Role of nitric oxide in the physiopathology of pain

ZllbUdUdi4m Many painful conditions are -iated with h)vrthermia of tbc overlying skin. Thege are often referred to as inflammatory pain. Some of these situations respond to antiinflammatory drugs, whereas others are refractory to common nonopioid analgesics or non-

corticoid anti-inflammatory agenl5. Temporomandibular disorders (TYD). for instance. pose a challenge to the practice of dentistry because of the cumtxrsomr and pcrsistent pain associated with there d@unctionr and the limited success in managing these conditions by surgery or other treatment% The same is true of riwumatoid arthritis @A), which is generallg aauwiated with a “hot” joint or joints. A major reason for the limited WCCAF in managing thou disorden is the lack of swflicicnt

understanding

of the

pathoph+ol-

ogy of painful joint d$mctions. which prcvents better targeted and optimized treatmew. In this paper, we present a hypothesis about the mechanism of pain midted with joint dy&mcdon. such as TMD or R1 We suggest that these types of pain are awociated with the extnvascular overpmdurtiun of nitric ouidc (NO), which actkatcs or sensitizes the nocirc~ pton in the affected area. This mechanism may ah apply to chronic orofacial pain and certain other painful conditions invohing the apoptosis and/or mhanced immune mpmooften aswciated with hurlls. al&raft rejection. or cancer. It ma) ulso ;1cc011111 for postoperatiw pain in a xwiety of situations. inchlding tl;e implantation u: .wtificial iiratwiab. and *My also for pain awx-iatcd with localired infections. To support this hypothesis. we review the published literature since 1993. many of ~hr-.w paperj cite important earlier studies. The available data provide much circumstantial evidence for the proposed mechanism, which fSh in line with the biological role of NO in other organ systems. Since this mechanism has not yet been proven directly, we sugget pas sible uays to corrobomte it experimentally. Because much of the information a+lable on tbc correla!ion between pain and skin hypertherma is derived lmm the study of painful TMD, we will we this condition ELIa model. If thii proposed mechanism is correct. optimal stntegies could be designed to treat painful joint dysfunctions. especially TMD and RA. ar well ar other paintid inflammatory conditions. ?here tiat+ies are di.ud in the last part of thii paper. .

.

PaittawktedwithlMDhasbeendefinedas a ppin in the -@III (TMJ) i.CgiORhdUdtllg~Uupon--uVaB.ItbgencraUyaam&tedtithtendemesrcd themasticatorymlrsdcr.pintsound9.andlimi. tadon (or disturizance) of mandibular morrmmt.‘2 IMD ts a common s)mptom aecting llMM-C(hanKt%ddtiat~OllCtitimc.md one io thee adults over their lifespan.’ A

nit:ional wrwy comprkiiig 42.(wm1’5 hw holds. awed suhj~c~s owr age t R !ran of age atld ILund 6% of thr population reported expericncing a qmptom pattern inwhitlg pain in the ,jaw joim and/or face.’ Wom& reported fxiat p;rio ?niptom5 more than nxe nr fnc qucntty as ~neti.~ In spitr of iu ext~emrly high kidwcr. thrrc i* kit) consciiw~ on a scientific hasis of trra~nrn~~ that might hvnrlir typical 7‘hID patkntv with pair,.’ A highh pcrtincnt cor#&~iotl has hrel? ~)hwr\ccl hctweeu pain nwocia~~d with TMD and tlw trmprratwc of the skit1 over the ;~lkcred TM1 arw Telethermog~:~phv (compurrri/rd. infrared rmis*ion arca trterhrrmomctrv). which ir rrwd to measure the tcmpcutuie of the face without cwtacting the kx has stwwn that while the mean temperawrc of diflcrent anatomic regions of the norm.41 her ranges owr 1.4X.” “normal” or ;L*ymptomatic TMJ sul+cts haw swnmetrical (or similar) thermal patterns and similar temperatures over the opposing TMJ regions. The ohserved differencr between the mean temperature of the TM.1 region from side-tc-side (ST) in asymptomatic subjects was 0.1 * O.IT.“.’ This is in agreement with older studies on the symmetry of skin temperature distrihution in normal subjects on other party of the human body.” On the other hand. TMJ pain patirntr were found to have asymmetrical thermal pattern% with increased temperatures over the TMJ region of their face (61‘ = +0.4 * 0.2-C).’ Furthermore. patients with painful TMJ due to internal derangement ;:nd patients with osteoarthritis of the TMJ were found to have comparable asymmetrical thermal patterns.“‘~” In other words, the aswciation between TMJ pain and hypenhermia of the owrlying region seems to be independent of he etiology of the TMJ disorder (for rxamplc. osteoarthritis versus internal derangement). A subsequent study of mil& moderate TMD patient showed that 8T increased in parallel with the patient’s perceiwd pain.” An additional doubleblinded clinical study compared active orthodontic patients, vetsus TMD patients, versus normal (control) subjects. and show& ST = -LO.P’C. +0.4X:. and +0.1-C :or these three groups. respectiwly.‘” I%* drmorwt ,tzd a significant difference between patienrr undergoing active orthodontic VCatment and patients with TMD.

In a preliminary duuhlc-blind study. it was found that local analgesia by lidocaine injccdon does not significandy afTec~ the perceived facial paiu or the 6T in TMD paricne.” From these studies. it appears chat there is a strong correlation between pain and local hyperthermia. measured as ST. caused hy \aundlation and suhsequrnc legional hyperperfusion. Furdwr, it was shorn that ST mejr rurementr can he useful in staging TMD.!’ and offer a mluahlr mcasurc of dw OIIICO~C of uratment.“’

Nitric oxide (NO) has been shown in recem years to lx involved in a large xwiety of bit> logical functions,‘.G” which has led to the suggeotion that this premordial chemical agent is a fundamental component of all living syxterns.” The involvement of nitric oxide in the manifestations ofjoint inflammadon ac well as in other peripheral inflammamry conditions, is. therefore, not surprising. There arc two manifestations of interest-hypenhermia and pain. In this section. we shall discus. the mechanism of h~rthcrmia. to lx followed by a section on the mechanism of peripheral nociception. Because both mechanisms involve nitric oxide as a primary factor. the observed correlation bcrween pain and hyperthermia is explained. This supports a working hypothc.is tiac the obserwd vawdilation in painful TMD and other joint disorders is mediated by nitric oxide produced in the extnvawdar space. The following is a brief rev& of the properties and fwxtions of NO that are relevant ICI painful TMD and other joint disc&en. Nihic

