breaking the pain barrier

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NEWS AND VIEWS NATURE MEDICINE VOLUME 9 | NUMBER 11 | NOVEMBER 2003 1353 developed long-lasting tactile allodynia and thermal hyperalgesia. When rats received artemin at the time of nerve injury, both types of pain were fully reversed. Artemin also provided partial pain relief when injected after the neuropa- thy was fully developed, two weeks after ligation. In the next set of experiments, the authors evaluated the effects of artemin at the biochemical level (Fig. 1). Spinal nerve ligation prompts neurochemical changes in the spinal cord and sensory ganglia, which contain the cell bodies of the injured neu- rons. In the spinal cord, these changes include increases in calcitonin gene–related peptide (CGRP) and dynor- phin, peptides that contribute to the main- tenance of pain. Breaking the pain barrier Halina Machelska, Paul A Heppenstall & Christoph Stein Artemin reverses pain and neurochemical changes after nerve injury in an animal model. The molecule could potentially treat neuropathic pain, in which even the slightest touch can hurt (pages 1383–1389). Some of the worst types of pain comes from no defined source, and can flare up in response to normally innocuous stimuli such as brushing of the skin or contact with clothing. Such pain, called neuropathic pain, is a major and often debilitating con- sequence of nerve damage. It is poorly understood, and existing treatments are largely ineffective. In this issue, Gardell et al. provide evidence that artemin, a protein that promotes neuronal survival, at least partially reverses sensory and neurochemi- cal abnormalities in an experimental model of neuropathy 1 . Neuropathic pain can be caused by infec- tious agents or metabolic diseases such as herpesviruses or diabetes. It also can appear after nerve injury, as in amputation or cancer-induced nerve compression, or as a result of multiple sclerosis or chemotherapy. Patients often feel sponta- neous cramping, burning or shooting pain. When provoked by normally innocuous stimuli such as brushing of the skin, the pain is called ‘allodynia’. When the pain is enhanced after stimuli such as heat or pres- sure, it is termed ‘hyperalgesia’ 2,3 . Neuropathic pain is accompanied by changes in the expression of neuronal ion channels, neurotransmitters, peptides and their receptors 4 . Current therapies consist mostly of antidepressants, anticonvulsants and opioids 5,6 . Although in many cases these drugs provide some relief, they are limited by serious side effects that preclude long-term use and sufficient dosing. Artemin is a member of the glial cell–derived neurotrophic factor (GDNF) family, which consists of secreted proteins that promote neuronal survival. Their expression alongside blood vessels sup- ports the development of sympathetic axons 7 ; they also promote survival of peripheral sensory nerves 8 . These func- tions, coupled with observations that the receptors for these molecules are upregu- lated after nerve injury 9 , suggest that GDNF family members might have regen- erative effects on injured sensory neurons. This hypothesis was recently tested for the prototypic factor, GDNF. Boucher et al. 10 gave a continuous spinal infusion of GDNF to rats with experimental neuropa- thy, and found that it reversed the pain. Now, Gardell et al. report that the related factor artemin has similar effects when given systemically. To evoke neuropathic pain, the authors ligated rats’ spinal nerves, a common model that may resemble nerve damage caused by events such as cancer-induced nerve compression or traumatic disruption of large nerves. The operated animals Halina Machelska, Paul A. Heppenstall and Christoph Stein are at the Klinik für Anaesthesiologie, Charité-Universitätsmedizin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany. e-mail: [email protected] Control Artemin Marker CGRP DYN Control Artemin Marker CGRP, SP, Na v 1.8, IB 4 , P2X 3 NPY, galanin GFR- α 3 Spinal co o ord Spinal co o ord L L L 5 5 DRG DRG DRG L 6 DRG Ligature c Sciatic e nerve Figure 1 Gardell et al. induced experimental neuropathy in rats by ligating L 5 and L 6 spinal nerves. In the spinal cord, this caused an increase in the release of CGRP and boosted levels of the opiod dynorphin (DYN), peptides that can contribute to the maintenance of pain. In the L 5 dorsal root ganglia (DRG), there was a decrease in the expression of CGRP and other markers of pain-sensing nerves, such as substance P (SP), sodium channels (Na v 1.8), purinergic receptors (P2X 3 ) and isolectin B 4 (IB 4 ). In contrast, the expression of neuropeptide Y, galanin and the artemin receptor (GFR-α3) was enhanced. Artemin fully abolished the changes in the spinal cord, while partially reversing the changes in the DRG. The compound did not affect (–) the nerve injury–induced increase in expression of GFR-α3 in the DRG. With further study, artemin might represent an effective treatment for neuropathic pain. Kimberly Homer © 2003 Nature Publishing Group http://www.nature.com/naturemedicine

