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Seminars in Anesthesia, Perioperative Medicine and Pain (2007) 26, 17-21

he role of adrenergic receptors and pain: The good,he bad, and the unknown

an Carroll, MD, MS,a Sean Mackey, MD, PhD,b and Raymond Gaeta, MDb

rom the aDepartment of Anesthesia, Stanford University, and the

Pain Management Clinic, Stanford University Hospital, Stanford, California.

Adrenergic receptors appear to play an important role in the modulation of pain. There is now abundantevidence that activation of adrenergic receptors can, in certain circumstances, generate impressiveanalgesic effects. However, under other circumstances, adrenergic receptors can contribute to chronicneuropathic pain and hyperalgesia. This review will focus on the beneficial effects of adrenergic painmodulation, and the circumstances when this modulation appears to magnify pain. This review will alsoaddress controversies surrounding how these two opposing processes occur via the same mediators.© 2007 Elsevier Inc. All rights reserved.

KEYWORDS:Pain;Neuropathic pain;Sympatheticallymaintained pain;Adrenergic receptors;Alpha receptors;Beta receptors;Clonidine;Epinephrine;Norepinephrine;Chronic pain

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he good: evidence supporting an analgesicr anti-hyperalgesic role of adrenergiceceptors

asic science

As early as 1980, Reddy and Yaksh1 demonstrated thenti-nociceptive effects of intrathecal norepinephrine inats and cats. This analgesic effect was antagonized by theddition of the alpha-blocker phentolamine but was notffected by pre-treatment with the beta blocker propranolol.n addition, no cross tolerance with morphine was observed,uggesting that the morphine analgesia was not mediated byhe adrenergic receptors. These results implicated alphadrenergic receptors in the mediation of noradrenergic an-

Address reprint requests and correspondence: Dr. Ian Carroll, Stanfordniversity, Department of Anesthesiology and Pain Management, 780elch Rd. Ste 208E, Palo Alto, CA 94304.

eE-mail: irc38@pain.stanford.edu.

277-0326/$ -see front matter © 2007 Elsevier Inc. All rights reserved.oi:10.1053/j.sane.2006.11.005

lgesia and suggested an opioid-independent modulation ofain.

Recent work utilizing patch clamp analysis of membraneotential and currents has provided insight into noradrener-ic anti-nociceptive mechanisms. Sonohata et al. examinedembrane potentials of substantial gelatinosa (Lamina II)

ociceptors neurons in the dorsal horn of the spinal cord inive rats under anesthesia. Perfusion of the spinal cord withorepinephrine resulted in hyperpolarization of these noci-eptors with suppression of discharges that appeared to beediated by G-protein-mediated activation of K� channels.his effect on post-synaptic fibers was mimicked by thelpha-2 agonist, clonidine, and was blocked by the alpha-2ntagonist, yohimbine. Alpha-1 receptor and beta receptorntagonists appeared to have no effect on these currents.2

Pre-synaptic actions of norepinephrine have also beendentified on these same substantia gelatinosa neurons. Nor-pinephrine reduces A delta-fiber and C-fiber postsynapticlutamine-induced excitatory currents. This effect of nor-

pinephrine was mimicked by clonidine (a nonspecific al-

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18 Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 26, No 1, March 2007

ha 2 agonist) and oxymetazoline (an alpha 2A agonist).he effect was antagonized by yohimbine (an alpha 2 an-

agonist). However, norepinephrine did not affect the am-litude of miniature excitatory postsynaptic current toMPA, an excitatory neurotransmitter, suggesting that nor-

drenergic suppression of postsynaptic excitatory currentsccurs through inhibition of presynaptic glutamine release.3

The importance of alpha-2 receptors to the analgesicctions of norepinephrine is underscored by studies of tiza-idine, a centrally acting alpha-2 agonist. In a chronic con-triction injury model (CCI), tizanidine showed completeeversal of thermal hyperalgesia when given systemicallyompared with normal saline with no behavioral correlatesf sedation in the rats.4

The sodium channel-blocking anticonvulsants carbamaz-pine and oxcarbazepine produce a dose-dependent de-rease in inflammatory hyperalgesia initiated in rats byoncanavalin A injection. Surprisingly, the anti-hyperalge-ic effects of these sodium channel blockers were reducedy yohimbine, an alpha-2 antagonist, suggesting at leastartial contribution of alpha-2 agonism in the mechanism ofction of these anticonvulsants. The addition of clonidine tohe anticonvulsants produced synergistic effects as mea-ured by isobolographic analysis.5 The real importance ofhese finding remains to be determined, but possibly sug-ests a larger role for adrenergic modulation of neuropathicain than previously suspected.