Oxi&

Cd” influx. in concert with acrtvlcholine rcleawd from sympahetic nmrws.“~“‘.‘“’ (h”’ influ can aka be increaed hy opening of Cid’)+ channels ty hrad+inin.” or b rkcuical fiild srimuhdon.‘“-*’ Acetvlcholine can induce NO production ir. certain endothelial cells b a mechanism that does nut inwhv the wgular Ck” channrk tihiih arc ncmnally opened b hmdvldnin.~’ III other mdothelial celh. ace+ choiine seem.9 to wqdrr SO to open calrium ion channek.Y’ impl$ng a posidw fwdbrk in SO pnxluction. which ma\ cwntrract dw in& hition of &OS activity by NO.‘“‘” A srcund 9-p~ of calciumdcpcndmt SOS b nNOS. which h;n heen idenrified in neur~n~.‘~~~ ILVI SO .S a chemical mcwngrr hrtwecn ~~curom.“‘.*‘.‘~ and. like eNOS. is inhibited b NO.” In addition. h’0 an be produced in large amounts by a calcium-independent mime that is synthesized on demand in mxrophages and related cell lines (including osteohlasu and chondraytes) in reaction to a variety of immune response fartor~.~ Unlike the constitutive enzymes eNOS and nN0.S. which are present in cells awaiting a almadulin signal to start producing NO, this enzyme. named inducible NOS (iNOS). must be synthesized de nova in the generating cells, which calls for an extensive induction per%~I.~ Other dii ferences in s~uctum and function between the isoforms of NO!?““.” are outside the scope of this paper. Inducible NO.5 is generally calcium independent. but certain forms. like iNOS of bovine chondro+es. may be calcium dependent.*’ The role of NO in immune response involves its cymstatic or cytotmdc activity. At high concentrations, NO can modulate the activily of cymchromes and them 7 inhibit the production of ATP in target cells. u5

and It.5 i&thml

Ph~dogical Fimctionr NO is an intermediate chembl mcacnger between the nervous system and vascular mu5de.‘“~‘” Vawdiladon k fzmsed hy rdaxadon ofvdscukr-thmusdaimIucedhycCMP (cyclii guqdyl monophosphau).‘5p NO ha heen shown to enhance cCMP pmducti~n.~ NOkfmmedfmLaginineimideenduthc iiil cells by the enzyme nitric oxide synthase (endothelial NOS. cNOS).*~ Endothelial NOSi3XliVdWdbyalmodulininRIponsclO

Becawe NO diffuses readily throughout dr sues and there seems to be no effecdw enz)~ matic oxidatin process to rcmm it, NO diffuses freely far beyond ti confines of its point of production. Consequently, if NO is overpm duccd in P certain locale. it will diffuse throughout the wrrmmdin~ tisues and alge basaiilation of the regional micrmascuhturr. resulting in local hyperpcrfusion. If the &CtCdICgiOIlhClOSCtOthCSkifl,WkC~heu

is normally diwpated by blackbody infrared radiation or by convection. such h!Frperfn sion is manifested as local hypes-thrrmia. Thiq mechanism. which has been offered as nn explanation of breast hyperthermia aswciated with breast cancer* and other inflamm,tor! diirder~,” c.m explain the observed local hyperperfusion tbat manifests as a “hot” TMJ region on the face of patient* with painful TMJ disorders. or as “hot” join& in RA or in osccoarthritis (OA). Rheumatoid wthritis and ostcoarthritir. which are closely related to TMJ disordrn.‘* have been shown to be associated witb enhanced local NO production.‘“*’ The a~+ ciation between artltritis and h10 is strong enough to suggest the use of NO a biological marker of the d&we.“’ It wz concluded that chondrocytes are die main source of SO in inflamed joints.‘” Independent studies, done years before the causal correlation hetwrcn NO and ~awdilatory hyperperfusion wb dis. cowred. have shown the usefulness of mcd?ju~’ ing hyperthermia of affected joints zu a diag nostic and management techniqtte..w’J In spite of its limitations.w.” static thrrmogmphy. which assesres changes in spatial distribution of temperatore over the skin of atTccted joints, is still being used as a clinical tool in the management of rheumatic disorden.~‘” The rationale for suggesting that painful ThID and RA are associated with enhancrwent of local NO level is based on the follow ing obsmations: Temporomandibular d%orders and RA hypertbermia can be classified as inllammatory immune responses. It has been shown that hyperthermia awxciated Gth inflammatory immune response is due to raodilation. induced most proobabty by nitric oxide (NO) overproduced by macmphages’7 and chondroC)US.” This hypodtesis is supported by demOnsvation of the presence of Snitmtymsine in woriai fluid from patients with rheumatoid arthritic inflammatory joint disease:P” Snitn+nnine is a characteristic pduct of NO Oxidatiw metaboiism.n~” These patients alao show significattdy higher lewls of om-atc in their urin~.~ In organ cultures. boti 5ynavid fluid and cartilage from patients titb rheumatoid arthritis were shown to produce N0.4” Aho. OA patienu showd elevated leveb of nitrite in their SynovLl fluid.~ TMD wils

shown to be oftrn aw~ciatrd with osteoarthritis.” which interfere5 with tbr normal mechanicall) uimallawd renmdeling of tbc joint. ‘and human ostroarthritis-sected chondrocytes were shown to produce NO generated b! an induriblr NOS.” Furthermore. hum.!!brrniatcd ccniral mtervcrtebral discs were shown to gt~~cratc NO. unlike nonhrrnialrd discs;“‘.“’ this is probab+ due to the ~-c*po~w of tbc o\twrytes to the necrosis and/or the bone resorption aswciated with hrrniation. Also, the level of tiitritc and nitrare in the rerebrospinpl fluid ((SF) of paticrw with Iwnhar spondylosis arc signilicantI! rlrvatcd. c~,mparcd with as\mptomatic subjccts.x” Inbibivd bone ~crwdelinR aswciated with TMD .wd RA czn br related to locally enhanced NO production. It war show that proinflammatory rytokiner induce NO pro duction in osteoblast-like cells by INOS, and that NO is involvrd in down regulating their growttl.‘~~“’ It was further reported that cndothciial NO. produced by constitutive NOS. down regulate the growth of osteoclascs,probably by direct ;.xerference with tranwrip tion.*’ In othe. wrds. NO seems to be overproduced in afTected joint area by osteoblasts and chondrocyws. in addition to macrophages, and this overproduction of NO inhibits bone rcmodcli~ig.“’ w Because osteoclasb and macrophager have the same progenirors.“g~w osteoclasts also ran be induced to generate SO.““ Moreover, macrophages. which can pry duce NO, were reported to be involved in bone rwxption. Specifically, these cells actirite osteublasts to secrete sobstanr~r which enhance osteoclastic activity;” as positive feedhack, osteohlasts produce a macrophage colony~timulating fa~:or.~ Gm9equendy, the nsodilation auociatcd with painful TMD, CIA. and RA seems to be coincidental with an auto catalytic owrpduction of NO.“.!‘:’ In inflammation that does not involve bone tiuue. extra\ascular NO must be generated primarily by mxrophages or other leukocytes. It is noteworthy that certain macrophage lines harvested from humans showed substantkdly lower NO productivity than murine macrophages.” which haw been the subject of the majority df studies on macrophage activity. This has led to the nodon that animal studies of local inflammation and infection haw lim

ited clinical relevance.“:’ However. the inhihitory effect of NO on human T-cell activatio”P’~‘” and the effect of N O generated h, human macmphages on the proliferation c,f human lymph~.!” both of which manifest negative feedback in the control of inflamma tion (similar to the effect on NO on oswocyta in bone remodeling. discussed above). This corroborates the involvement of NO in processes other :han boric lemodrling alw in humans.

