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R. L. NAHIN & J. C. LIEBESKIND
Depa rtm ents 0/ Ne uroscience and Psych ology,
include the discovery of analgesia elicited by electrical stimulation of the medial
brain stern, referred to as stimulation-produced analgesia (SPA), the identification of
opiate bind ing sites in the central nervous system, and the subsequent discovery and
synthesis ofopio id pept ides in the brain, the enkephalins and endorphins.
Although the existence ofspecific opiate receptors in the bra in had been suspected
for man y years (Gold stein, Lowery & Pal, 1971), it was not until 1973 that three
separate laboratories (pert & Snyder, 1973; Simon, Hiller & Edelman, 1973;
Terenius, 1973) were able to demonstrate high affmity bind ing sites for op iates. Th is
exciting discovery was followed several years later by the identific ation of the
morphine-Iike penta peptides, methionine- and leucine-enkephalin (Hughes , 1975;
important role in the analgesic mechanisms of SPA. There is also evidence that
opioid peptides mediate certain forms of'stress-induced ana1gesiaand that such forms
of stress may represent natural inputs to this endogenous ana lgesia system (Lewis,
Cannon & Liebeskind, 1980). Adequate review of this burgeoning literature would
exceed the range of this chapter, but several major points will be discussed in the
sections to follow. It may first be noted that opioid peptides (cf., Akil, Watson, Berger
& Barchas, 1978; Bloom, Battenberg, Rossier, Ling & Guillemin, 1978a; Bloom ,
Rossier, Battenberg, Bayon, French, Henriksen, Siggins, Segal, Brown, Ling &
Gu illemin, 1978b) and opiate binding sites (Atweh & Kuhar, 1977a&b; Kuhar, Pert
& Snyder, 1973) are found in bra in regions known to support SPA and opiate
analge sia deri ving from local rnicro-injections. Opiates and opioid pept ides also
& Cicero, 1974) or when adm inistered into the lateral ventricle (Belluzzi, Grant,
ANALGESIA BY STIMULATION OF THE NERVOUSSYSTEM 329
Garsky, Sarantakis, Wise & Stein , 1976; Bloom , Segal, Ling & Guillemin, 1976).
Such analgesia, as weil as SPA , are reversed or blocked by the opiate antagonist,
naloxone (Akil , Madden , Patrick & Barchas, 1976a; Akil , Mayer & Liebeskind,
1976b; Bloom et al., 1976; Jacquet & Marks, 1976). Moreover, SPA alters the amount
cerebrospinall1uid (Akil et al., 1978; Hosobuchi, Rossier, Bloom & Guillemin, 1979).
Stimulation-produced analgesia (SPA)
Wolfle , Akil , Carder & Liebeskind , 1971 ; Oliveras, Redjemi, Guilbaud & Besson,
1975), cat (Liebeskind, Guilbaud, Besson & Oliveras, 1973), monkey (Goodman &
Holcombe, 1976), and in man (Hosobuchi, Adams & Linchitz, 1977; Richardson &
Akil , 1977). SPA has been shown to inhibit behavioural responses to a variety of
noxious stimuli including electric shock (Mayer et al., 1971),electrical stimulation of
the tooth pulp (Oliveras et al., 1975), pinch (Liebeskind et al.. 1973), heating of the
The experimental evidence supports the view that SPA is mediated by mechanisms
invol ved in the suppression ofnociceptive information. This idea was first proposed
by Mayer et al. (1971), who suggested that a process is initiated by SPA resulting in
the activation of a descending pain inhibitory path, Supporting th is suggestion are
observations that SPA produces few apparent sensory or motor deficits other than
analgesia (Mayer et al., 1971 ; Ol ivera s et al.. 1975). The analgesic specificity ofSPA
has also been demonstrated with electrophysiological methods (Morrow & Casey,
1976; OIeson , Twombly & Liebeskind, 1978).