Another non-intuitive postulated mechanism of action ofdrenergic pain modulation is through immune modulation.eripheral nerve injury produces hyperexcitability in axo-

omized and nearby spared unaxotomized dorsal root gan-lion neurons. Liu et al. reported that clonidine injectederineurally 2 weeks after partial sciatic nerve ligation inats decreased hyperexcitability across all fiber types. Theyostulated that clonidine reduces inflammatory cytokines,nterleukin 1-beta and TNF-alpha, along with prostaglan-ins which may induce phenotypic changes in the neuronfter peripheral nerve injury producing an inflammatoryeuritis.6

Anti-inflammatory effects of clonidine have been sug-ested by experimental data in a rat model of acute inflam-atory neuritis. In this model, perineural clonidine reduced

he number of leukocytes and macrophages present as wells decreased the expression of TNF-alpha following nervenjury. These effects were countered by the administrationf an alpha-2a antagonist.7 These possible immunomodula-ory effects do not explain the immediate analgesic effectsf norepinephrine described above but may contribute toong-term anti-hyperalgesic effects described below.

In summary, a broad set of experimental data suggest annalgesic modulation of pain through adrenergic receptors,ith evidence pointing to alpha 2 receptors (possibly alphaa receptors) as the significant inhibitory modulator. Postu-ated mechanisms of analgesia engaged by alpha-2 receptorsnclude: activation of post-synaptic g-protein mediated hy-

erpolarizing potassium currents, pre-synaptic inhibition of i

lutamine release, immunomodulation, and modulation ofodium channels.

linical science

In humans, there is clear evidence of clinically relevantdrenergically mediated analgesia. Clonidine exhibits anal-esic properties in a dose-dependent fashion when admin-stered intrathecally in the first stage of labor in women. Aandomized double-blinded administration of 50, 100,r 200 mcg of clonidine intrathecally produced increasingime to the request for additional analgesia with a mean of43 minutes at 200 mcg compared with 45 minutes in the0 mcg group. Concordantly, Visual Analog Pain ScoresVAPS) were lower with 200 mcg compared with the 50 mcg.8

Epidural clonidine has also been reported to reduce painn those suffering from Complex Regional Pain SyndromeCRPS; formerly known as Reflex Sympathetic Dystrophy,SD). However, the hypotensive, bradycardic, and sedativeffects were reportedly significant.9

More intriguing than the acute analgesic properties oflonidine is the potential long-lasting anti-hyperalgesic ef-ect. In a startling clinical trial, 60 patients undergoing rightolon resection were randomized to receive either 300 mcgf intrathecal (IT) clonidine, normal saline, or bupivacaine.n the short term, significantly lower PCA morphine re-uirements were seen in the IT clonidine compared with ITorphine or saline. Additionally, mechanical hyperalgesia,

s measured by von Frey hair testing, showed a significantlymaller area of sensitivity in the clonidine group (3 sq cm)ersus morphine (35 sq cm) or saline (90 sq cm). Mostmportantly, however, was the finding that at 6 monthsesidual pain was seen in 0/20 clonidine patients comparedith 6/20 saline patients (P � 0.05), demonstrating the

ong-term benefits of IT clonidine in this population. Bu-ivacaine appeared to have a trend toward long-term reduc-ion of pain but was not as effective as clonidine.10 Theseong-lasting effects of a single dose of clonidine given at theime of nerve and tissue injury may reflect decreased centralensitization in the dorsal horn of the spinal cord or may behe result of immunomodulatory effects described above.he mechanisms underlying these findings merit further

nvestigation.

