Recent studies which suggest the existence of an endogenous neural substrate of pain inhibition are reviewed. Electrical stimulation of some areas of the medial brain stem in laboratory rats has produced a dramatic degree of analgesia. Such stimulation-produced analgesia is partially blocked by an opiate antagonist drug. This observation has proved seminal to those searching for endogenous opiate-like neurochemicals, the opioid peptides (enkephalins and endorphins). Particular attention is focused on studies of stimulation-produced analgesia, the underlying anatomy and physiology of endogenous analgesia systems elucidated by such work, and the relation of these findings to discoveries about opiate receptors and opioid peptides. Very recent work suggesting that certain forms of stress are natural triggers for activating endogenous analgesia mechanisms is described. Although certain stressors cause analgesia mediated by opioids, other stressors cause analgesia by neurochemically different means. Thus, multiple analgesia substrates, opioid and nonopioid, appear to exist.
MelzackR., WallP.D.Pain mechanisms: A new theory. Science1965; 150: 971–979.
2.
BonicaJ.J., Albe-FessardD. (eds.). Advances in Pain Research and Therapy, Vol 1. Raven Press, New York1976.
3.
BonicaJ.J., LiebeskindJ.C., Albe-FessardD. (eds.). Advances in Pain Research and Therapy, Vol 3. Raven Press, New York1979.
4.
CannonJ.T., LiebeskindJ.C.Descending control systems. In: BeersR.F.Jr., BassetE.G. (eds.). Mechanisms of Pain and Analgesic Compounds, Raven Press, New York1979; 171–184.
5.
MayerD.J.Endogenous analgesia systems: Neural and behavioural mechanisms. In: BonicaJ.J., LiebeskindJ.C., Albe-FessardD.G. (eds.). Advances in Pain Research and Therapy, Vol 3.Raven Press, New York1979; 385–410.
6.
ShermanJ.E., LiebeskindJ.C.An endorphinergic, centrifugal substrate of pain modulation: Recent findings, current concepts and complexities. In: BonicaJ.J., ed. Pain, Raven Press, New York1980; 191–204.
7.
MayerD.J., LiebeskindJ.C.Pain reduction by focal electrical stimulation of the brain: an anatomical and behavioural approach. Brain Res1974; 68: 73–93.
8.
MayerD.J., WolfeT.L., AkilH., CarderB., LiebeskindJ.C.Analgesia from electrical stimulation in the brainstem of the rat. Science1971; 174: 1351–1354.
9.
OliverasJ.L., BessonJ.M., GuilbaudG., LiebeskindJ.C.Behavioral and electrophysiological evidence of pain inhibition from midbrain stimulation in the cat. Exp Brain Res1974; 20: 32–44.
10.
HosobuchiY., AdamsJ.E., LinchitzR.Pain relief by electrical stimulation of the central gray matter in humans and its reversal by naloxone. Science1977; 197: 183–186.
11.
RichardsonD.E., AkilH.Pain reduction by electrical brain stimulation in man. Part 1: Acute administration in periaqueductal and periventricular sites. J Neurosurg1977; 47: 178–183.
12.
RichardsonD.E., AkilH.Pain reduction by electrical brain stimulation in man. Part 2: Chronic self-administration in the periventricular gray matter. J Neurosurg1977; 47: 184–189.
13.
GybelsJ.M.Electrical stimulation of the central gray for pain relief in human: a critical review. In: BonicaJ.J., LiebeskindJ.C., Albe-FessardD. (eds.). Advances in Pain Research and Therapy Vol 3. Raven Press, New York1979; 499–509.
14.
RhodesD.L., LiebeskindJ.C.Analgesia from rostral brain stem stimulation in the rat. Brain Res1978; 143: 521–532.
15.
FieldsH.L., BasbaumA.I.Anatomy and physiology of a descending pain control system. In: BonicaJ.J., LiebeskindJ.C., Albe-FessardD.G. (eds.). Advances in Pain Research and Therapy Vol 3.Raven Press, New York1979; 427–440.
16.
SatohM., TakagiH.Enhancement by morphine of the central descending inhibitory influence on spinal sensory transmission. Eur J Pharmacol1971; 14: 60–65.