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Page 1: Breaking the pain barrier

N E W S A N D V I E W S

NATURE MEDICINE VOLUME 9 | NUMBER 11 | NOVEMBER 2003 1353

developed long-lasting tactile allodyniaand thermal hyperalgesia. When ratsreceived artemin at the time of nerveinjury, both types of pain were fullyreversed. Artemin also provided partialpain relief when injected after the neuropa-thy was fully developed, two weeks afterligation.

In the next set of experiments, theauthors evaluated the effects of artemin atthe biochemical level (Fig. 1). Spinal nerveligation prompts neurochemical changes inthe spinal cord and sensory ganglia, whichcontain the cell bodies of the injured neu-rons. In the spinal cord, these changesinclude increases in calcitoningene–related peptide (CGRP) and dynor-phin, peptides that contribute to the main-tenance of pain.

Breaking the pain barrierHalina Machelska, Paul A Heppenstall & Christoph Stein

Artemin reverses pain and neurochemical changes after nerve injury in an animal model. The molecule couldpotentially treat neuropathic pain, in which even the slightest touch can hurt (pages 1383–1389).

Some of the worst types of pain comesfrom no defined source, and can flare up inresponse to normally innocuous stimulisuch as brushing of the skin or contact withclothing. Such pain, called neuropathicpain, is a major and often debilitating con-sequence of nerve damage. It is poorlyunderstood, and existing treatments arelargely ineffective. In this issue, Gardell etal. provide evidence that artemin, a proteinthat promotes neuronal survival, at leastpartially reverses sensory and neurochemi-cal abnormalities in an experimentalmodel of neuropathy1.

Neuropathic pain can be caused by infec-tious agents or metabolic diseases such asherpesviruses or diabetes. It also canappear after nerve injury, as in amputationor cancer-induced nerve compression, oras a result of multiple sclerosis orchemotherapy. Patients often feel sponta-neous cramping, burning or shooting pain.When provoked by normally innocuousstimuli such as brushing of the skin, thepain is called ‘allodynia’. When the pain isenhanced after stimuli such as heat or pres-sure, it is termed ‘hyperalgesia’2,3.

Neuropathic pain is accompanied bychanges in the expression of neuronal ionchannels, neurotransmitters, peptides andtheir receptors4. Current therapies consistmostly of antidepressants, anticonvulsantsand opioids5,6. Although in many casesthese drugs provide some relief, they arelimited by serious side effects that precludelong-term use and sufficient dosing.

Artemin is a member of the glialcell–derived neurotrophic factor (GDNF)family, which consists of secreted proteinsthat promote neuronal survival. Theirexpression alongside blood vessels sup-ports the development of sympatheticaxons7; they also promote survival ofperipheral sensory nerves8. These func-

tions, coupled with observations that thereceptors for these molecules are upregu-lated after nerve injury9, suggest thatGDNF family members might have regen-erative effects on injured sensory neurons.

This hypothesis was recently tested forthe prototypic factor, GDNF. Boucher etal.10 gave a continuous spinal infusion ofGDNF to rats with experimental neuropa-thy, and found that it reversed the pain.Now, Gardell et al. report that the relatedfactor artemin has similar effects whengiven systemically.