Earl y work in this area (Ma yer et al., 1971) pointed to some striking sim ilarities
between SPA's and morphine's mode of action. The PAG has been found to be
extremely sensitive to morphine, microinjections in doses as low as I lJ8 producing
analgesia (Jacquet & Lajtha, 1976; Sharpe et al.. 1974; Yaksh, Duchateau & Rudy,
1976). Additionally, mapping studies showed that man y of the same brain sites
support both SPA and morphine analgesia (Liebeskind , Giesler & Urea, 1976). SPA
and opiate action have been further connected in that cross-tolerance between SPA
and morphine analgesia has been reported (Ma yer & Hayes, 1975; Mayer &
Murphin, 1976). Basbaum, Marley, O'Keefe & Clanton (1976) demonstrated that
lesion s of the spinal cord dorsolateral funiculus block both SPA and morphine
analgesia. Finally, SPA can be either partially (Akil et al.. 1976) or completely
(Hosobuchi et al., 1977; Oliveras, Hosobuchi, Redjemi, Guilbaud & Besson , 1977)
sources of this variance have been identified (Cannon , Prieto, Lee & Liebeskind,
1980a; Prieto, Giesler & Cannon, 1979). It was found that although SPA can be
elicited equally weil from dorsal and ventral PAG, naloxone reduces analgesia only
from ventral PAG (Cannon et al., 1980a; Prieto et al., 1979). Furthermore, a latency
of 10-18 min was observed before naloxone manifested its effect (Cannon et al.,
1980a). These findings are in accord with the observations that ß-endorphin fibres
are found in much hea vier concentration in ventra l than dorsal periaqueductal grey
(Bloorn et al.. 1978a&b ; Watson, Akil , Richard & Barchas, 1978). Moreover, Akil ,
Hewlett, Barchas & Li (l980a; 1980b) reported that ß-endorphin dissociates from
opiate receptors at a much slower rate than do the enkephalins, perhaps accounting
for the long latencies required for naloxone antagonism of SPA in contrast to the
drug's rap id antagonism ofopiate analgesia.
330 R. L. NAHIN & J. C. LIEBESKIND
The neural activating effect ofSPA and morphine
If SPA and morphine aet ivate a descending inhibitory system, it would be expe eted
that an inerease in PAG aetivity would be eorrelated with thi s aetiva tion. Such has
indeed been found . Multiple un it aetiv ity (MUA) reeo rdin gs from the PAG have
shown that systemie morphine (Oleson et al.. 1978; U rea, Na hin & Liebeskind ,
1979b), intraventrieular morphine (U rea, Frenk, Liebeskind & Taylor , 1977) and
SPA (Oleson et al.. 1978) result in naloxone reversible inereases of PAG MUA that
are highly eorrelated with the time course of analgesia. Eleetrode sites at a distanee
from the PAG either show no effeet or a deereased MU A following SPA or morphine
administration. In drug naive an imals, a significant eorrelation was found betwe en
the on set lateneies to MUA inereases and to behavioural ana lgesia follo wing a single
morphine injeetion (U rea et al., 1977; U rea et al., 1979b) .
MUA inereases in response to morphine administration a re in eontrast with
previou s fmdings demonstrating that single unit aetivity is either depressed or
unaffeeted by opiate drugs (Frederiekson & Norris, 1976; Gent & Wolsteneroft,
1976). Two faetors may eontribute to this diserepaney. Fir st, it is po ssible that
neurones, whereas the gro sser eleetrodes used in MUA reeording may predominantly
awake , intaet animals, single un it studies generall y util ize deeerebrate or
anaesthetized preparations. U rea & Liebe skind (1979) found that morphine deereases
PAG MUA in ur ethane-an aesth etized rat s, whereas it inereases thi s aetivity in the
If morphine-indueed inereases in PAG MUA refleet the PAG's aetive role in a
deseending analgesia system, then the magn itude ofthe MUA respon se to morphine
should mirror the degree of analgesia. Urea, Nahin & Lieb eskind (1 979a) have found
that the development of an algesie toleranee to mo rphine is refleeted in the PAG by a
temporall y eorrelated deerement in th e morphine- indueed MUA inerease. lt
appears, therefore, that SPA and mo rph ine seleetive ly aetiva te th ose brain areas
involved in mediating pa in inhibition.
Descending paths and spinal sites of analgesia
As pre viou sly ind ieated, seleetive aetivation of th e PAG, whether by morphine
administration or by SPA, seems a neeessary step in a descending pa in inhibitory
system. Important questions ar e how and where doe s thi s aetivat ion produee
analgesia? lt has been noted that stim ulation in the PAG ean block spinal noeieeptive
reflexe s (Mayer et al., 1971). Th is observation was followed by the demonstration that
stimulation ofthe PAG (Liebeskind et al., 1973) or the nucleus raphe magnus (Fields,
Basbaum, Clanton & Anderson , 1977) as weIl as systemie (LeBars, Menetrey,
Conseiller & Besson , 1975) or loeal PAG injeetions of morphine (Bennett & Ma yer ,
1976) all preferentially inhibit those dorsal horn neurones (laminae I and V) that are
noei eeptive. Earlier work had established that neurones in th ese laminae are
uniquely or max imally responsive to noxious stim ulation (Christensen & Perl , 1970;
Wall, 1973). On the other hand, it has also been found in spina l animals that
intravenou s injeetions of mo rph ine inhibit the aeti vity of those lamina V neurones
dri ven by the small diameter afferent fibres (A and C) kno wn to eonve y noeieeptive
information (LeBars, Guilbaud, Jurna & Besson , 1976). This inhibitio n is naloxon e
reversibl e. This same depression has been observed with morphine ionto phoretieally
applied to lamina V (cf. Duggan, 1979). Intratheeal injeetions of opi at es also produee
ANALGESIA SY STIM ULA TrO N OF THE NERVOUS SYSTEM 331
analgesia in a variety of species including the rat (Yaksh & Rud y, 1976; Yaksh &
Rudy, 1977), the cat (Yak sh, 1978), and humans (Wang, Nanss & Thomas, 1979).
