CASO DE PRUEBA DE ACEPTACIÓN

4.1.1 H is to r y o f th e S tu d y o f C a p sa icin

C ap saicin (8-m ethyl-N -vanillyl-6-noneam ide) is th e p u n g e n t agent present in capsicum peppers. This substance w as first described in the century by C hristopher Columbus who noted th a t h o t chilli peppers were widely eaten by the New World natives. However, it w as n o t u n til th e 19^^ century th a t the pharm acology of capsaicin w as pu b lish ed and th e 1970s w hen capsaicin was finally recognised as a useful tool for neuropharm acological purposes (see Szolcsanyi, 1984 for a full h isto rical review). In view of its alm ost specific actions on the nociceptive polymodal C fibres, m uch of th e w ork concerned w ith th is su b stan ce h as revolved around th e tran sm issio n of p a in and nociception. Indeed, it has been most useful in the anatom ical m apping of th e sm all diam eter unm yelinated p rim ary afferen ts an d in investigations involving peripheral nerve in ju ries (Dickenson, 1991a).

4.1.2 E ffe c ts o f C a p sa icin

(a) Im m ediate Actions on Afferent N eurones

(i) Excitation of Afferent T erm inals

Contact of th e skin, th e m ucosal m em branes a n d th e viscera w ith capsaicin excites afferent nerve endings w hich re s u lts in an irritatin g ly 'h o t’ sensation. In general, only th e polymodal C- afferent term inals respond to capsaicin stim u latio n , w hile the high- an d low -threshold m echanoreceptors, th e cold-sensitive therm oreceptors, the Ap fibres and m ost of th e Aô fibres are relatively im m une (Bevan an d Szolcsanyi, 1990; Lynn, 1990).

Chapter 4 : Neonatal Capsaicin Treatment

(ii) D epolarisation of A fferent Fibres an d Cell Bodies

W hile capsaicin ap p ears to

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depolarise selectively m ost of the p rim ary afferent fibres in dorsal roots (Ault an d E vans, 1980) as well as the som ata of m atu red (M arsh et aL, 1987) an d cultured em bryonic (Wood et aL, 1988) prim ary afferent C type neurones, there have been reports th a t a sub-population of th ese C -afferent fibres an d ganglia are in fact capsaicin-resistant (H ayes et aL,

1984; H eym an an d Rang, 1985; M arsh et al, 1987). C u rren t evidence confirms th a t the m em brane depolarisation observed upon acute capsaicin application is due to th e occupancy of a pharmacologically active receptor site present on sensory neurones. D a ta contributing to th is school of th o u g h t have a risen from binding studies with [% -R T X (Acs an d B lum berg, 1994) and electrophysiological experiments with the selective an d competitive a n ta g o n ist, capsazepine (Dickenson an d D ray, 1991; U rb an and Dray, 1991). A ctivation of th e receptor is believed to open non- selective cation channels in th e m em brane which th e n leads to an influx of Na^ and Ca^^. However, it appears th a t the depolarisation is prim arily due to the increase in Na^ conductance, as th e absence of Ca^^ not only does not in h ib it b u t in stea d enhances the excitatory reaction elicited (M arsh et aL, 1987; D ray et aL, 1990). U p ta k e studies w ith fu rth e r suggest th a t th e ability of capsaicin to concentrate Ca^^ in the p rim ary sensory afferents (Wood et a l., 1988) causes th is Ca^^-independent response which contributes u ltim ately to the u ltra s tru c tu ra l dam ages observed w ith electronm icroscopy (Joo et aL, 1969; M arsh et aL, 1987).

(iii) D esensitisation of N eurones

It is widely accepted, a t least in m am m alian neurones, th a t

Chapter 4 : Neonatal Capsaicin Treatment

following the initial depolarising action, capsaicin desensitises the neurones to itself as well as to o th er noxious stim uli (M arsh et a l. , 1987; Holzer, 1991). This conduction block ap p ears to be lim ited to the C-fibre polymodal nociceptors which have cell bodies in the dorsal root ganglia. Sim ilar effects have been observed in vivo in several m am m alian species following th e application of high concentrations of the neurotoxin to cutaneous nerves (see Lynn 1990 an d references therein).

