AKK1-IN-1 associated with chronic pain [34]. Activated MAPK contributes to NF-B p65 activation, which promotes the production of proinflammatory cytokines such as TNF- and IL-1 and prospects to the development and maintenance of pain [35]. Our results found that em l /em -CDL obviously inhibited the expression of p-ERK, p-p38, p-JNK, p-p65, TNF-, and IL-1 in the DRG and sciatic nerve, which was reversed by NGF, indicating that em Pim1/AKK1-IN-1 l- /em CDL suppressed NGF to attenuate CCI-induced neuropathic pain though the inhibition of downstream MAPKs and the proinflammatory cytokines TNF- and IL-1. TAK1 is usually a member of MAPKKK family and is usually upstream of MAPK [36]. Inhibition of spinal TAK1 attenuates nerve injury-induced neuropathic pain [8]. While the expression of TAK1 in the periphery has not been clarified in neuropathic pain, we examined whether peripheral NGF-induced activation of MAPK was mediated by TAK1. Our results indicated that this expression of p-TAK1 was also upregulated in the DRG and sciatic nerve, and intraplantar administration of TAK1 inhibitor significantly attenuated CCI-induced neuropathic pain and inhibited the expression of MAPK in both the DRG and sciatic nerve. Both em l- /em CDL and anti-NGF mAbs suppressed the expression of p-TAK1, and em l- /em CDL-induced inhibition of p-TAK1 was reversed by NGF. In our research, em l- /em CDL was found could attenuate CCI-induced neuropathic pain in the operated sides but not in controls. Our results indicated that em l- /em CDL did not inhibit the expression of mNGF or proNGF in the DRG and sciatic nerve in control rats (data not shown) which might be different from the effect of NGF mAbs. And em l- /em CDL induced inhibition of p-TAK1, p-MAPK, NF-kB and proinflammatory cytokines were all could be reversed by NGF, indicating that em l- /em CDL inhibited the upregulated NGF in.