he bad: evidence supporting a nociceptive oryperalgesic role of adrenergic receptors

asic science

The axons of intact nerves are normally incapable ofenerating impulses upon slow or prolonged depolarization.owever, in 1983, Devor noted that, following injury or

ocal demyelination, “the primary change in sensory fibers

n damaged nerves is their transformation from impulse

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19Carroll Adrenergic Receptors and Pain

onductors to impulse generators.” Devor proposed that “anctopic pacemaker” with chemosensitivity to alpha adren-rgic agonists develops in these areas of nerve damage. Inupport of this postulate, he noted that epinephrine andorepinephrine injected close intra-arterially increased thepontaneous discharge rate seen in injured nerves. This waseproduced by the alpha 1 agonist phenylephrine but not theeta agonist isoproterenol, and concordantly was blockedy the alpha blocker phentolamine but not the beta blockerropranolol.11

Since then, investigators have clarified that Devor’s pos-ulates were essentially correct. Injured sensory nerves inats increase transcription of alpha 1b adrenergic receptorRNA but not other alpha 1 mRNA. This receptor may playrole in conferring adrenergic sensitivity to nerves in rats

ollowing nerve injury and thus contribute to a sympathetic-ensory coupling that results in adrenergic amplificationather than inhibition of pain.12

In rabbits, direct electrical stimulation of the sympatheticrunk 2 to 4 weeks following greater auricular nerve injuryirectly activates c-fiber polymodal nociceptors in the in-ured auricular nerve. Similar activation of these c-fiberociceptors can also be elicited by injection of epinephrinento the great auricular artery feeding the distal portion ofhe injured nerve. This nociceptor activation by sympathetictimulation or epinephrine injection can be inhibited byhree alpha2 adrenergic blockers: yohimbine, rauwolscine,nd clonidine. Of note, only 20% to 30% of nociceptorsecame responsive to sympathetic stimulation or epineph-ine.13 These studies suggest that, in addition to previoustudies demonstrating alpha adrenergic sensitivity in pri-ary afferents ending in neuroma, such signals can also be

enerated at the peripheral nociceptor terminals. Under sim-lar condition in the absence of previous auricular nervenjury, these cutaneous nerves are not responsive to epi-ephrine or sympathetic stimulation.14

Similar responses are seen in rats 6 to 12 days followingciatic nerve transection and neuroma formation. A total of0% of assayed A-beta and A-delta fibers gained chemo-ensitivity to catecholamines as assessed by changes inaseline firing frequency in response to epinephrine. Most,ut not all, of these fibers responded with an increase inring rate. A small minority of chemosensitive fibers re-ponded to epinephrine by decreasing their production ofpontaneous ectopic discharges. Receptor selective agonistsnd antagonist indicate that this chemosensitivity was me-iated by alpha 2 receptors in 65% of afferent fibers sam-led, and by alpha-1 or both alpha-1 and alpha-2 in 23% ofbers. These results indicate that the sympathetic-sensoryoupling occurred at the peripheral neuroma and in axoto-ized dorsal root ganglia (DRG) neurons. They also sug-

est that sympathetic-sensory coupling was mediated pri-arily by alpha 2 receptors.15

In a rat model of segmental nerve injury pain (ie, ligatingspinal nerve), rat pain behaviors develop that can be

meliorated by sympathectomy. In these models, the pain (

ehaviour can be rekindled following sympathectomy byntradermal norepinephrine and alpha 2 but not alpha 1drenergic ligands. This rekindling can be blocked by alphabut not alpha 1 antagonists.16 These data further support

he key role of alpha 2 adrenergic receptors in the rat modelf sympathetically augmented neuropathic pain, and sug-est that the salient receptors are located not just at theutative site of nerve injury, but more distally in cutaneousissue.