To evoke neuropathic pain, the authorsligated rats’ spinal nerves, a commonmodel that may resemble nerve damagecaused by events such as cancer-inducednerve compression or traumatic disruptionof large nerves. The operated animals

Halina Machelska, Paul A. Heppenstall and

Christoph Stein are at the Klinik für

Anaesthesiologie, Charité-Universitätsmedizin,

Campus Benjamin Franklin, Hindenburgdamm 30,

D-12200 Berlin, Germany.

e-mail: [email protected]

Control ArteminMarker

CGRPDYN

Control ArteminMarkerCGRP, SP,Nav1.8,IB4, P2X3

NPY,galaning

GFR-α3 —

Spinal cooordSpinal cooord

LLL55 DRGDRGDRG

L6 DRG

Ligature

cSciaticenerve

Figure 1 Gardell et al. induced experimental neuropathy in rats by ligating L5 and L6 spinalnerves. In the spinal cord, this caused an increase in the release of CGRP and boosted levels ofthe opiod dynorphin (DYN), peptides that can contribute to the maintenance of pain. In the L5dorsal root ganglia (DRG), there was a decrease in the expression of CGRP and other markers ofpain-sensing nerves, such as substance P (SP), sodium channels (Nav1.8), purinergic receptors(P2X3) and isolectin B4 (IB4). In contrast, the expression of neuropeptide Y, galanin and theartemin receptor (GFR-α3) was enhanced. Artemin fully abolished the changes in the spinal cord,while partially reversing the changes in the DRG. The compound did not affect (–) the nerveinjury–induced increase in expression of GFR-α3 in the DRG. With further study, artemin mightrepresent an effective treatment for neuropathic pain.

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Page 2: Breaking the pain barrier

N E W S A N D V I E W S

1354 VOLUME 9 | NUMBER 11 | NOVEMBER 2003 NATURE MEDICINE

In sensory ganglia, the authors observeddecreased expression of CGRP, in contrastwith increased release of this peptide in thespinal cord. Further alterations in sensoryganglia include a decreased expression ofsubstance P, increased expression ofgalanin and neuropeptide Y (all three pep-tides are involved in pain transmission).Decreased expression of the artemin recep-tor GDNF family receptor-α3 (GFR-α3)also occurred. The expression of markersselective for pain-sensing nerves (puriner-gic P2X3 receptors and isolectin B4) wasdecreased, and one of the sensory neu-ron–specific sodium channels (Nav1.8, anion channel implicated in spontaneousnerve firing) had been translocated to thesciatic nerve, although the exact locationrelative to the ligature site was unclear.

All these alterations, except for thedecrease in GFR-α3, were partially reversedby artemin (Fig. 1). This suggests that theantihyperalgesic effect of artemin mightresult from the normalization of CGRPrelease and of the expression of CGRP, sub-stance P or P2X3 receptors, and thatartemin’s antiallodynic effect might berelated to the reversal of changes in neu-ropeptide Y. However, it is not clear whyartemin only partially restored most ofthese changes while fully abolishing painbehavior. It remains to be seen whetherthese biochemical changes represent non-specific actions of artemin or mediate itspain-suppressing effects.

The challenge now is to determine howartemin might be working. One commonfeature of neuropathy is continuous painresulting from spontaneously generatedneuronal activity in sensory fibers—so-called ectopic firing. Boucher et al.10 foundthat GDNF reduced ectopic firing, proba-bly by reversing injury-induced changes insodium channel expression. Does arteminwork in a similar way? If so, do both ofthese molecules use a common signalingpathway that could be targeted to treatneuropathic pain?

Because artemin changed the expressionof dynorphin, perhaps it could affect alsoother opioids such as enkephalins, anal-gesic peptides in the peripheral and centralnervous systems. Similar effects areobserved with opioid peptides in the brain,which contribute to the pain relief pro-duced by another trophic protein, brain-derived nerve growth factor11. The exactreceptor selectivity of artemin also isunclear, but the identification of specificantagonists should aid in receptor identifi-cation.

