Analgesic Activity Of Catalpol In Rodent Models Of Neuropathic Pain And Mechanism

Objectives: Neuropathic pain(NP) is a serious health issue for people that represents a great social and economic burden in the world. Most current drugs for NP fall into the categories of opioid analgesics, NSAIDs, a2 adrenergic receptor agonist, Antiepilepticand antidepressants. Unfortunately, these medications may provide unsatisfactory results and produce various side effects, which underscore the need for novel analgesics. The catalpol is an active component in Rehmannia glutinosa, and has shown potent anti-inflammatory, anti-diabetic, and neuroprotective activities. However, no reports have been published on the analgesic effects of catalpol. Thus, the study aimed to charact- erize the anti-allodynic effects of catalpol in models of neuropathic pain induced by chronic constriction nerve injury(CCI) and lumbar 5(L5) spinal nerve ligation(SNL).Method:The model study of chronic constriction nerve injury(CCI) and lumbar 5(L5) spinal nerve ligation(SNL) was used, we measured MWT(mechanical paw withdrawal therold) value, MPE(maximal possible effect) value, and detected the level of Iba-1(the microglia activation marker), NF-κB activation, production of IL-1β,IL-6 and TNF-α,to analysis the data and evaluate the effect of catalpol in the model of the CCI and SNL.Results:(1) For catalpol group in the model of CCI, 2-way ANOVA on MWT demonstrated a significant treatment effects between groups(F(6, 388) = 216.9, P<0.001), a significant effect of time(F(8, 388) = 149.45, P<0.001). Post hoc Bonferroni’s tests showed that CCI significantly decreased MWT(P<0.001 vs. sham control),and administration of catalpol once per day reversed mechanical allodynia(P<0.001). The anti-CCI-induced allodynia effects of catalpol were dose-dependent, and no development of tolerance to the anti-allo- dynic effects was seen. The MPE of catalpol at doses of 1, 5, 25, and 125 mg/kg on the 7th day after treatment was 31.94 ± 5.64, 38.06 ± 5.78, 61.94 ± 5.14, and 69.13 ± 5.12 %, respectively, and the MPE for gabapentin at 50 mg/kg was 61.19 ± 6.18 %.(2) The effect of catalpol in the SNL was similar to results of CCI,2-way ANOVA on MWT demonstrated a significant treatment effects between groups(F(6, 386) = 239.72, P<0.001), a significant effect of time(F(8, 386) = 173.75, P<0.001). Post hoc Bonferroni’s tests showed that SNL significantly decreased MWT(P<0.001 vs. sham control),and administer- ation of catalpol once per day from days 4 through 10 reversed mechanical allodynia(P<0.001). The anti-allodynia effects of catalpol were dose-dependent, and no development of tolerance to the anti-allo- dynic effects was seen,too. The MPE of catalpol at doses of 1, 5, 25, and 125 mg/kg on the 7th day after treatment was 18.12±6.45%, 31.04±5.82%, 64.05±5.67%, and 71.94±4.13%, respectively, the MPE for gabapentin at 50 mg/kg was 47.01±6.33%.(3) In the sham control rats, staining for the microglia activation marker Iba-1 in the spinal cord was barely detectable, the number of Iba-1 immuno-reactive cells significantly increased in the dorsal horn ipsilateral to the CCI injury, but catalpol reduced the enhanced Iba-1 immuno-reactivity in the spinal cord.(4) CFA increased NF-κB activation and production of TNF-a, IL-1b, and IL-6 in the rat spinal cord on the 10 th day after CCI induction. Catalpol at 25 and 125 mg/kg attenuated CCI-induced increases in TNF-a, IL-1b, and IL-6,and activated NF-κB levels were also sign- ificantly reduced with catalpol.Conclusion:(1)CCI and SNL decreased MWT and MPE,however, catalpol reversed mecha- nical allodynia and significantly reduced neuropathic pain in two preclinical models,the level of MWT and MPE rised after injecting catalpol.(2) Repeated administration of catalpol resulted reversal of mechanical allodynia in CCI and SNL models, suggesting that catalpol may be efficacious in reducing neuropathic pain. It should be noted that the effects of catalpol on tactile allodynia were dose-dependent and occurred as early as the first administration in neuropathic pain models, with higher efficacy than gabapentin. In addition, the trends of mechanical withdrawal threshold curves for groups treated with catalpol suggest that consecutive administration of these molecules allows different doses of catalpol to reach higher effective levels.(3)The catalpol decreased the microglia activation,NF-κB activation and expression of TNF-a,IL-1b, and IL-6 in the rat spinal cord.The mechanism was related to adjustment of TNFR and Akt,through inhibiting the conduction of NF-κB and microglia activation,and release TNF-a,IL-1b, and IL-6.Thus,the neuropathic pain was reduced.