II has been known for a long time that inflammatory processes are associa!ed with enhanced production of a number of sub stances. mostly polypeptidn. such as bradykinin. inrcrleukin-1 beta (ILI). tumor necrosis factoralpha (TNF). substance P, prostaglandin E2 (PCE2!, interferonqtmma (IFNG). calcho nin gene-related pepride (CGRP). verve growth factor (NCF), serotonin and hisumine.= Our discussion would not he complete if we failed 10 discuss the effects of these sub stances in conjunction with our proposed mechanism of NO-enhanced perfusion and nociception. Ptacticalty all of these substances. some of which are produced by neurons, have heen shown IO be asociated with enhanced production of NO. Some of these subslanc~ have been shown 10 be precursors in the sequence of steps that results in \asodiia*ion and nociccption, wherea others were shown to be regulated by NO a an intermediate me+ senger. Brxiykinin. which has been reported to a& M W nocicepton and induce local rasodilation in rheumatic diaeases.l’w~‘“’ induces TNF release. which in turn induces iNOS to generare ew~ravascular NO.“” The vasodilator~ effect of bradykinin. which cwntually lea& IO enhanced cGMP production. was shown to be mediated by NO through enhancement of iNOS synthesis.‘“~“” Ahhough lhcre are conflicting reports concerning the effects of NO mediation 011 certain effects of tindykinin. such as bradykinin-mediated inflammatory edema.1”5~“‘b there is little doubt that NOinduced awdiladon is no1 m&iiared @ bradykinin. whereas bradykinin-induced vaodiktion’ ir mediated by NO.‘” Because there is a differrncc between the mechanisms

vf va.wdilation and mirrmawul;ur pcrmrxhilin (which result\ in edema). bmdvkinin ma\ h.nr difierml functions in these two proccw~ I,I any case. hradykinin ir a precurv~r in the sequence of substances that rrwlt< I,, wthimcemcn~ of iNOS svntheG and r~rntual va.9odila1ion.“‘” Interlcukin-I beta. likr hradvllnin. u~egulatcs iNOS in many cell line. mxrmpkages in pa&~lar.~~“““” It HZ show1 in ccrtain cell lines that the induction of SO pnrhrc. lion hy IL1 requires TNF a\ a c&actor. wl.lli.ll” This finding is in conccr~ Alh recem IindinF concerning tinrue specificiw of iSO%“” IL-1 SLTXILC not only to enhanrr iNO!, nntlw&, but il also cnhancm the uanrpwt ofqinw thr pwc”Mr of No.‘= The Cffecl of IL1 cm c.:her inllammaro~ mcdiaron. such as adrencrorticotmphic hcmne. seems to bc doun+quhtc~I bv NO.“’ indiiating negaiw feedback rrguk lion of the inflammatory process.” The pain-rclaced rffect 4 subarawr P. which inwlvn neurons inneruting bet niatrd discs.“’ is enhanced in rhr spine ur.der conditions of penistent pain.“cc”5 Thrse processes ako have heen shown to be invohd in the local nociccption that accompanies both RA and OA.“m ‘* The nociceptiw effect of sub stance P was shown to be mediated h\ SO both ar the local and spinal Ie~els.‘~.‘~ and could br blocked hy inhibition of NO synthesis.‘““-‘“’ Also. enhancemrnr of microvascular permrabili~ induced locals h sulxwance P MU re~nedly inhibited b blocking NO qnthesis. ml” In other word,. notwirhstanding the effect of bradykinin dir cusud afxxe. NO may play a primary rolr al541 in inllammacory edema. Prostagiandins. especi+ PC&. have been implicated in inflammatory pmesses. i icluding rheumatic dismders.*‘~“~c’.‘u The interreladonship between PC& and NO prodwtion is complex, depending on the riswe studied. Like subscanee I’, PGE, dot-s not rnhance SO or cCMP pmduction in neuronal adlures.‘” but enhance?, the production of IFSG and TNF, which in turn enhances the qn.hesir of iNOS by macmphages.‘35 Mowover, in cetin macrophage lines. NO enhances TNF outP”‘. ‘% ThLL is another aulorata~tic NO route of pmduch. in addition to the ferricin path way d&cussed elsewhere.* In Kupffer cells. which are fixed macruphages in the liver.

Vd 14 No. 4 Orrobn 1997

Nilrir(hddrdPnin

or immunological rejjecrion). inflammation caused by infection.“’ burn injury.“’ or 3lhIgraft reject10n.“2 is associated with enhanced NO levels (generally produced by macrophages).‘~‘n This results in vasodilation and/or enhanced microvascular permeability (edema).‘” Skin inflammatory dermaIOSCS, such as psoriatic lesions. exhibit abnormally higb levels of mRNA of iN0.S.“” which explains the local vasodilation and hypenhermia’w awociated with these disorders. Ahhougb enhanced levels of exwavacular NO have a bactericidal’““.‘“’ or protozoicidal’R’-‘“5 effect following one or more of several alternative molecular n;echanisms.‘5~‘““‘w infection-induced NO production does nor necessarily mean that NO is alwayseffective asa baclcriostaric orbxteritidal agent.‘” In brief. there is ample evidence thal most of the “classical” inflammatory substances. polypcptides or modified amino acids. are associated with NO production, either as pw cursotx of enhanced NOS actiiity or as bie chemical agents released in response Lo enhanced NO production. In any case. inflammation is generally awciated with enhanced local level.5 of NO. t&rmas&r

By Mechanical

Nitric Oxi& Initnkm

iMast

In addition to being induced by cytokines. 2s discussed above. SO could be produSx-d in an inflamed joint by an ahernative mechanism. It is possible Lhat mechanical strw aw* ciated with microtrauma in the alTec~ed joint region inducn endothelial or other crlls to gcnemte excessive NO. The mechanism of this mode of NO generation is similar 10 that of c~l~an~wl NO reirasc avacialed with shearing hemodynamic forces.‘“‘.“’ cvclic strain.‘~’ or even loGal ‘prcss”re.‘!“~’ ‘j pululile flow.“~ Tbv piezoelectric effect of mechanical stress on bodm could contribute to local NO prv duction by increasing CL?’ influx by an rlectic field effect.‘“.‘” “’ Any of phase mechanical r*ff+as on cell membranes are likely 10 ion flux into cells and. bj afkct the Ca” increaing the level of calmodulin. aaivae constitutive NOS.‘“‘.‘” This mechankm may proceed in parallel with mhanrrd NO prw duction by cylokines associated with bone remwieling and inflammation.

231

Nitric. Oxi& Hyjmduity

R&me

By Nmnmnl

Cytokines lha~ induce be

produced

nor

only

NO production hy lymphocytm

can and

OJrewyIes. iu discuvd above. hut S}- neuronal cells as well. Hard and soft tisruer within the affected TMJ region contain nerve fiber+. If these nerve fiben arc irritated due to microor marrc+ trauma, they may rcleaw NO by a non-adrenrrgic, nonxholinergic nrurogenic mrchanism.‘w’B*’ Mechanical irritation ma) induce neurogenic SO release similar IO the demonstrated eNect of chemical nerve irrictti~n.~“.~’ it i5 alw po4ble that in the caw of TMD. constant peripheral :wcicrptirc inpul causes changes in thr central nervous s~wzrn (CNS) that rewlts in udxmced prcduclion of ?!O by rhe peripheral trigeminal IICW~. The lalrer mechanbms might perhaps rwplain the idtntification of enhanrrd nNOS in oatwarlhritic jointa.x”

Enhancrd level of X0 in thr TMD alr~ or in other arthritic ioinw could occur becauw of NO generated by osteoc)tes. chondrocytes. macmphages. endothelial cells. or neumns. or by nvo or more of these padways. The elTcw of enhanced regi~mal, exua\auular NO lewl on the hemcd}wwnics of the local nsculature. manifrsred in the neural temperature contml of thr skin. is similar 10 that of a nerve blnck.~” because the extra\awular SO overrides the neural NO-mediated control of Ironstriction and rawdilarion. Onrc CXW-.X; r&.r NO Gffuses m m a blood \rwl it is wavenged by hemoglobin and rxhed out b) the circulaCng blood.“’ Consequently. 10 maintain local hyperpcrfusion. ex%wascular SO must contintrously be produced 9 one or more of the mechanisms divussed above. Enhanced perfusion, which entaib btwer oxxxen and nuirienl apply and phagwywsis. in the inflamed region are jmt two of the many functions of NO in inflammation. Enhanced nociception. which will be discuswd below. is a function that afTects the behavior of animal or humans. NO wecms to have also a biochemical regulatory role in local iqflamm;rtion. In addition to its effect on ILI. dircuwd

