Neuropathic pain following nerve injury may have clinical manifestations such as hyperalgesia, allodynia and spontaneous pain . This can be a result of hyperexcitability in peripheral nerve fibres, but may also involve induction of long-term potentiation (LTP) in the CNS. In this issue of the Scandinavian Journal of Pain, Bojovic and coworkers address the possible role of changes in the immediate early gene proteins (IEGPs) Arc, Zif268 and c-Fos expression in the dorsal horn during neuropathic pain following noxious conditioning stimulation of the sciatic nerve . The aim of the study was to compare the effect of this noxious conditioning in neuropathic rats versus non-neuropathic rats.Previously, Bojovic and coworkers have shown that the noxious conditioning changes the expression of the IEGP mentioned above , as well as induce spinal cord LTP . Earlier data suggest that the LTP phenomenon induced by noxious stimuli represents a cellular memory of nociceptive information. Several lines of evidence show that extracellular signal-regulated kinase (ERK) is activated in the dorsal horn neurons following noxious sciatic nerve stimulation . ERK can be translocated to the nucleus where it activates the cAMP element binding protein (CREB), which in turn stimulates transcription by binding to the regulatory cAMP response element (CRE). Many IEGPs including Arc, Zif268 and c-Fos may be induced by the ERK-CREB pathway.The IEGP responses are complex and may include induction of many different transcription factors as well as growth factors, signalling enzymes, phosphatases and structural proteins. Since the late-phase LTP in the dorsal horn may be blocked by protein synthesis inhibitors , it seems likely that maintenance of LTP in the spinal cord involves de novo protein synthesis. A primary nuclear event in this process may be the induction of IEGs. Evidence exists that peripheral inflammation also increases the expression of the CRE-containing IEGs in the spinal cord .The results of Bojovic and coworkers showed that Arc, Zif268 and c-Fos exhibited a significant increase in the dorsal horn immunoreactivity the first hours after the sciatic conditioning compared with time-matched, sham operated controls. As in previous reports , the authors show that maximal IEGP expression may be found 2 h after the conditioning. Interestingly, the increase in IEGPs following sciatic conditioning was more pronounced in the neuropathic rats than in the non-neuropathic rats. If this up-regulation of the IEGPs induces spinal hyperexcitability, these data indicate that noxious input after nerve injury through the IEGPs may result in increased susceptibility to further noxious stimuli.The study of Bojovic and coworkers may be informative for both basic scientists and clinicians interested in neuropathic pain. However, whether or not induction of spinal cord LTP induced by the experimental conditioning stimulation of the sciatic nerve really is relevant for sensitization in patients may be debated. Moreover, the authors have not directly examined the relationship between the changes in the IEGPs and development or maintenance of neuropathic pain, only demonstrated an up-regulation of three IEGPs. Hence, when it comes to the clinical interpretations, the study has clear limitations, which also are emphasized by the authors in their discussion .Conflict of interest: The author declares no conflict of interest.ReferencesDworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR, Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA, Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C, Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003;60:1524–34.1462372310.1001/archneur.60.11.1524Dworkin RH Backonja M Rowbotham MC Allen RR Argoff CR Bennett GJ Bushnell MC Farrar JT Galer BS Haythornthwaite JA Hewitt DJ Loeser JD Max MB Saltarelli M Schmader KE Stein C Thompson D Turk DC Wallace MS Watkins LR Weinstein SM Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations Arch Neurol 200360152434Bojovic O, Bramham CR, Tjolsen A. Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy. Scand J Pain 2016. pii:S1877-8860 (15) 00095–6.Bojovic O Bramham CR Tjolsen A Stimulation-induced expression of immediate early gene proteins in the dorsal horn is increased in neuropathy Scand J Pain 2016S1877886015000956Bojovic O, Panja D, Bittins M, Bramham CR, Tjolsen A. Time course of immediate early gene protein expression in the spinal cord following conditioning stimulation of the sciatic nerve in rats. PLOS ONE 2015;10:e0123604.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000352590300105&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=b7bc2757938ac7a7a821505f8243d9f310.1371/journal.pone.012360425860146Bojovic O Panja D Bittins M Bramham CR Tjolsen A Time course of immediate early gene protein expression in the spinal cord following conditioning stimulation of the sciatic nerve in rats PLOS ONE 201510e0123604Haugan F, Wibrand K, Fiska A, Bramham CR, Tjolsen A. Stability of long term facilitation and expression of zif268 and Arc in the spinal cord dorsal horn is modulated by conditioning stimulation within the physiological frequency range of primary afferent fibers. 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Scandinavian Journal of Pain – de Gruyter
Published: Dec 29, 2017
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