(b) Long-term Functional C hanges

(i) Anatomical A lterations

W hen capsaicin (>50mg/kg) is injected subcutaneously into n eo n atal ra ts betw een the ages of 1 an d 14 days, it p rev en ts the form ation of m ost dorsal root ganglia an d u n m y elin ated p rim ary afferent C-fibres in the ad u lt anim als (Jancso et at., 1977; Law son a n d Nickels, 1980; Jancso an d Kiraly, 1981; N agy et al, 1983; Arvidsson and Ygge, 1986). This phenom enon does not seem to be restricted to the fine polymodal C-fibres since th e relativ e ratio of the different types of C-afferents does not a lte r w ith th e tre a tm e n t (L ynn, 1984). In the ad u lt anim al, however, non-nociceptive C- fibres have been reported to be more re s ista n t to capsaicin tre a tm e n t (see Lynn, 1990 an d references th erein ) alth o u g h the reasons as to why th is is so rem ain elusive.

Since the unm yelinated efferent fibres of the autonom ic system (Cervero and McRitchie, 1982) and the rest of the CNS (Jancso an d K iraly, 1980; Fitzgerald, 1983) are relatively unaffected by n eo n atal capsaicin treatm en t, it would ap p ear th a t the actions of th is substance, a t least in the n eonatal phase, are specific to the

Chapter 4 : Neonatal Capsaicin Treatment

nociceptive sub-population of the p rim ary afferen t fibres (see references in Fitzgerald, 1983). F u rth e r anatom ical investigations hav e, however, dem onstrated th a t n eo n atal capsaicin tre a tm e n t m ay n o t compromise all of the C-fibres, an d th a t m yelinated Aô afferen ts are also susceptible a t h ig h concentrations of the neurotoxin (Jancso et al, 1977; Lawson an d N ickels, 1980; N agy et al, 1983). In fact, most investigators concur th a t approxim ately 5% of the C-fibre afferents in the dorsal roots are capsaicin-insensitive

{eg. Lawson and Nickels, 1980; N agy et al., 1983; R en et al., 1994) although th ere have been discrepant accounts {eg. Lynn, 1984; A rvidsson an d Ygge, 1986). These observations concur w ith the electrophysiological d a ta m entioned in Section 4.1.2(a)(ii). At p re s e n t, there seems to be no consensus on th e capsaicin- v u ln erab ility of the Aô fibres b u t it h a s been reported th a t less th a n 35% of these m yelinated afferents are affected by the neonatal capsaicin procedure (Lawson an d N ickels, 1980; N agy et al., 1983). Nagy al. (1983) dem onstrated th a t despite increasing the dose of capsaicin adm inistered, th e population of Aô fibres did n o t fall beyond the 35% m ark an d suggested th a t th is could be because the anim al requires a certain proportion of in tact Aô fibres for survival. The contradictions in capsaicin-sensitivity reported in the literature can only be explained by an d are m ost probably a re s u lt of the different doses used coupled w ith th e dissim ilar dosing regim es practised by the various groups of investigators.

T he morphological changes {eg. m itochondrial swelling;

d e g en eratin g boutons, on-site gliosis) trig g ered by n eo n atal capsaicin-treatm ent in the susceptible afferen t fibres are observed w ith in 30m in of adm inistration (Fitzgerald, 1983) w ith 50mg/kg being the sa tu ra tin g dose for axon term in al deg en eratio n (Jancso a n d Kiraly, 1981). The degree of dam age a tta in e d is also age-

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d e p en d e n t (Jancso an d Kiraly, 1980) w ith less evidence in the m atu red an im al (Jancso et al, 1985). T his is probably due to the incomplete differentiation and developmental s ta tu s of th e CNS in th e neonate. However, it h as been reported th a t th e sm all d iam ete r nociceptive afferents of ad u lt ra ts tre a te d system ically w ith capsaicin do undergo u ltra stru c tu ra l changes w hich are appairent even m onths after the injection (Joo et at., 1969; Jancso, 1992). H igh concentrations of th is drug applied to th e a d u lt r a t peripheral nerve also cause discrete graded degenerations of th e C- fibre axon endings which term in ate p rim arily in th e su b sta ntia gelatinosa (Jancso an d Lawson, 1990; Jancso, 1992).