232

‘4nbm ad Gmn

above. NO acts synetgically with transforming growth factor beta (TGF-beta) and dexamechasotte to suppress histamineindured edrma.m It thus c0tlstitlltcs part of a negative fkdback loop to control the extent of the edemat”us pr”cess.~ The regulatory role of NO in inflammatory procesres~‘~‘~ is, however. outside the purview of this paper.

hWC&idt?tJ7ldPt?Tiphtd NtUkpth We have seen that local inflammation ir invariably associated with enhanced levels of intravascular and extramscular NO, and that most of the incrcared local level of NO is prw duced by cxtravaw~lar iNOS.Y’M.Y’” and bv some extmvarular constitutive NOS.“” Thi association between inflammation and NO is strong enough to suggest NO as a diagnostic marker of inflammation.*” Ir war concluded that NO has both anti-inflammatory and proinflammatory properties, depending on and phase of the inflammatory prc+ Ihe T= We now suggest that NO at the inflamcessm matory site is rhe agent which enhances peripheral tmciception. which may drive the perception of pain. The perception of pain caused by inflammdlion depends on three levels of neuronal function: peripheral nociception at the site of inllammation,P” spinal processing and uanrmiuion.““““” and cerebral percep tiot~.*‘~ NO seems to be invot~rd z .di thew thrit kwls. that is. at the cerebral.‘m-‘“.“‘c”’ spinal. l2l.l’m2n-ssI =“d pcriphem, ,e”els,‘:w This paper focuses on the suggested effect of NO on peripheral nociception and its E”I ~!alion with local msodilAon. Spinal pain arscxiated with herniated dii~*‘~“‘~~~ can be r’aailied as peripheral nociception. because the spine b in thii case the site of inflammation. It ha ken concluded that pain awociated with OA is due to synovird inflammation.‘~” and that pain in RA is assoc:ated with enhanced sufxtance P and IL2 in the syn”Gal fluid.‘n~ Bc& these subsnnres induce pry duction of NO: As described abow. substance P is known to induce NO prodoction. and it has been shown that the s)no&l fluid is the swrce of NO in RA patients.” Furthermore, the local inflatmnatory, vasodilatory etTect of 8ahwtnx P on the mictwaxulature b NO

Vd 14 No. 4 Odobcr 195’7

mediaicd.“‘.‘” Also IW-induced vasodilarion and opillary leakage are mediated by NO,‘“‘210 an I induction of NO synthesis by IL2 was directly observed in natural killer cells”’ and in splencwvtes.“” In hrief. these cytokines induce NO production and, consequently, their suggested nociceptivc effect may be mediated by NO. II ha been show in muline models. that NO enhances the sensitivity of peripheral nocirrp ,“ls,?l‘l and that inhibitors of NOS can act ar analgesic agents at the cerebral.“‘“““’ spi”a,,‘w4~+ 2.52and peripheral”“‘~5?.ie’7 levels Kiuir oxide senritizes nocicepton that respond 10 morphine.‘.w’w’ and to kctorolac.S’ Also, NO is a cofactor in pain induced by p~ostagl~din FTmz It KU also reported that peripheral inflammation affects the response of the NO-medidted spinal nociception.w There is direct widenre that NO c.m induce pain locally. lntrdcutaneoos injections of NO IO humans were shown to induce dosrdependent local pain.‘w and similar findings were “bra&d more recently when YO was injected intravenourly.““5 The latter finding suggesrs chat NO is the chemical link in prtiphctal and w~ular nociception.” This conclusion is in line with the amplification of the allodynic effect of formalin i.ljection in mice by topical L-arginine.Pw which enhances Ioral NO production. These fil.ding are romplemented by the observation that the an*i~~~-ir:,Ge effect of topical lidocaine and iu analogwn on ocular hemodynamics is asso. ciated with inhlbition of the local production of NO.‘&’ Local dilation asuxiated with mechanically induced pain also has been demcxmated.‘w NO mediates local basodilation in response to ultraviolet-9 irritation.‘4’ and a correlation between local pain and xtsodila~dr~~e~gywd in a study of carpal tunnel The local effect of NO may involve the release of calritonin gene-related peptide (CGRP) and the subsequent release of PCE, from afTeren nerve fiber~.‘~’ Furthermore. the classical algetic agent capsaicin has been rvpeatedly shown to induce neurona! NO pre duction. resulting in local vasodiladon.“““‘,*” In higher or repeated doses. rapsaicin has also been shown to be neur~ toxic. to unmyelinated axons of nociccp tors.e”l An effect on these axons explains its

Vd I4No.4CktchW97

Nitric -Oxi& and Pa’n

suggested use as an analgesic in the treatment of facial pain.“” A study of pain-induced vasodilation showed that it could by modulated by analgesic dmgs,n’ and this effect on ~asodilation shown to be related to interference of thw analgesics with NO synthesis.“7.w2,p7s Further. it ha been suggested that migraine, which is known to be associated with enhanced lewls of N0.1S7~27’.“5 is caused by a specific cranial nociceptive effect and not by sheer Msodilation.2’R In contrast to the foregoing data, topical nitroglycerol wa re orted to alleviate pain in thrombophlebitis,‘R.Z7R These obwrvationb are. however, moot probably due to the vasodilatory elTect of NO, which alleviates local ischemia and its asscriatrd vawconstric[i\v pin,Y’4.m In brief, if NO is overproduced by an immune response and diffw to nearby no& ceptors. it is expected to sensitize them, making that region tender or painful. Because NO diffuses readily throughout a much wider region than its site of production (for example, in the damaged joint), and because in the ewtravascular space there is no eflective mechanism to eliminate NO and prevent its spread. TMJ pain and other intlammator! pains may be poorly localized and impreciseI> described. The associanon between pain and local hyperthermia is not unique to TMD. It ha? been repeatedly demonstrated in cases of RA.“‘.‘*‘-“’ and in jwenile RA.‘“” and W&F corroborated by the reported correlation between pain in patients with RA and axon reflex usodilation.m’ We suggest that pain in all these disordeo bar thr sxnc cause: cxcc+ sivc loc3l level of NO. There arc. howrv,a, also conflicting findings. In the case of the cancerou> hreact. where NO ha been implicated as the cause of local h>perthermia,* and whcrr the nroplas tic cells themselves were shown to produce NO,‘“‘~‘“” no excessive pain is generally reported. Furthermore. prcliminar) findinp using dynamic area telerhermometry (DAT)“.“” have demonstrated loss of local neuronal \;ucular thrrmoregulation in this case. The low level of perceived pain ass&ated with cancer in the breast may suggest that not all nociceptors arc sensitive to NO. as was showa also in rat~.~.~ or that some local

