Pharmaceutical composition for treating pain
A technology for drugs and opioids, applied in the field of pharmaceutical compositions for treating pain, can solve the problems of aggravating pain and tolerance, increasing drug dosage and the like
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Embodiment 1
[0103] Example 1. Screening of AC1 & 8 mixed inhibitors
[0104] A panel of biochemical screening assays was performed to find potential AC1 and AC8 co-inhibitors (or referred to as AC1 and 8 inhibitors). A cAMP assay, gene activation (pCREB) assay, and comprehensive physiological assays were performed in AC1 or AC8 expressing cell lines to screen for potential compounds A and B acting on AC1 and AC8. Both NB010 and NB011 were found to produce significant inhibition of AC1 as well as AC8 activity at 100 μM (see Table 1). For the test method, see Wang, H.S., et al., Identification of an Adenylyl Cyclase Inhibitor for Treating Neuropathic and Inflammatory Pain. Science Translational Medicine, 2011.3 (65).
[0105] Table 1. Effects of NB010 and NB011 on the activity of adenylyl cyclase subtypes 8 and 1
[0106]
Embodiment 2
[0107] Example 2. Evaluation of Anxiety-Related Cortical LTP by NB010 and NB011
[0108] Previous studies have shown that synaptic LTP induced by repetitive stimulation requires AC1 and AC8 activity (Zhuo, 2016). To assess the effects of NB010 and NB011 on the activity of neurons AC1 and AC8, the inventors recorded both forms of LTP in ACC cortical slices of adult mice.
[0109] As previously described, theta-stimulus stimulation induced a potentiation of synaptic responses lasting at least 40 min ( figure 1 A, n=8 slices). Pretreatment with NB010 (25 μM) can block the induction of ACC LTP ( figure 1 A, n=5 slices). Similar results were obtained using NB011 for preprocessing (see figure 2 , n=6 slices). In contrast, the same dose (25uM) of the non-selective AC inhibitor SQ22356 did not cause a significant decrease in pre-LTP ( figure 2 , n=5). As a comparison, pre-LTP was not blocked by GABApention (25 uM) (n=5). A recent report by ACC (Chen et al., 2014) also foun...
Embodiment 3
[0113] Example 3. Behavioral Effects of AC1 and AC1 & 8 Inhibitors on Morphine Tolerance
[0114] First, the inventors wanted to examine whether AC1 knockout mice affected morphine tolerance induced by repeated injections of morphine. As previously reported by the inventors, the inventors injected morphine (10 mg / kg, s.c.) daily for 7 days to measure morphine-induced tolerance. The inventors found that in AC1 knockout mice, compared with saline-treated wild-type mice (n=5-8 mice: day 7: control mice, MPE 18±6%, AC1KO, 40±8%) In contrast, morphine produced significantly greater analgesic effect; P image 3 ).
[0115] A previous study of AC1 and AC8 double knockout mice found significantly reduced morphine tolerance (Li et al., 2006). The inventors anticipate that AC1 & 8 inhibitors may also have the beneficial effect of reducing morphine tolerance. Similarly, pretreatment with NB010 or NB011 (5 mg / kg, i.p.) (n=5-8 mice, p<0.05 compared to control treatment in each case) pr...
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