17.
YakshT.L., RudyT.A.Narcotic analgetics: CNS sites and mechanisms of action as revealed by intracerebral injection techniques. Pain1978; 4: 299–359.
18.
MayerD.J., PriceD.D.Central nervous system mechanisms of analgesia. Pain1976; 2: 379–404.
19.
AkilH., RichardsonD.E., BarchasJ.D., LiC.H.Appearance of beta-endorphin-like immunoreactivity in human ventricular cerebrospinal fluid upon analgesic electrical stimulation. Proc Natl Acad Sci (USA)1978; 75: 5170–5172.
20.
HosobuchiY., RossierJ., BloomF.E., GuilleminR.Stimulation of human periaqueductal gray for pain relief increases immunoreactive beta-endorphin in ventricular fluid. Science1979; 203: 279–281.
21.
AkilH., MayerD.J., LiebeskindJ.C.Comparison chez le rat entre l'analgesie induite par stimulation de la substance grise periaqueductale et l'analgesie morphinique. C R Acad Sci (Paris)1972; 274: 3603–3605.
22.
AkilH., MayerD.J., LiebeskindJ.C.Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist. Science1976; 191: 961–962.
23.
MayerD.J., HayesR.L.Stimulation-produced analgesia: Development of tolerance and cross-tolerance to morphine. Science1975; 188: 941–943.
24.
YakshT.L., YeungJ.C., RudyT.A.An inability to antagonize with naloxone the elevated thresholds resulting from electrical stimulation of the mesencephalic central gray. Life Sci1976; 18: 1193–1198.
25.
CannonJ.T., PrietoG.J., LeeA., LiebeskindJ.C.Antagonism of stimulation-produced analgesia by naloxone: effects of stimulation site, dose and time. Fed Proc1980; 39: 603.
26.
PrietoG.J., GieslerG.J.Jr., CannonJ.T.Evidence for site specificity in naloxone's antagonism of stimulation-produced analgesia in the rat. Soc Neurosci Abstr1979; 5: 614.
27.
OlesonT.D., TwomblyD.A., LiebeskindJ.C.Effects of pain-attenuating brain stimulation and morphine on electrical activity in the raphe nuclei of the awake rat. Pain1978; 4: 211–230.
28.
UrcaG., NahinR.I., LiebeskindJ.C.Development of tolerance to the effects of morphine: association between analgesia and electrical activity in the periaqueductal gray matter. Brains Res1979; 176: 202–207.
29.
UrcaG., NahinR.L., LiebeskindJ.C.Effects of morphine on spontaneous multiple unit activity: possible relation to mechanisms of analgesia and reward. Exp Neurol1979; 66: 248–262.
30.
UrcaG., FrenkH., LiebeskindJ.C., TaylorA.N.Morphine and enkephalin: analgesic and epileptic properties. Science1977; 197: 83–86.
31.
UrcaG., LiebeskindJ.C.Electrophysiological indices of opiate action in awake and anesthetized rats. Brain Res1979; 161: 162–166.
32.
LewisJ.W., CannonJ.T., LiebeskindJ.C.Opioid and nonopioid mechanisms of stress analgesia. Science1980; 208: 623–625.
33.
LewisJ.W., ShermanJ.E., and LiebeskindJ.C.Opioid and nonopioid stress analgesia: assessment of tolerance and cross-tolerance with morphine. J Neurosci1981; 1: 358–363.
34.
LewisJ.W., ChudlerE.H., CannonJ.T., LiebeskindJ.C.Hypophysectomy differentially affects morphine and stress analgesia. Proc West Pharm Soc1981; 24: 323–326.
35.
JacksonR.L., MaierS.F., CoonD.J.Long-term analgesic effects of inescapable shock and learned helplessness. Science1979; 206: 91–93.
36.
LevineJ.D., GodronN.C., FieldsH.L.The role of endorphins in placebo analgesia. In: BonicaJ.J., LiebeskindJ.C., Albe-FessardD. (eds.). Advances in Pain Research and Therapy Vol 3.Raven Press, New York1979; 541–551.