analgesic factor is produced of neoplasia. countcrdcting

233

in the rariv stagthe algrsic cffecu

of cy~okines and NO and pouihly facilitating the insidious behavior of early cancer. The later hypothesis warrants intensiw inwstigation bcrause the identification of such a cancerassociated mdogenous analgtric might be a used as a biological marker of the disease. We do not undcntand .S !x t the molerular mechanism of NOinduced ncriceptor sensidzation. which might have been perfected over thr eons of metazoan evolution. Three alternative mechanisms aw plausible: (::) SO mav enhance the rrlease of an algeric wbsencr. for example. PGE,. z2 (b) NO may inhibit the action of an endogenou~ andnoclceptive sub stance that ac& on peripheral nocicepmrs. or (c) NO might act directly on the nociceptor~. As dircuwd above, NO induce\ the release of PGE,. and it was ru:&rttd that PM, induces wlt+effated Na’ currents in ncrirrptors. increasing their excitability.““’ Howcwr, at the spinal level it was reported that the PGE,-induced allodynia is mediated by NO may act SO.““~‘m ’ that is, neurogenic downstream from PGE, rather than being ils precursar. It has also been suggested that inflammatory pain is mediated by the nerw growth factor (NC.F) at the peripheral le~cl.“~ and that NO ha a critical role in the differcrntiation of o~urons that produce NGF.“’ :n conjunction with the second mechankm. it hat been reported that Fteamine has an antinocicrptive efTcc1 antagonized bv samatcntatin.w which has been shorrn clinically to have an analgesic effect of its own.“‘.“’ Somatostatin prohahly inhibits Cn” channels Ic~ally.~*~“” or modulates pain signals r: !he spinal le~el.~ Beraw NO wa5 shown to rap idly nitrozatc RSH groups, incloding thmc on romatostatin.“Y’ it is expected to exert a pcripher-al allodynic effect. This mechanism implin tha scavenging of HO, radicals, for exrmplc. b ascorbic acid. would havr an analgt5ic rffect. In the direct action mechanism, NO is likcl! to act as neurotransmitter at the peripl~enl level. as nas soggested haed on histochcmical obser~ations.~” Altemadvcl~, it may ac* as a retrograde potrntiator. in analogy to it5 modrr of action in the bmin.Y’.Y”~N” In addition to enhancing cGMP produrtion. NO was also shown to uimulatc the Na+-K+-ATPaw activ

AJbr

W

ity,w which may result in enhanced nocicep tion. Altema~ly, by binding to an iron or cop per mctalloprotcin or by inducing &Ml’ pmduction. NO could open up Ca’+ ion thannets in nociccpton Thiir effect of No Ha5 aclu2lly tkmrmsuated in mtiml cellP-%” 2nd in Anew (NMDA) gated hippocampal slff.~ The effect of NO on peripheral nociceptors may aho inwlve mnlubtinn of‘ Ihr NMDA rec~=ptor ion chan~wl similar lo its action at the spinal Iewl~w7 Nitric oxide is abn inwIved in he NMDA receptor activation -iatcd wiith Vammirsion of fit sign& from tbe retina to mxl the ciredian rhythm.” an effccr lha1 WAS co”firmed in viw.‘“.“” Though perception of light and of pain are obviously different. it is e&n lo see Ihe cor~l2lion belween the two, cspeci2ll) remem~ that stimuladon by high inter+ light can be petreiwd ilr, pain. Although mow decsfkd studies of the mcch2nii of sensitize dou of nociv by NO arc highly w.wranced. tbcrr fs sufliciinc experimenlal evidence IO sup pwcae ansociatin of pain tidl enhanced kvels OfNo. .

.

.

=--In spite of the overwhelming evidence that the a.uociadon between pain and local vasodikdon in localized inflammatory processes is due to, or augmented by, NO produced in the kinal extravacular space, one must consider the possibility that the observed rrgiwul hyperperfwion and hypenhermia are caused by neuroml signals originating in tbe spine, or even in the brain. m response to stimuli originating in the affected area. The perception of pain is a cerebral phenomenon, and the as* ciadon between pain and local hypetperfusion also could be mediated by Qe CNS. Ii was ruggCSlCd-lh2ll20)WS2gOlh21hX2lpaill may cause local inflammation (&a~ is. hyperpcrfusff) indirecdy, and that local inflammadon may in turn induce “local” pain. ratldng in a viciotu cyck of posit& feedback.“’ This suggulfon has been resmed more recently in chc dencal !itetature: “A prolonged, painful sdmulation may grncnte increased blood flow and intlammation. and vice vetxa. in-matfm may kad to pin.“‘” it has been shown lh21 spiml stimuhtion by petiphetal infkmm&m an induct hyperexcitability of donal

and emu

Vd 14 No. 4 Odbrr 1997

horn neuronc.=” which may induce uwdilation in the affected peripheral region.” ‘J”’ u well as pain enhancement.“’ Analogous hehwior w-a ohserved in the innamed hladder of GIIS.~~’ Furrhrrmore. pain-induced stimulation of the spinal cord. whirl) nruln in autonomic stimulation of the periphery. can he mediated hv .VO .‘PL”zw*“.J’~ and the &WI of ccnain znalgcsicb, including ibuprofen. can bc manifeswd through inhibition of NO prc* duction in the spinal cord.““’ Specific change itr IIW CNS caused hy pcnisrent pain have been demonstrated horh in the spinal cord” I.L!I’I.‘I.ESY a”d i” ,hr hr2i”,~~.“l’.“17-)1!1 II has been also suggested that pcroistent TMD pain induces changes in the CNS.“*’ Interestingly. it ha5 been shown that new ronal plasticity is NO dependent. invohing iNO. rather than nNOS.“‘.“‘~“‘” It is also noteworthy rhat TMD aswciated pain involws the trigrminal nerve. and there is oidcnce rhac NO is involved :ts a neurou-ansmitter in the cranial anglionic interface of the trigeminal nerve.’ s” Consequently. it might be suggestrd that the local vasodilation -iaced with painful TMD is mediated by the CNS. This would differentiate TMD from otherjoint diwrderr (aA or RA). Thr latter mechanism would involve NO at two sites: (a) as an intracranial neurottansmilWT. and (h) locally, as a incrdwular chemical meswngrr induced by xetylcholinc and Ca”. This mechanism imp!ies unimpaired local auwmomic nervous regulation and control. The findings that local lidocaine injections do not alfec~ the pain scores or the hyperthetmia of TMD patients” strongly suggesl chat tbe conuibution of the CNS mechanism is minimal. at least in TMD associated pain and hyperperfusion. because lidocaine is expected to break the vicious cycle. The same treatment of normal subjects would have cawed a nerve hlmk. local numbness, and exceGw vawdiladon.* On the other hand, these findings are consistent with the pmductiotl of excessive extn~~~ular NO in due periphery. sensitizing the peripheral nocicepron and probably inrcrfeting with the analgesic effect of iidocaine, as it does to the analgesic effect of morphi”e.‘-.R2~J.“23.‘2” Must importantlv. these findings indicate that the wscubturr is already dilated tu capacity. Consequently. it does not trspond to blockage of CNS signals any fur-

W. I4 No. 4 &I&,

1997

Nihir

Iher. Furthermore. it has been reported that lidocaine interferes with the production of endothcl& N O W ’ If the nsodilation in TMD wac fully ncumgenic. that is. caused .solelv by eN0.S generated NO, as implied in the (:NS mediated mechanism, lidocainc would be expected to act locally as a vasoconsttictor. contrary to observation. Dynamic area telrthcrmomeuy (DATI”.“” could confirm or exclude the CNS control of the observed vasodilation in TMD. because peripheral cxtmvaular production of NO by macrophages and/or ostcocytcs is expected to signiticandy attenuate or eliminate neuronal nro47 regulatory function.

