It is proposed that analgesia might be achieved by pharmacological interruption of sensory input to the C.N.S. at the level of the spinal cord. On the basis of early reports that baclofen mimicked presynaptic inhibitory mechanisms in the spinal cord, baclofen was tested for potential analgesic activity in the mouse hot-plate test. Baclofen appeared to have some antinocisponsive activity in its own right and it potentiated the antinocisponsive effect of morphine. This observation has been confirmed and extended by several authors and the antinocisponsive activity appears to reside in the 1-isomer. Both spinal and supraspinal sites have been suggested for the locus of action in the C.N.S., whilst the underlying cellular mechanism may be inhibition of neurotransmitter release (via a bicuculline-refractory GABA receptor) or antagonism of the post-synaptic actions of substance P as a neurotransmitter.
Baclofen is compared with two other antinocisponsive agents (morphine and clonidine) in terms of its effects on release of neurotransmitters. Consideration is given to the possibility that a further characteristic is shared by these compounds, namely that following chronic administration, abrupt cessation of therapy might be accompanied by withdrawal or ‘rebound’ effects.
HughesJSmithTWKosterlitzHWFothergillLAMorganBAMorrisHR. Identification of two related pentapeptides from the brain with potent opiate agonist activity. Nature1975; 258: 577–579.
2.
BeaumontAHughesJ. Biology of opioid peptides. Ann Rev Pharmacol Toxicol1979; 19: 245–267.
3.
CostaETrabucchiM, (Eds). The Endorphins. Adv Biochem Psychopharmacol1978; vol 18.
4.
SnyderSH. Clinical relevance of opiate receptor and opioid peptide research. Nature1979; 279: 13–14.
5.
CuttingDAJordanCC. Alternative approaches to analgesia: baclofen as a model compound. Br J Pharmacol1975; 54: 171–179.
6.
PierauF-KZimmermanP. Action of a GABA-derivative on postsynaptic potentials and membrane properties of cat's spinal motoneurones. Brain Res1973; 54: 376–380.
7.
PierauF-KMathesonGKWursterRD. Presynaptic action of β(4-chlorophenyl)-GABA. Expl Neurol1975; 48: 343–351.
8.
KääriäinenIVikbergP. Effects of aminooxyacetic acid and baclofen on catalepsy, striatal homovanillic acid increase and antinociception caused by methadone in rats. Acta Pharmac et Toxicol1976; 39: 536–544.
9.
LevyRAProudfitHK. The analgesic action of baclofen (β-4-chlor-phenyl-γ-aminobutyric acid). J' Pharmacol Exp Ther1977; 202: 437–145.
10.
LiebmanJMPastorG. Analgesia elicited by intracerebral micro-injections of baclofen and muscimol. Neurosci. Abstr1968; 4: 461.
11.
ProudfitHKLevyRA. Delimitation of neuronal substrates necessary for the analgesic action of baclofen and morphine. Eur J Pharmacol1978; 47: 159–166.
12.
WilsonPRYakshTL, Baclofen is antinociceptive in the spinal intrathecal space of animals. Eur J Pharmacol1978; 51: 323–330.
13.
ZielR. Potentiation of analgesia in the mouse by baclofen. Experientia1978; 34: 931.
14.
LevyRAProudfitHK, Analgesia produced by microinjection of baclofen and morphine at brain stem sites. Eur J Pharmacol1979; 57: 43–55.
15.
KoellaWP. Pharmacological aspects of spasticity with special reference to Lioresal. Postgrad Med J1972; 48 (Suppl.5): 13–18.
16.
PierceyMFHollisterRP. Effects of intravenous baclofen on dorsal horn neurones of spinal cats. Eur J Pharmacol1979; 53: 379–382.
17.
YakshTLRudyTA. Analgesia mediated by a direct spinal action of narcotics. Science1976; 192: 1357–1358.
18.
YakshTLRudyTA, Studies on the direct spinal action of narcotics in the production of analgesia in the rat. J Pharmacol Exp Ther1977; 202: 411–428.
19.
SaitoKKonishiSOtsukaM. Antagonism between Lioresal and substance P in rat spinal cord. Brain Res1975; 97: 177–180.
20.
OtsukaMYanagisawaM. The action of substance P on motoneurons of the isolated rat spinal cord. In: SimonP Ed Advances in Pharmacology and Therapeutics (Vol 2), ‘Neurotransmitters’. Oxford: Pergamon Press1978; 181–190.
21.
TheriaultEOtsukaMJessellTM. Capsaicinevoked release of substance P from primary sensory neurons. Brain Res1979; 170: 209–213.
22.
HökfeltTKellerthJ-ONilssonGPernowG. Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons. Brain Res1975; 100: 235–252.
23.
HökfeltTEldeRJohanssonOLuftRNilssonGArimuraA. Immunohistochemical evidence for separate populations of somatostatin-containing and substance P-containing primary afferent neurones. Neuroscience1976; 1: 131–136.
24.
HökfeltTLjungdahlATereniusLEldeRPNilssonG. Immunohistochemical analysis of pathways possibly related to pain and analgesia: Enkephalins and substance P. Proc Natl Acad Sci USA1977; 74: 3081–3085.
