GLIA: A NOVEL DRUG DISCOVERY TARGET FOR CLINICAL PAIN

REVIEWSa Intact sidec Intact sidehyperalgesia, also blocked glial activation 10,11 .Thesestudies established that glial activation, at minimum,closely tracked neuropathy induced allodynia and hyperalgesiaas well as their pharmacological resolution.The potential implications of the data collected byGarrison et al. were breathtaking. If glial activation wasindeed a causal factor in the development of allodyniaand hyperalgesia, rather than simply being correlatedwith these conditions, it would be a dramatic departureb Nerve-damaged sided Nerve-damaged sideFigure 2 | A historical look at glial involvement in pain. The first evidence that glia wereinvolved in pain modulation came from the work of Garrison et al. who showed that astrocytes inspinal cord were activated (as reflected by immunohistochemistry for the astrocyte-specificactivation marker, glial fibrillary acidic protein) in response to sciatic nerve damage. They examinedthe effect of chronic constriction injury (CCI), as it is one of the best-validated animal models ofpartial nerve injury leading to chronic pain. Although previous studies had identified central nervoussystem glial activation as a rapid response to peripheral nerve injury, the work of Garrison et al. wasthe first to link such glial activation to a functional outcome, namely, enhanced nociception. In theupper panels (a and b), the spinal cord ipsilateral of sciatic CCI is compared with the spinal cord onthe healthy sciatic side. Clearly, these two sides look different. To more clearly see what thisdifference is due to, the lower panels (c and d) provide a higher-power image of dorsal hornastrocytes. Compared with astrocytes on the healthy spinal cord side (c), astrocytes on the nervedamagedside (d; same magnification as c) are hypertrophied and more darkly stained, which is asign of astrocyte activation. Modified, with permission, from REF. 10 © Elsevier Science Ltd (1991).from the classical view that exaggerated pain states arecreated and maintained solely by neurons. In practicalterms, if glia were key players, it would open up wholenew approaches for clinical pain control, as drugs thatalter glial function were likely to be unique from drugstargeting neurons.So, how could one test whether glia are necessary orsufficient for allodynia and hyperalgesia? Neitherquestion proved easy to address, given the limitedpharmacological tools available, and the even morelimited knowledge of how glia might alter nociception.What became clear, however, was that every modeltested that induced allodynia and/or hyperalgesia wasassociated with the activation of both astrocytes andmicroglia 12 (FIG. 3). So, finding ways to test glialinvolvement became essential.The question of whether glia are necessary for allodyniaand hyperalgesia addresses whether exaggeratednociceptive responses will occur if neurons, but not glia,are present. In practice, this translates to pharmacologically‘removing’ glia by disrupting their function. Twodrugs have been employed for this purpose: fluorocitrate,which selectively disrupts the Krebs energy cycle ofglia by inhibiting the glia-specific enzyme aconitase 13,14 ;and minocycline, which selectively disrupts the activationof microglia without directly affecting neurons or astrocytes15 .Both agents have been found to be effective inblocking diverse models of allodynia/hyperalgesia 16–21 .Two intriguing, and interrelated, findings are worth noting.First, fluorocitrate, which disrupts astrocyte as well asmicroglia function, seems to exert more profound blockadeof exaggerated nociceptive states than does minocycline,which targets only microglia. Second, minocyclineis far more effective in blocking, than reversing, exaggeratednociceptive responses 20,21 .The most importantrole of microglia might be involvement in the initialinduction of exaggerated responses to noxious stimuli.Microglial activation leads, in turn, to astrocyte activationthat maintains the facilitation of nociception 20 .Developing an effective strategy for testing whetherglial activation is sufficient to induce allodynia/hyperalgesiais dependent on identifying ways to selectivelyactivate these cells. Although studies of glial cultureshave identified neurotransmitters that can activate glia 9 ,that information is of little use here for two reasons.First, virtually all data on glial responses to neurotransmittershave been derived from glia isolated from thebrain. Given the marked heterogeneity in both receptorexpression and response properties of glia isolatedfrom various CNS regions 22,23 ,extrapolating results frombrain to spinal cord glia is problematic. Indeed, there areeven heterogeneities between glia in nocisponsive layersof the superficial dorsal horn (laminae I–III) versusother spinal regions 24–26 . Little information is availableas to what neurotransmitters excite dorsal spinal cord gliato produce and release neuroactive substances 27,28 .Giventhat dorsal horn glial activation occurs in response toperipheral injury and inflammation 12 , it would seemreasonable to predict that neurotransmitters are releasedin spinal cord in response to peripheral injury, and thatinflammation will be found to activate these cells.976 | DECEMBER 2003 | VOLUME 2 www.nature.com/reviews/drugdisc