--the

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and dependent ctTcct of NO on os~cocl~u.r” the inhibitory effect of progesterone on iNOS.‘.w all strongly suggest the enhanrement of iNOS by cscrogcn. Fwthcrmorr. the cstab lishcd effects of women’s sex hormones on eNOS and nN0.S activity arc sufficient to explain the prcpondenncr of TMD asociatcd pain in women. a~ well a5 similar epidemic. logical findings in the manifestation of painful rheumatoid ;Irtbritir.“P”’ Because the effect of estrogen on cNOS and 1190s are nrtemic. the prcscncc”’ or ahscncr”” of dctectahlr estrogen receptors in the TMJ tissue is irrclCxl”l.

Al#rm&rViewonbhcRde ofNi&ic Oxide in Painfkl Local

izz&eqpa?uiTMJPain

Injbmmalion

As stated. painful TMD patiewc arc prcdominantly female.’ In view of the suggaed role of NO in the phpiopathology of TMD associated pain. it is likely that this demographic observation is associated with the effect of cstrogcn on NO production.JY* Esttw gcn enhances tbc synthesis of cNOS in rasct~lar endothelial cells. resulting in enhanced NO production and a more extensive Msodilation,3~~’ at leau in certain part3 of the vasculat~re.~“‘~~“’ This effect may be negated by progc~terone;“~ which was shown to inhibit iNOS also.‘” These finding arc COTroborated by demonstrating that the levels of serum nitritc/nitnte arc modulated contemporaneou.dy with tbc mcnscrual cy~le.“~ It has been reported that cndothclial production of NO is si~ificantly enhanced during pregnancy,=“-” ptrwmably as a result of estrogen substitution treatmen?S NO was ako shown to bc involved in estrogen-media-d coronary rclaxati~n;~’ The c&et of estrogen may also be expreJvd in r~euronal calciumdependent ~INOS.“‘-.~ The c!%cr of cstrogcn on pain sensation and analgesia in fcmalc mice with n.w normal estrogen levels rclatrd IO the rcs c In of the NMDA rcccptor in nociceptors: contrast with the known e&a of other cndogenou steroids.% the authors arc not aw-arc of any study that directly mcasurcd the cfiect of estrogen on iNOS. However. the critical involvcmcnt of Ill-bcta-cnhanced NO ill owlation.“7 which has been described 3s an inflammation-like process.“’ the cstrogen-

It has been pointed out that NO is ver! itwfficient as a cbcmical m~ccnger.” NO must br produced in situ on demand. hecause it rannot be stored in any biological comparrmcnt. Therefore. the &clime of its concmnation is relatively slow. The tirtime of iNOSger.eratcd SO is evco slower (of the order of hours) hpcausc of the need IO transcribe and synthesize the enqmc. Bccausc of its nonspecific binding IO most ironarrying prouins. the biological activity of NO is lea specific than that of most other chemical messengers. Because there is no cfTective rnrymaic pw CCIS to remove it irrcwnibty, iu conccntt-ation at the target site is poorly rontrolled (cxcrpt inside the varukture where NO is scavenged by hemoglobin). which limits the rate of repeated chemical mcwges. Bccauv of ie rapid isotropic dilTusion. NO must be p’~ duccd in large qwmtitics and only a minute fraction of it reaches b intended target. In hricf. unlit had a uniqoc sun-iul nhte. ELI functions, for example. its role in rdsadilation. would haw been replaced b cwlution of a more specific and. thercforc. more c!Tcctivc chemical messenger. A tic prcmiw in biology is that no biological function can sunivc the thermal. photochemical. and radiic pmcesu=s in nature. which destroy genes by nndom mutations. unless it has a survival value for the organisms invohvd. It is rcaooablc. tbercfore. to assume that the biological funaions of NO have starvivcd billions of years in practically all life

hms because ol’ its unique contribution. to their survi~l. It w-as suggested that this contribution comprises its synergic synchronizing intracellular. intercellular and inter-organ functions, all of which must have high survha! dws.~s~ Nociception is a biological func tion with a high surtil value by itself, and a discwwd above. it seems to be associated with the production ofextrdvascuk~r NO. Thu Argo ciaion is 10 be expected in a generic biological c”“tcxt. Nocicepdon probably developed already in protozoa to facilitate avoidanre of contar! with adverse environments or potentially hostile objects (for example. excessive heat. cold. mechanical pressure or laceration. tonic chemicals, or alien organisms) hy locomotion. When nocicrption developed, NO was undoubtedly around in its ubiquitous role zs an intracelhdar chemical messenger.2” and early on it might have had also a protective role as a cymtoxic agent wed agaimt alien organisrn~.~~ Ir seems reasonable 1” aswmc thal in concert with the production and release oi NO a5 a protective agent against alien organisms, NO was the messenger that affected the primitiw nociceptors to induce disengagement from those adversaries. The premordial nervous system in melazon prob ably developed sensory nerves and neuromus cular control in parallel. and used these to pursue food or to avoid detrimental conditions. In more complex organisms, nocicep tin developed htnher to discourage the temporary usage of an injured organ until it recovered. This intra-organismic function of nociception has a survi\al value by minimizing additional injury either by evasive motion or by immobility. in pamllel. the circulatory s)surn dewloped cells that specialiied in pmtective antibacterial use of NO: in mammalian s+terns. mxrophages are examples of such cella that produce NO in response to immune stimulation. While the most important role of NO may be as an intncellti synergic synrhmnizing regdtory agent.” h has been suggeswd that the survival of NO as an intercellular chemica messenger in mammalian systems implies a similar sync ‘c role in highly evolved meta-34 small splems. The production of NO in the differtnt organ *enIs proceed8 by dilferent *ways hhing diLTeren1 ctlzpcs. confirm-

ing the need to conserve iu hiologiral function in dilferent organ ?%tems under mutational pressure. Still. irs bi”l,+cal functicn at the target cell is identical. irrespective of its point of origin o: mode OI production. If NO is generated in one organ system. for example, in the vascular system. and diffuses into another “l-p” y5trnl. for ruamplr. neurons behind thr blood-brain barrier, it would exert a biologiral efTect normally “reserved” lor a genuine intcrneuron transait~er produced inside the latter organ system. The same would be true if NO wa% originally produced inside bnin tiwuc and diffwed imo the surrounding arterioles and ve~~ules. as demonstrard in the rase of capsaicin-indulccrl NO release by ne~r”ns.~~~ If this cross-talk hcwrrn organ s)?rems induced bv NO would have ‘Lem derrimental. evolutit,n would have developed “berter” chcmiral meswngcm for both systems. that i% messeng~n that do not crow over and intcrl’ere with each other. Gutanylate c!rlase acti\+ and subsequent smooth muscle relaxation can be induced by chemical messengers other than NO, including 5hydr”xytryptamine355 or brain natriurctic peptidc.‘% Thuc. NO is not ataolutely necessary 115 mediator in vasodilation or in otJ.er funrtions that depend on cCMP. The vasodilatory function of NO has probably silrvived brcause of the beneficial interactions with other “rga~, systems. In brief. to have wr\ived evolution. this inter-organ-system crosstalk must be beneficial. The following are a few examples: 1. When NO is generated inside brain tissue and is used as a neororransmiuer (for example. for long-term p”1entiatic4l).‘“‘~” .%a there m w bc a higher local demand lor ox)xen or glucose due to a temporarily enhanced localized neuronal activity. IX demand can be automatically met by local crrodikuon induced by neurona’ NO which diiws into the nearby micmawulature. ‘this pmce~ is faster and much mom ef% cient than generaring an electric signal through the nerwms system that releavs intrawalar acecylch~line exacd~ &en and n+mr the kxalii rasodibh is mcded. laalhighkxkofO,maybeneededalso to quench the neumtmtrrPnitter signal by binding to hcmogldan and/or b ox&tion