These fmd ings have led to the suggestion that opiates ma y also, at least partially,
inhibit the perception of pain by their direct action on the spinal cord (cf. Yaksh ,
1979). The identification of opi ate binding sites (Atweh & Kuhar, 1977a ,b; LaMotte,
Pert & Snyder, 1976) in the dorsal horn of the spi nal cord furth er supports thi s contention.
Espec iall y interesting is the high den sity of opiate binding sites in the substa ntia
gelat inosa (SG) (cf. Duggan , 1979). The SG has been thought to playa major role in
the processing ofnociceptive information from the spinal cord to higher centres. Two
differing views of thi s role are most prominent. The first hold s that the SG is the site
where pre- and post-synaptic interactions between large and small afferent fibres act
to filter somatosensory information relayed to the brain (Kerr, 1975; Melzack &
Wall , 1965). The second proposal suggests that the SG integ rate s input from
nociceptive and non-nociceptive Csfrbres, integrated output then continuing to
somatosensory pathways such as the spi nothalarnic system (Kumazawa & Perl ,
1978). To date the evidence tends to support the second of these concepts (Price,
Hay ashi , Dubner & Ruda , 1979; Kerr, 1975). Whatever the final outcorne of this
debate , a large body of evidence has accumulated indicating that opiate and SPA
depression of dorsal horn cells is processed by the SG . Dendritic projections from
selectively depresses the activity oflamina V neurones to noxious heating ofthe skin.
In both cases the depression is naloxone reversible. Recent observations indicate that
stalked cells in the SG send axons to lamina I (Price et al.. 1979), where it is thought
the axons make excitatory synapses (Bennett, Ha yashi , Abdelmoumene & Dubner,
1979). Furthermore, the stalked cells are known to receive input from primary
afferent fibres (Price et al.. 1979), suggesting sensory information is conveyed to
lamina I via the SG . These sta lked cells appear to be in an appropriate position to
recei ve descending input from serotonergic supraspinal pathways (Kerr, 1975; Ruda
& Gobel, 1980). It has therefore been proposed (Ruda & Gobel , 1980) that descending
SG neurones (Cervero, Molony & Iggo, 1979).
Also supporting this contention is the presence ofserotonergic endings in the SG
that are thought to be the terminals of a descending system (Ruda & Gobel, 1980).
Drugs int erfering with 5-h ydroxytr yptamine's (5HT) interaction with receptors
(Vogt , 1974; Yaksh, Yeung & Rud y, 1976a) block morphine analgesia, as doe s
p-chlorophenylalanine (Ten en , 1968), wh ich depletes 5HT levels in the brain .
Furthermore, increasing 5HT levels potentiates morphine ana lgesia (Calcutt,
Handley, Sparkes & Spencer, 1972). Drugs that interfere with 5HT's action block
SPA (Akil & Liebeskind, 1975) and its inhibitory action on spinal cord nociceptive
neurones (Guilbaud, Besson, Oliveras & Liebeskind, 1973). Finally, iontophoresis of
5HT onto nociceptive dorsal horn neurones leads to inhibition of normal electrica1
activity (Randic & Yu , 1975).
Histofluorescent techniques have found that the raphe nuclei contain high levels of
5HT (Dahlström & Fuxe, 1975). In particular, the nucleus raphe magnus (NRM), a
site known to produce potent analgesia upon electrical stim ulation (Oleson et al..
1978; Oli veras et al.. 1977), sends serotonergic fibres to the dorsal horn (Da hlström &
Fuxe , 1965). At thi s time it has not been confirrned that these are the serotonergic
fibres synapsing on the stalked cells of the SG . However, autoradiographic studies
have revealed that NRM projects to laminae I, 11 , V, VI and VII of the spinal cord
(Basbaurn, Clanton & Fields, 1978).
332 R. L. NAHIN & J. C. LIEBESKIND
The pathway of this descending system was found to be contained in the dorsal
latera l funiculus (DLF) (Basbaum er al., 1977; Fields & Basbaum, 1979). Lesions of
the DLF effectively blocked SPA and morphine analgesia (Basbaum er al.. 1977).
