The Mechanism Of Formoterol In Paclitaxel-Induced Neuropathic Pain In Rats

Objective: To observe the role of formoterol,a long-acting β2-adrenoreceptor(ADRB2)agonist,in paclitaxel-induced neuropathic pain(PINP),and further explore its related mechanism.Methods: Male Sprague-Dawley rats were intraperitoneally injected with paclitaxel 2mg/kg on day 0,2,4 and 6 to establish the model of PINP.The mechanical paw withdrawal threshold(MPWT)of rats was measured by Von Frey to evaluate the pain behavior.Western blot was used to detect the expression of ADRB2,peroxisome proliferator-activated receptor γ coactivator-1α(PGC-1α),nuclear respiratory factor 1(NRF1),mitochondrial transcription factor A(TFAM),glial fiberillary acidic protein(GFAP),NF-κB p65,p-NF-κB p65,TNF-α and IL-1β.Immunofluorescence ws used to study the localization of ADRB2,PGC-1α,NRF1 and TFAM in the spinal cord and spinal astrocyte reaction.Mitochondrial DNA(mtDNA)copy number was detected by RT-PCR.In addition,the role of PGC-1αmediated mitochondrial biogenesis in PINP was investigated by using PGC-1α agonist ZLN005 alone or combined with PGC-1α inhibitor SR-18292.To investigate the role and mechanism of formoterol in PINP,formoterol was administered alone or combined with PGC-1α inhibitor SR-18292.Results:(1)MPWT of PINP rats was significantly decreased,beginning on day 7 and lasting to day 21.Paclitaxel significantly reduced the expression of ADRB2 in spinal cord of rats on day 14 and day 21,and ADRB2 was colocalized mainly with neuron,rarely with microglia and astrocyte.Intrathecal injection of formoterol could relieve mechanical allodynia in PINP rats.Early administeration of formoterol significantly increased MPWT of PINP rats on day 7,but not on day 14 and day 21.Multiple intrathecal injections of formoterol at 14-18 d significantly increased the expression of ADRB2 in the spinal cord of PINP rats.(2)The mtDNA copy number and the expression of PGC-1α,NRF1 and TFAM in the spinal cord of PINP rats were significantly decreased on day 14 and day 21.PGC-1α,NRF1 and TFAM were all colocalized predominantly with neurons.Intratheral injection of PGC-1α agonist ZLN005 alleviated mechanical allodynia in PINP rats,and this effect was blocked by SR-18292.Early administeration of ZLN005 significantly increased MPWT of PINP rats on day 7 and day 14,but not on day 21.(3)SR-18292 could partially abolish the analgesic effect of formoterol against PINP.Multiple intratheral injections of formoterol significantly increased the mtDNA copy number and the expression of PGC-1α,NRF1 and TFAM,inhibited the activation of astrocytes and NF-κB and decreased the expression of TNF-α and IL-1β in spinal cord of PINP rats.Conclusions:(1)The expression of ADRB2 was decreased in the spinal cord of PINP rats.ADRB2 activation with formoterol could significantly relieve PINP and delay the onset of PINP.(2)Spinal mitochondrial biogenesis was impaired in PINP rats.Induction of PGC-1α-mediated mitochondrial biogenesis could significantly relieve PINP and delay the onset of PINP.(1)Formoterol alleviated PINP probably by promoting spinal mitochondrial biogenesis and reducing spinal neuroinflammation.