Besides exerting neurotoxic effects, neonatal capsaicin tre a tm e n t also alters the topographical distribution of nerve fibres w ithin the sp in al cord an d in parallel w ith this, atypical connections i.e.

sy n ap ses arise, the functions of which rem ain undeciphered (S hortland et at., 1990; H am m ond an d R uda, 1991; W intered al.,

1993). However, it h as been suggested by Cervero et al. (1984) th a t ad m in istratio n of capsaicin a t th e n eo n atal stage could ultim ately lead to a shift in the type an d location of neurones able to effect th e 'w ind-up' phenom enon.

The rew iring of the neuronal network probably re su lts because the levels of n eurotrophins in the CNS are a t th e ir p eak d u rin g the developm ental period (see Cuello et al., 1993). Following the n e u ro n a l in su lt, these neurotrophic factors are hence capable of prom oting axonal grow th an d elongation of th e developing capsaicin-insensitive neurones into the synaptic sites vacated by th e ir capsaicin-sensitive counterparts. The poor regenerative ability of the capsaicin-sensitive neurones is possibly indirectly due to th e lack of grow th-prom oting environs as th e axonal tra n sp o rt

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m echanisms of these dam aged neurones are im paired, so lim iting the delivery of neurotrophic factors to in itiate n eu ro n al regrow th and re-connection activities (W intered al., 1993).

(ii) Neurochem ical A lterations

As reviewed by Maggi and Meli (1988) and Holzer (1988), th ere are as m any as ten neuropeptides associated w ith th e capsaicin- sensitive p rim ary afferent neurones. Since a decrease in the population of C-afferents would correspond to a fall in th e num bers of th e C-fibre axon term in als w ithin the su b sta n tia gelatinosa

(Jancso et al., 1977; Ribeiro-da-Silva et al., 1986; Jancso an d Lawson, 1990; Jancso, 1992), neonatal cap saicin -treatm en t would be expected to sim ultaneously reduce the levels of these neuropeptides in th e dorsal horn of the spinal cord. Indeed, in neonatally capsaicin-treated anim als, depleted contents have been rep o rte d for substance P (SP; Gamse et al., 1980, 1981; Cuello et al., 1981; N agy et al., 1981), calcitonin gene-related peptide (K ash ib a et al., 1990; H am m ond and R uda, 1991), som atostatin (H okfelt et al., 1976; Nagy et al, 1981), vasoactive in te stin al p ep tid e an d cholecystokinin (Jancso et al, 1981; G iuliani et al.,

1991), all of which are associated w ith p rim ary afferen t term in als, dorsal root ganglia and dorsal horn. W hile less severe depletions of th ese neuropeptides occur w hen capsaicin is ad m in istered systemically to the adult anim al, the loss is recoverable to different degrees in various regions (Jessell et al., 1978; G am se et al., 1981).

According to Gam se et al. (1982), direct application of th is neu ro to x in on the a d u lt peripheral sensory C afferents does not cause neurodegeneration b u t resu lts in th e reversible depletion of SP a n d som atostatin. D ata from Lynn an d colleagues do not

Chapter 4 : Neonatal Capsaicin Treatment

concur and instead indicate th a t such direct a d m in istra tio n of the neurotoxin does cause some degeneration of th e C-fibres (see references in Lynn, 1990). This neurochemical loss is n o t a p p a re n t in m otor fibres and seems to be specific to th e fine u n m y elin ated fibres. The initial loss in peptide content is therefore believed to be due to an interruption of the axonal tra n s p o rt system (resu ltin g in th e inhibition of axonal neuropeptide delivery) and/or a destruction of neuronal term in als (due to lack of protection by the perineurium ; Gamse et al., 1982; Chung ef al., 1990). On th e o th er hand, th e delayed reductions are probably th e re s u lt of th e direct cytotoxic effects inflicted by capsaicin its e lf (Jancso e t al, 1985).