Whereas sti mulation in the PAG as weil as in the NRM produces analgesia, the PAG
sends a n insignificant number of projection s to the cord as compared to the NRM
(Basbaum & Fields, 1977; Ca st iglion i, 1980; Castiglion i, Gallaway & Coulter, 1978).
This fact suggests that an alge sia produced in the PAG may be e1icited via NRM
ac tion on the dorsal horn. Supporting this hypothesis are autoradiographic (Ruda,
1975) and HRP (Gallager & Pert, 1978) studies revealing projection s from the ventral
lateral PAG to the NRM. Furthermore, the crude somatotopic organization found in
the PAG is preserved in the NRM (Watkins, Griffm, Leichnetz & Mayer , 1980). lt
ha s been shown that thi s connect ion is excitatory: Systemic a nd local injections of
morphine into the PAG increase th e activity ofNRM cell s (Behbehani & Pomeroy,
1978; Deakin er al.. 1977). In addition, lesions of the NRM disrupt analgesia
produced by glutamate microinjections into the PAG (Behbehani & Fields, 1979).
However, it has been found that lesions of the classically de fmed NRM extending
along the midline from the inferior olive to the decussation ofthe trapezoid body are
not sufficient to block SP A deriving from the ventral PAG (Cannon, Prieto &
Liebeskind, 1980b). Larger lesions extending rostrally do produce a significant
elevation in analgesia thresholds (Cannon er al., 1980b). Preliminary work indicates
th ese extended lesions do not disrupt analgesia from dorsal PAG placements, those
sites yielding analgesia insensitive to naloxone blockage (Cannon er al., 1980a ; Prieto
Much ofthe aforementioned evidence indicates the existence ofan endogenous pain
inhibitory system. The quest ion that must now be as ked is when is th is system
documented situation in the literature is the analgesic effect of stress (Akil er al..
1976a). However , until recentl y, stress ana lgesia has not been conclusivel y implicated
in an endogenous opiate system . lt had been reported that naloxone inhibits stress
analgesia (Ak il er al., 1976a) and that cross-tolerance de velops between opiate and
It was noted that the stress paradigms used in the above stud ies were qualitatively and
was or was not inhibited by naloxone depending on the temporal parameters of the
shock (Lewis er al., 1980). Analgesia elicited by footshock delivered intermittently for
stress analgesia, only one of whi ch is apparently med iat ed by an endogenous opiate
system. It was further found that dexamethasone, a synthetic glucocorticoid, blocked
onl y the naloxone sensitive stress analgesia (Lewis et al.. 1980). Dexamethasone has
been previously shown to block stress-produced rises in plasma AC T H and
ß-endorphin levels (French, B1oom, Riv ier , Guillemin & Ro ssier , 1978; Ro ssier,
French, Rivier, Ling, Guillemin & Bloom, 1977). Taken together with the fact that
hypophysectomy blocks stress a nalgesia (Amir & Amit, 1979; Bodnar, Glusm an ,
Brutus, Spiaggia & Kell y, 1979), these findings suggest that pitu itary ß-endorphin is
signi fica ntly involved with so me ty pes of stress analgesia. Another ind ication that
ANALGESIA BY STIMULATlON OF TH E NERVOUS SYSTEM 333
stress analgesia may be mediated by an endogenous opiate system was the fmding
that morphine manifests cross-tolerance with stress analgesia produced by the 30 but
not the 3 m in shock paradigm (Lewis et al., 1980). It appears that at least certain
forms ofstress are a deq uate stim uli for activating an opioid system ofpain inhibition.
Most ofthe important factors del ineating this sort ofstress and distinguishing it from
the stress activating non-opioid analgesia have still to be determined. The neural and
neurochemical bases ofthe non-opioid system or systems are also as yet unknown.
W e a re grateful to Ms. Sheila Roberts for her careful preparation ofthis manuscript.
Our research is su pported by NIH grant NS07628.
Akil, H., Hewlett , W. A., Barchas, J. D. & Li, C. H. (1980a). Binding of[3H)-ß -endorphin to rat
brain membranes: characteri zation of opiate properties and interaction with ACTH. Eu r.
Akil, H. & Liebeskind , J. C. (1975). Monoam inergic mechani sms of stimulation-produced
analgesia. Brain Res.. 94, 279-296 .
Akil, H., Madden , J., Patrick, R. L. & Barchas, J. D. (1976a). Stress-indu ced increase in
cndogenous opiate pept ides: concurrent analgesia and its partial reversal by naloxone. In
Opiates and Endogenous Opioid Peptides ed. Kosterlitz, H. W. pp. 63-70 . Amsterdam:
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