Ninit

of SO by Hbo,. thus incrrving the rate of silpal transmission and confining its elferr to a limited volume of the brain. Furthermore. bccmsr NO can be ne;rrotoxic when produced in excessive amounts,56y the simultaneously induced vasodilarion sup plies blo wl that minimizes this potentially daimcl Ial et~ecl. while llknving a s&StanIhI o-dnsient increae in .NO lewl to occur. Funhern~o.c, NO can act as mnlrdator of ncumn.al czll respiration by competition for mitochm~drial qtochrome c~xidase.~” This guamitc 5 thal the receptor neumnal cell \*a rnicr a quiescenr reftactorv phase after the NO tignal was received. Gmversely, wt~e,l NO is generated as a result of sheering forces inside a constricted xterinle in response to a nervous stimuhion it may liff&c out into the adjacent nerw celk and slow down their metabolic act+. Interestingly, a~ least in mice. the NO that is responsible for long-term potrntiation is$?neraled by an eNOS rather than a nN0.S; suggesting that thii particular CNS function might have emhvd from cmwalk between the va+ cular and ncurondl systems, that is, a vasodilatory and not a neuronal signal might have originally induced long-te:m po1endati0n. awoci2. The role of NO in hypenhermia ated with inflammation prrsen~s a second example of NO-mediated synergic interorgan communication. As discussed above. NO may be produced by macrophages, chondrocytes. or osteocyres by a calcium-independent enzyme. This NO can diEuse into the regional nsculature and induce non-neuronal &MP production and subsequent smoothmuscle relaxation. which results in nsodilation. This vascdihtion increases the supply of oxygen and nutrients to the affected area. II also increases the influx of additional Ivmphocvtes to the affected area @o&e AI the same time, under condifeedback). tions of limited oxygen wpply, such as may prevail in inflammation, NO may enhance oxygen uansfer from oxyhcmw globin inside erythmcytes to the hypcrmetabolic lymphocytrs.~w’ The simultaneous nuxiilation of the regional wnules by the ex~ravascular NO enhances the

Ox&

and Pain

237

remoxal of CO, and aher met+olitcs, preventing local acidosis. Thus there are two mechanisms of local hypcrpcrfusion--an autonomic ncuronal thermorcgula~ory m rhanism dependent on eNOS and pcmibly also on nNOS. and a regional rron-neuronal mechanism. iuwciated with immune response, dcpcndrnt on iNOS. Tbc :atter mechanism. in which ilnmunr-response-indured localized wwdilation enhances the rffrcriwnrss of nmcrophage activity, is suf5cient 10 explain the evolutional maintenance of the cndothclial NO rasodilator~ function. because it undoubtedly has a survival V&e. This NO-mediated inter-organ s!rtrm rmwalk may. howxr. lead also to catastrophic ~rsults. The SO-induced bypotension if: sepsis and the subsequent multiple-organ failure.“‘5-s7 including cardiac ta~lurr,‘” IS caused by the auto catalytic overproduction of NO in reaction lo pervasive microorganisms or exlrnsive apoplosis,l’.wc”7’ Herr. the inter-organ ryaem crwstalk seems to have a negative rurvi~l value. In some animal models. inhibition of iNOS was reported IO hate enhanced survi\al. wi Howver. in other animal models the inhibition of NO prw duction in apsis wemingb dc~wased the sur,i\al ra,r 5T1.2?3 suggesting that czen under those extreme conditions, the heneficial bactericidal effects of MY” may outweigh the detrimental consequences of h!porension. In any car. like lethal maligwant h)Frthermia or hvpothermia.‘75 the occurrence of which does nol degrade the survival value of physiological thermoregulation. sepsis is an example of an extreme catastrophic situation where NO-induced synergism may run out of COtlWOl. example da hrmod$amic inter5. Another organ system crosstalk invohmg NO r:lat has a sun~al Vats is the binding of NC ~,~~~~~“,&y”

:$m;rzz

tion of NO by HbO,.wo..w’ This sequence of biochemical processes may not be merely coincidental with the nscular funcrim of NO. Binding to Hb attenuates the

Anbmand

vasodilatory effect of endothelial NO under normal conditions, while cnhanring vandilation under anemic conditions. il) expected from a s)~tem rhat regulates oxygen supply to tissues. A vasodihting mechanism not associated with NO would lack this regulatory feedback. A related inter-organ~~tem crosstalk mediated h! NO is dw inhibition of platelet aggregdti”n.M2 whicll enhances blood flow in msodilated arterioles and venules.“” 4. The association of sensation or enhanrcmen1 of pain (a nervous system process) with local inflammation (an immune response). mediated by NO, has a sorvival value in mammals, and possibly also in other vertebrates; it might reduce the USC‘ of an infected limb or of an inflamed joint, thereby helping their recovery. This might explain the conservation of the positive response o’ nwicepmrs to NO. The sensitization of nocicepton hy extraa+ cular nitric oxide is, thererow just one of many facets of this unique prrmordial chemical species. The interaction between infection or apoptosis and hyperperfusion, di.scossed above. is a parallel inter*rgan-s)stem intrrxlion. The proposed synergistic relation betwcrn hyperperfusion and pail1 is thus an indirect. second order interface between the oscular and the t~ervous system. coopled hy excessive exuavauular NO. II evidently has a combined survival flue higher than each of the two individual inter-orgao inwractionsinctrasing the probability of recovery from infection. This rcond order coincidental inter-organ-sytem interaction, which must be unique I” NO because of itr muhiface~ed biw logical function. is probably not the only one of its kind. There must be many other similar timcdonal manifestations of NO ar an inter“tpIl-yle” synergiuic agent.

rcYtiM .flX¶iCeV The monitoring of NO or its metabolites iv blood of TMD padents may not be sendtie enough to detect changes due to local inflamttdon. TMD is not a syxtemic disorder like RA OT OA where such changen were observed.

cnou

Vd I4 No. 4 orrobn 1997

ar discussed above. Fsen if a positive correlation was fount: ben~een TiUJ pain and the roncenrration of NO is blood or of nitrate/nitrite in urine, it is also not specific enough to COTrohmte that the extra NO originarrd from the inflamed tissue: the excnsivc NO could be produced ekewhere. for example. in the CNS as a rcsuh of the peniswnt pain. Onr coold corroborate “or hypodwsis by dratring r~no\i;d lloid from the TMJ and assaving nitrite or nitro~rosine,g’ subsequrnll~ carrelating the Icvel of NO metaboliws with the wbjerGve level of pain or with the Irvel ot h!perthermia. Howrvcr. this ix .tis~ zpproxh is noi pr.wiral in a clinical study on many drntal paGents. 0~ most resort. therefore. to au indirect non-invasivr assessmcot of local NO. The most rffecti-e inrlirect approach !” SSC’SI dw local level of NO in viva is probably through iu vawdilatorv effect. Because, as drwibrd abow, excessive ext~ax~~ular NO is expected to interfere with the normal control of \agcular tone by overriding autonomic consrricrion, this effect could be demonstrated by monitoring autonomic vasoactitity. It has heen shown that by precisely monitoring skin temperature over time, using dynamic area tclrthermometry (DAT),“’ one can derive information on tie aownomic :hermoregtdatory activity from the modulation of skin trmpcratore. which normally oscillates with an amplitude of about 50 millide~~eu.“‘~“‘~~~~~~ Fat Fourier Tranrform (Ffl) analysis of this modulation yields the amplitudes of aote nomic thermor~datory frequencies (TRFs;. The TRF spectrum changes with thermal s~rcss. during steep and following nerve initalion.“.65 When a varcolar bed is perfined with excessive exranst ( lar NO and the autonomic thrrmoregulation .j impaired, as manifested in local hyperthrrmia. the TRF spectrum undergoes significant changes. Monitoring of tltr modulation of skin temperature is, therefore, a much more sensitive method to quantitatively asses.5 aberrations in autonomic vaxw lar control of perfusion than measuring ST, the temperature difference between the average telnperatures of two skin areas at one point in time, as ha, been done in the numerous dental studies described above. Consequently. unlike 8T measurement, DAT could