(iii) Sensory A lterations

In general, ad m in istratio n of capsaicin to n eo n atal r a ts re su lts in a p erm an en t destruction of nociceptive chem ical tran sm issio n (Jan cso e t al, 1977; Fitzgerald, 1983; Cam pbell et al., 1993) w ith less reduction in noxious therm al (Hammond an d R uda, 1991; Ren

et al., 1994) and no depression of noxious m echanical (Jancso e t al, 1977; Lynn, 1984; Ren et al., 1994) sensitivity. B ased on these reports, it has been suggested th a t the hypoalgesic effects observed following neonatal capsaicin tre a tm e n t m ay be due to th e fall in th e fibre population and not dim inished sen sitiv ity of th e cu tan eo u s receptors (Lynn, 1984). It should be noted th a t long­ term sensory alterations in adult ra ts are only a p p a re n t a fte r they |(s.c.) h av e been systemically^dosed w ith >50mg/kg of th e neurotoxin w hile acute doses (1-lOm g/kg) elicit b rie f d u ratio n s of antinociception which do not last beyond a few hours (G am se et a l.,

1981; Campbell et al., 1993). This therefore p a ra lle ls the depolarisation-desensitisation phenom enon described above.

Chapter 4 : Neonatal Capsaicin Treatment

4.1.3 T h e r a p e u tic P o te n tia l o f C a p sa ic in

Although capsaicin selectively exerts its effects on C-sensory fibres, and to a certain extent Aô neurones, its th era p eu tic p otential is by no m eans constrained to the field of p ain an d nociception. In fact, it m ay be clinically useful in any condition th a t involves im p aired C -afferent function(s) and these include am ongst others p ru ritu s, b lad d er hyper- reflexia and a sth m a (see Campbell et a l., 1993).

In ro d en t models, acute system ic a d m in istratio n of capsaicin causes hypotherm ia, a fall in blood p ressu re an d p o ten tiatio n of ulceration in th e gastric mucosa (see references in Lynn, 1990 an d Cam pbell et at.,

1993). The sm all th erap eu tic window betw een th e induction of an alg esia an d these responses coupled w ith th e poor system ic bioavailability therefore lim its th e p o ten tial clinical application of capsaicin via th is route of ad m in istratio n (Cam pbell et a l. , 1993).

More prom ising th erap eu tic indications have come forth from topical applications of the vanyllilnoneamide. Application of capsaicin onto the skin of ra ts resu lts in vasodilation an d increased or no change in the nociceptive thresholds; this latter effect being d ep en d en t on the vehicle in which the neurotoxin is adm inistered in (see Lynn, 1990 and Campbell et al., 1993 as well as references therein). However, in those m odels which have dem onstrated a n a ltera tio n in nociceptive sensitivity, capsaicin evokes an initial axonal flare response which ends in a period of desensitisation so m irroring th e electrophysiological d a ta a lre a d y discussed (Lynn, 1990; C am pbell et al., 1993). S im ilar desensitising phenomena have been observed w ith topical applications of capsaicin on th e skin of feline an im als a n d on rep eated exposure of the oral m ucosa to the neurotoxin (Lynn, 1990).

^ lm ptei^ 4^ N eon^ alC o£saicm

For a long tim e, the d a ta for local capsaicin tre a tm e n t in neuropathic I conditions were irreconcilable possibly due to th e different aetiologies

(Dubner, 1991). Recently, however, there h as been in creasin g evidence from clinical trials supporting the use of topical capsaicin in a ran g e of n eu ro p ath ies eg. trigem inal neuralgia, diabetic n eu ro p ath y , post­ herpetic neuralgia, phantom lim b pain, etc. (see C am pbell et al., 1993). A lth o u g h work in th is area is still in the p relim in ary stages, it is ex citin g to know th a t capsaicin analogues could provide a m eans of an alg esia for certain conditions which still pose as p rim ary clinical problem s. N evertheless, m uch research is req u ired before an y final conclusions m ay be m ade. In p articu lar, th e issu es of th e undesirable

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