After nerve damage but not in its absence, sympatheticerve signals and norepinephrine are excitatory for skinociceptors in rats. These effects become apparent withinays following the nerve lesion, and occur at cutaneouseceptive terminals in fibers that have escaped degenerationssociated with the injury and are mediated by alpha 2drenergic receptors.14

Similar changes occur in the monkey. Following ligationf the L6 nerve root, partial denervation occurs on theorsum of the monkey’s foot with a 45% reduction inutaneous unmyelinated c-fibers. Single nerve cell record-ngs from the uninjured c-fiber nociceptors innervating theorsum of the foot reveal: a high incidence of spontaneousctivity, a high incidence of increased firing in response tohe alpha-1 agonist phenylephrine, and also to UK14304 anlpha 2 agonist.17 Thus, in the monkey, results similar to theouse are seen. The only significant difference is the re-

ponsiveness observed to alpha-1 agonists that is not usuallyeen in the rat models. Indeed, in the monkey model, al-ha-1 adrenergic receptor agonists were more salient acti-ators of c-fiber nociceptors than alpha 2 agonists. Based onhese monkey data, and human clinical data, it has beenostulated that primates may differ from sub-primates in theelative importance of alpha-1 and alpha-2 receptors inmplifying neuropathic pain.17

How might catecholamines reach injured nerves to stim-late them in adrenergically amplified pain states? Thebove data suggest that adrenergic sensitivity can occuristally in the skin. Other investigations suggest that sym-athetic-sensory coupling may occur at the level of theRG as well. Following experimental sciatic nerve injury,

ympathetic postganglionic nerves sprout to form basket-ike structures around somata of primary sensory neurons inhe DRG. These structures have been seen in experimentallynjured rats and in human neuropathic pain patients.18

linical science

The data suggesting that adrenergic stimulation can pro-oke or augment pain in humans have not been universallyccepted.19,20 Nonetheless, there is significant evidence thatdrenergic receptor activation plays an important, clinicallyelevant role in augmenting pain under a variety of circum-tances. Evidence implicating adrenergic receptors in hu-an chronic pain states comes from two lines of evidence:

1) direct augmentation of pain by adrenergic agonists, and

2) relief of ongoing pain by adrenergic blockade.

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20 Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 26, No 1, March 2007

ugmentation of pain by adrenergic agonistsIn patients with sympathetically maintained pain, but not

hose with sympathetically independent pain (as categorizedy response to sympathetic blocks), iontophoretic applica-ion or cutaneous injection of norepinephrine can increasepontaneous pain in symptomatic areas of skin comparedith saline placebo.21 Going one step further, Ali et al.erformed sympathetic blocks on 12 patients known toeport relief to sympathetic blocks. Not surprisingly, theroup reported significant relief (70% reduction in paincores). Patients were then injected with either saline ororepinephrine cutaneously on both the affected side andhe contralateral side. On the affected side but not theontralateral side, norepinephrine induced significantlyore pain than saline placebo in a dose-dependent fash-

on.22 This experiment demonstrates that, in patients withympathetically maintained pain, inhibition of noradrener-ic neural transmission results in pain reduction in painfulreas that can be rekindled specifically by adrenergic ago-ists but not saline placebo. The experiment also suggestshat this effect is specific to regional areas affected byympathetically maintained pain.

Rowbotham et al. examined 15 subjects with chronicost-herpetic neuralgia not suspected to have sympatheti-ally maintained pain, in a placebo-controlled, double blindtudy of cutaneous adrenergic sensitivity. Subjects alter-ately received injections of saline or epinephrine into ei-her neuralgic skin or mirror image normal skin. Injection oformal saline and adrenergic agonists into normal skin didot differ significantly and provoked mild transient pain.ain following saline injection into allodynic skin elicitedore pronounced transient pain that was nonetheless fol-

owed by significant resolution of pain. However, followingpinephrine injection into allodynic areas of post-herpeticeuralgia, pain and allodynia were more severe and contin-ed to worsen significantly up to 15 minutes post-injec-ion.23

Chabal and colleagues injected nine patients withhronic neuromatous pain with saline placebo, epinephrine,r lidocaine. Epinephrine significantly augmented patientsersistent pain and lidocaine significantly reduced it.24