W

14 No. 4 ckfdwr

quantitatively in the TMJ

1997

a.ue~ regions

the rxmtivr of patients

NiWic Oxi& and Pain

NO activity with TMD

associated pain. DAT will detect abnormal autonomic thermoregtdation in caes of bilateral TMD. which cannot be handled by telethermography. This is a highly significant advantage over meas”rement of bT.” The extent of change in the TW spectrum is expected to correlate with the levels of pain and hyperthermia. Moreover. it is expected that the changer in the TRF spectrum will diminish after administration of systemic or topical analgesics that were reported to inhibit NO producti”“,“YJ.‘~:~‘“.Y”’ In a more sophisticated experimental setup. one could correlate electroactivity of the brain, measured by electroenccphalography, characteristic of pain,W,.w with changes in the tbermoregulatory frequencies and amplitudes. which represent changes in the local neuromuscular control of the varculature. DAT could be used as a diagnostic technique in most situations ol local inflammation. including local infections, or immune responses to apoptosis due to mechanical irritation, irradiation or chemical toxicity. RA. OA, or other localized autoimmune reactions. Another approach to corroborate our hypothesis could possibly be to reduce the local level of NO by enhancing its oxidatiw. Increasing 0, blood levels increases the level of HO, radirals.w~“’ Elevated Irvels of HO, are expected from short-term hypcrowia, before compensatory huildup of superoxide dismutaseJ”‘-99’ and antioxidant.?‘” takes place. This will lower the level of NO, which reacts with HO, at a diffi~sionamtrolled rate to form perownitrite.‘*‘.““’ Under hyperoxir conditions. the level of Fe(U) will diminish as a result of its reaction with HO,. Because Fe(U) helps to m lintain a higher level of NO.“” the oxidaticm of Fe(U) will further lower the concentration of NO. If NO is responsible for TM,! pain. lowerin:: NO cwr to 100% centration by a short-term expose oxygen will temporarily decreax thr h!vpc” thermia (hyperperfusion). and resuh m a reduction in pain. This approach might yield meaningful information only if the senritiza lion of nocicepton by NO is a rc‘. G+ fast reverxible process. Otherwise ihr hyperthrrmia may be reduced without Icwering the h-vel of pain.

239

On the other hand. awn-hir arid might have the opposite rffect. Ascorbic acid srawnges superoxidc radicals but, unlike Gtamin E.“” does not -ge NOy” or interfere dth its producticn. Cansequentlg. arorbic acid is expected to increase the !ael of NO and. rherefore. might enhance pain. It weld he of interest to find out whether intake of ascorbic acid bill enhance the local hyperthermia. rcrolt in changes in the kral TW spermrm. and ~av&e pain in TMD paticne. A$ expected. the wmmal of HO, radicals b a=,cwhic acid reduces the niuwaion damage. expreswd in the lewl of nitmtymsineuu and nitmx~prolinr.“‘i and in certain \auUlar degrneratiw ,-Ifecu.” AwucHhir acid has hcen n-ported to haw a cardiwmuku protective effect including lonrrrd blood w1ile lhr beneficial long-t.?“” P==m.U”4N effect of ascorbii acid is pmbahl~ related to irs inhibition of dw oxidation of hpprotrins.*” the ohserwd invent correlarior~ bctwcn the level of auorhic acid in blood and Mood prcc wrr”” is line with the assumption that it incrravJ Ihe .steady sta!~ level of NO in circuk tion. On tie other hand. if the alg& efTect cd NO is coupled with nitmzation of wmatostatin. a% dkcmsed abow. auohic acid will ha\? an analgrsic cliect coup.-xl Gth u~hancal h!vrthrlmia.

CIlbZidZW tfthe.%hg@edhf* The sugpzstcd algesic etlect of extra\ascular immune-related NO, has implications for the management of TMD-associated pain and ploper;ltive pain. espcciallv when allograf* or potmtially antigrnic foreign materials are implanted. In addition to offering atl rxplanation of the preponderance of TMD pain in womm. our hypothesis predicts zg~P~ation of thr symptoms in postmenopausal patients treated with supplemental estrogen. rspecially in those who dr? not use pmgadn periodically. Pcntopcrative pain may follow a similar ph*o pathology because it, :oo. is signifirantb more prwalent among female ptirnt~.~” The .samc phgsiopathologic mcchanl=ms arc probably responsible for chmnic orofacia! pain. such as traumatic nra-algia (TS), in whach chronic facial pain is Ihe mult of mild-twnoderdte trauma to the trigeminal IWXW.“~ Like THD. TN ir chancterized by a highI> acymtnetzic dw

240

tribution high a entie wmen

Anbn and emu

of facial temperature. with 6T as and. like TMD and posw~p +1.0-C.“” pain. it is much more common in than in rn~n.“‘.“~ Once we better

Vd 14 No. 4 &I&T

1997

used. arc contraindicated, and that other analgesic straq$es that may affect pain pertrption ar d-te cognitive level pychologically4”.4’” or pharmacologically are preferred.

understand the role of esvogen in nocirep lion. it may be advisable to limit estrogen sub sdc~don therapy for TMD and RA patienu. or at ICUI invohe the patient. who must twz made W-AW of the algair effect of the hormone. in the decision. Inhibitors of iNOS among the nonstcroidal antiinflammatory drugs are curnndy beinR UJed as analgesics of TMD. TN and for the 77.7”.1”6.448 management of pawqntive pain. 2’2.b5-“’ InterestinRly. the damage many of these agents cause to the mucosa of lhe K”strointestinal tract wz reported 10 be contmllabk by agents that release NO lo~ally.“~ demonstrating that NO has a pn~ective effect in rapidly renewable tissue. just av it has in contilling inflammation. In other words. inhibiting ewwavacular NO may reduce pain but at the same time it may interfew with the healing process. Topically administered INOS inhibiton used as antiinflammatory agents. that are currently being developed, may avoid the side effects in gasuointesdnal tract. but they may still have a negative effect on the recovery. Since the mechanisms of the algrric and analgesic effects of capsaicin are betler undenuaod. one may question the use of this neumtoxic agent in Lhe twa~~~~ent of TMD associated pair~~‘~ The effect of dietary antioxidanta on painful TMD is not easily predictable. in view of the different potential effeclr of vitamins C and E. a~ discussed above. In any case. if vitamin C was shown to have a painpotendating effect. its use in large dares by pascoperadve patients should be resuicted. In summary, the excexsive NO in inflamed area3 may be gnemed by several alternative mechanisms. The determination of Ihc conuibudon of each of &-SC mutts may be key to the design of mom specific drue that inhibit the prrdominant pathways. thus minimizing adverse side effects. II must be remembered. however, that NO is not produced in the affected joint prim&Iv as a pain causing agrn~ Inhibition of local vasodilation may be detrimental to eventual recovery. Consequently, it is possible that analgesics that inhibit NO pmducdon. which are maa widely

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