In the study of Gardell et al., onceartemin was discontinued, the analgesiaand neurochemical changes vanished. Inclinical practice, therefore, artemin wouldrequire lifelong application. A detailedevaluation of artemin-induced side effectsduring long-term application in rats willtherefore be essential before this com-pound can enter clinical studies.Nevertheless, Gardell et al. move us onestep closer to a treatment for painful neu-ropathies.

1. Gardell, L.R. et al. Nat. Med. 9, 1383–1389 (2003).2. Ralston, D.D. Pain Rev. 5, 83–100 (1998).3. Suzuki, R. & Dickenson, A.H. Neuroreport 21,

R17–R21 (2000).4. Woolf, C.J. & Salter, M.W. Science 288, 1765–1769

(2000).5. Sindrup, S.H. & Jensen, T.S. Pain 83, 389–400

(1999).6. Dellemijn, P. Pain 80, 453–462 (1999).7. Honma, Y. et al. Neuron 35, 267–282 (2002).8. Baloh, R.H. et al. Neuron 21, 1291–1302 (1998).9. Bennett, D.L. et al. J. Neurosci. 20, 427–437

(2000).10. Boucher, T.J. et al. Science 290, 124–127 (2000).11. Siuciak, J.A., Wong, V., Pearsall, D., Wiegand, S.J. &

Lindsay, R.M. Eur. J. Neurosci. 7, 663–670 (1995).

Scientists have sought to use immunizationas a method of treating cancer since thebeginning of immunobiology. Over manydecades, various approaches to elicitingboth innate and acquired immuneresponses against tumors have been tried,some with a degree of success. However,immunotherapy has yet to be incorporatedinto first-line therapies for more than avery few types of cancers, such as the use ofIL-2 immunotherapy for metastatic renalcell carcinoma1.

Treating cancer with something thatlooks more like a modern-day vaccine, witha defined antigen and an optimized adju-vant and delivery platform, is still in thefuture. In this issue, Padua et al. edge uscloser to this goal by testing a vaccineagainst acute promyelocytic leukemia(PML) in a particularly informative mousemodel2. They found that the vaccine pro-longed survival in combination with all-trans retinoic acid (ATRA), a drug alreadyused to treat patients with this form ofleukemia. This finding is potentially rele-vant for patients because ATRA alone tendsto provide only short-lived remission,unless combined with other cytotoxic ther-

apies. And even when combined with othertherapies, ATRA results in a cure rate ofapproximately 50%, so there is room forfurther improvement.

There are three basic challenges inattempting to treat cancer by using theadaptive immune system: breaking peri-pheral tolerance to generate adaptiveimmune responses (T cells or antibodies)against self or slightly modified self anti-gens; causing the effectors to home to thesite where tumor cells are present; andmaintaining effector function in the tumor environment, which may containinhibitory agents such as transforminggrowth factor-β.

Obtaining proof of concept for candi-date immunotherapies presents additionalchallenges. Animal models that use humantumors implanted into mice requireimmune-deficient hosts, as hosts withfunctioning immune systems will rejectexogenous tumors. Immune-deficientmodels can be suitable for the study ofinnate immunity, but clearly not for thestudy of acquired immunity.

Putting human oncogenes into mousetumors allows for experiments showingthat an immune response can target a par-ticular tumor. However, the oncogene maystill essentially be a foreign protein, andthus may not accurately mimic the induc-tion of an immune response to self. Themost relevant tumor immunotherapy

Cancer vaccine targets leukemiaJohn Donnelly

Effective cancer vaccines targeted against specific antigens have eludedresearchers for decades. When combined with a drug, one such vaccinenow shrinks tumors in a mouse model of promyelocytic leukemia (pages1413–1417).

John Donnelly is at Chiron Vaccines,

4560 Horton Street, Emeryville, California

94608, USA.

e-mail: [email protected]

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