The above data suggest that there is something uniqueo the areas in which people are hyperalgesic, which endowshe affected nerves with the observed chemosensitivity.europhysiologic experiments in healthy humans suggest

hat norepinephrine further excites cutaneous nociceptorslready discharging in response to experimentally inducedyperalgesia. In thermal hyperalgesia induced by capsaicin,ontophoresis of tyramine to cause release of endogenoushysiologic levels of norepinephrine significantly augmentsyperalgesia. This enhanced hyperalgesia can be blocked byretreatment with cutaneous phenoxybenzamine (a nonspe-ific alpha blocker). In the absence of cutaneous hyperalge-ia induced by capsaicin, iontophoresis of the same dose ofyramine does not provoke pain or hyperalgesia.25 In this

odel, hyperalgesic changes are induced over a half hour m

nd are reversible, resolving over several hours. These ex-eriments suggest that the enhancement of nociception byutaneous alpha adrenergic receptors occurs only in a spe-ific hyperalgesic state that is related to the state of sensi-ization of the organism rather than to new gene expression.n other words, the change that is responsible for the pain-ugmenting effects of adrenergic stimulation may be one ofeural sensitization and activation rather than new genexpression.

elief of ongoing pain by adrenergic blockadeSympathectomy has long been reported to ameliorate the

ain of causalgia.26 Reduced sympathetic stimulation ofllodynic and hyperalgesic areas has been accomplished byvariety of means. Price et al. characterized the sensory

hanges experienced by patients with sympathetically main-ained pain before and after sympathetic blockade. Theybserved that, whereas sympathetic block produced nohange in thermal pain thresholds, sympathetic blockadepecifically reduced mechanical pain thresholds comparedith pre-block in patients with sympathetically maintainedain.27 Wahren et al. characterized the changes in painhresholds in patients following intravenous regional block-de with guanethidine. Mechanical vibratory pain thresh-lds and heat pain thresholds were markedly increased, upo the normal range following guanethidine treatment,hereas pain thresholds in the uninjured arm did not

hange.28

Raja et al. pioneered the use of intravenous phentol-mine, a nonspecific alpha adrenergic receptor blocker, toiagnose sympathetic pain. Their original work demon-trated high correlation of pain relief during phentolaminenfusions and sympathetic block.29 Subsequent work dem-nstrated that the response to phentolamine is dose depen-ent.30

Phenoxybenzamine, a nonspecific31 alpha blocker thatovalently binds to alpha adrenergic receptors, has also beensed for intravenous regional anesthesia for CRPS. Theuthors reported unusual prolonged analgesia, but the studyad few patients, no control group, and their results have noteen replicated.32

Clinical data seem to suggest that pain which is initiallyugmented by adrenergic stimulation may become insensi-ive to this stimulation over time. Torebjork et al. followedp on nine patients with sympathetically maintained painSMP) 12 to 16 years after initial evaluation. Only three stillad SMP. And four out of five had lost their previousutaneous sensitivity to norepinephrine.21

onclusion: the unknown

here is significant basic and clinical science to suggesthat, under specific conditions, pain is relieved by adrener-ic stimulation, and under other conditions pain is aug-

ented by it. In animals, both types of response appear to be

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21Carroll Adrenergic Receptors and Pain

ediated by alpha-2 receptors. The circumstances thatause adrenergic stimulation to become pro-nociceptiveather than anti-nociceptive in these animal models remainoorly understood. Initial reports implicated ectopic expres-ion of adrenergic receptors in response to nerve injury, butewer data showing that mere sensitization with capsaicinan rapidly evoke this phenotypic switch call this theorynto question. In humans, the specific receptors mediatinghe pro-nociceptive effects of adrenergic stimulation re-ains unsettled but appears to be alpha-1 receptors, a sig-

ificant deviation from animal models. Future work in thisrea to determine how these receptors promote the opposinghenomena of increased pain and analgesia under divergentonditions will improve our understanding of the role of theympathetic nervous system in chronic pain.

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3. Kawasaki Y, Kumamoto E, Furue H, et al: Alpha 2 adrenoceptor-mediated presynaptic inhibition of primary afferent glutamatergictransmission in rat substantia gelatinosa neurons. Anesthesiology 98:682-689, 2003

4. Hord AH, Chalfoun AG, Denson DD, et al: Systemic tizanidine hy-drochloride (Zanaflex) relieves thermal hyperalgesia in rats with anexperimental mononeuropathy. Anesth Analg 93:1310-1315, 2001

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