25.
Chan-PalayVPalaySL. Ultrastructural identification of substance P cells and their processes in rat sensory ganglia and their terminals in the spinal cord by immunocytochemistry. Proc Natl Acad Sci USA1977; 74: 4050–4054.
26.
TakahashiTOtsukaM. Regional distribution of substance P in the spinal cord and nerve roots of the cat and the effect of dorsal root section. Brain Res1975; 87: 1–11.
27.
Ben-AriYHenryJL. Effects of the p-chlorophenyl derivative of GABA on spinal neurones in the cat. J Physiol (Lond)1976; 259: 46P–47P.
28.
FotherbyKJMorrishNJRyallRW. Is Lioresal (baclofen) an antagonist of substance P?Brain Res1976; 113; 210–213.
29.
FoxSKrnjevicKMorrisMEPuilEWermanR. Action of baclofen on mammalian synaptic transmission. Neuroscience1978; 3: 495–515.
30.
OnoHFukudaHKudoY. Mechanisms of depressant action of baclofen on the spinal reflex in the rat. Neuropharmacology1979; 18: 647–653.
31.
PotashnerSJ. Baclofen: effects on amino acid release. Can J Physiol Pharmacol1978; 56: 150–154.
32.
PotashnerSJ. Baclofen: effects on amino acid release and metabolism in slices of guinea-pig cerebral cortex. J Neurochem1979; 32: 103–109.
33.
BoweryNGDobleAHillDRHudsonALShawJSTurnbullMJ. Baclofen: a selective agonist for a novel type of GABA receptor. Brit J. Pharmacol1979; 67: 444P–445P.
34.
BoweryNGHudsonAL. γ-Aminobutyric acid reduces the evoked release of 3H-noradrenaline from sympathetic nerve terminals. Brit J. Pharmacol1979; 66: 108P.
35.
PatonWDM. The action of morphine and related substances on contraction and on acetylcholine output of coaxially stimulated guinea-pig ileum. Brit J Pharmacol1957; 12: 119–127.
36.
SharkawiMSchulmanMP. Inhibition by morphine of the release of 14C-acetylcholine from rat brain cortex slices. J Pharm Pharmacol1969; 21: 546–547.
37.
JhamandasKPhillisJWPinskyC. Effects of narcotic analgesics and antagonists on the in vivo release of acetylcholine from the cerebral cortex of the cat.’Brit J Pharmacol1971; 43: 53–66.
38.
HendersonGHughesJKosterlitzHW. A new example of a morphine-sensitive neuroeffector junction: adrenergic transmission in the mouse vas deferens. Brit J. Pharmacol1972; 46: 764–766.
39.
HendersonGHughesJThompsonJW. The variation of noradrenaline output with frequency of nerve stimulation and the effect of morphine on the cat nictitating membrane and on the guinea-pig myenteric plexus. Brit J Pharmacol1972; 46: 524P–525P.
40.
MontelHStarkeKWeberF. Influence of morphine and naloxone on the release of noradrenaline from rat brain cortex slices. Naunyn-Schmiedeberg's Arch Pharmacol1974; 283: 357–369.
41.
LohHHBraseDASampath-KhannaSMarJBWayELLiCH. β-endorphin in vitro inhibition of striatal dopamine release. Nature1976; 264: 567–568.
42.
JessellTMIversenLL. Opiate analgesics inhibit substance P release from rat trigeminal nucleus. Nature1977; 268: 549–551.
43.
BoweryNGDobleAHillDRHudsonALShawJTurnbullMJ. This symposium, pp. 3–11.
44.
WernerUStarkeKSchumannHJ. Actions of clonidine and 2-(2-methyl-6-ethyl-cyclohexamine)-2-oxazoline on postganglionic autonomic nerves. Arch Int Pharmacodyn Ther1972; 195: 282–290.
45.
StarkeKMontelH. Involvement of α-receptors in clonidine-induced inhibition of transmitter release from central monoamine neurones. Neuropharmacology1973; 12: 1073–1080.
46.
PaalzowL, Analgesia produced by clonidine in mice and rats. J Pharm Pharmacol1974; 26: 361–363.
47.
SchmittHLeDouarecJCPetillotN. Antinociceptive effects of some alpha sympathomimetic agents. Neuropharmacology1974; 13: 289–294.
48.
PaalzowGPaalzowL. Clonidine antinociceptive activity: Effects of drugs influencing central monoaminergic and cholinergic mechanisms in the rat. Naunyn-Schmiedeberg's Arch Pharmacol1976; 292: 119–126.
49.
StarkeKAltmannKP. Inhibition of adrenergic neurotransmission by clonidine: an action on prejunctional α receptors. Neuropharmacology1973; 12: 339–347.
50.
HooblerSWSagasturneELong term clinical experience with Catapres; comparison with guanethidine. In ConollyME Ed Catapres in Hypertension. London: Butterworths1970: 207–225.
51.
LeesAJClarkeCRAHarrisonMJ. Hallucinations after withdrawal of baclofen. Lancet1977: 1; 858.
52.
StienR. Hallucinations after sudden withdrawal of baclofen. Lancet1977; 2: 44.
