Evidence that raphe-spinal neurons mediate opiate and midbrain stimulation-produced analgesias

&NA; The present experiments were undertaken to assess the role of neurons in the nucleus raphe nagnus (NRM) in mediating opiate and stimulation‐produced analgesias. A cannode for both electrical stimulation and local opiate microinjection was placed in the midbrain periaqueductal gray region of decerebrate or chloralose‐urethane anesthetized cats. Microelectrodes recorded the responses of medullary NRM neurons. Raphe‐spinal neurons were identified by antidromic activation from the cervical spinal cord. Fifteen of 20 raphe‐spinal cells tested were excited by electrical stimulation of the midbrain. Of 49 NRM neurons tested, 26 were excited by either systemic or midbrain injection of opiate agonist. Twelve of 33 NRM cells tested by midbrain microinjection were excited. In 10 the effect was reversed by naloxone. Seventeen raphe‐spinal neurons were tested; 5 showed naloxone‐reversible excitation to either midbrain or intravenous injection of opiates. NRM neurons respond to auditory and somatic stimuli; at least half respond maximally to somatic stimuli of noxious intensity. These findings are consistent with the hypothesis that the raphe‐spinal projection mediates opiate and electrical stimulation‐produced effects from midbrain sites. The properties of raphe‐spinal neurons suggest that they are part of a negative feedback system which monitors and limits the output of spinal dorsal horn pain‐transmission neurons.

[1]  M. Vogt The effect of lowering the 5‐hydroxytryptamine content of the rat spinal cord on analgesia produced by morphine , 1974 .

[2]  H. Fields,et al.  Nucleus raphe magnus inhibition of spinal cord dorsal horn neurons , 1977, Brain Research.

[3]  D. C. West,et al.  Location and conduction velocity of raphespinal neurones in nucleus raphe magnus and raphe pallidus in the cat , 1977, Neuroscience Letters.

[4]  C. Vierck,et al.  Attenuation of pain reactivity by caudate nucleus stimulation in monkeys , 1975, Brain Research.

[5]  F. Ervin,et al.  Striatal influence on facial pain. , 1966, Confinia neurologica.

[6]  A. Goldstein,et al.  On the role of endogenous opioid peptides: failure of naloxone to influence shock escape threshold in the rat. , 1976, Life sciences.

[7]  R. Hayes,et al.  Reduction of stimulation-produced analgesia by lysergic acid diethylamide, a depressor of serotonergic neural activity , 1977, Brain Research.

[8]  J. O’Keefe,et al.  Reversal of morphine and stimulus-produced analgesia by subtotal spinal cord lesions , 1977, Pain.

[9]  E. J. Simon,et al.  Distribution of stereospecific binding of the potent narcotic analgesic etorphine in the human brain: predominance in the limbic system. , 1973, Research communications in chemical pathology and pharmacology.

[10]  Donald D. Price,et al.  Central nervous system mechanisms of analgesia , 1976, Pain.

[11]  M. Kuhar,et al.  Autoradiographic localization of opiate receptors in rat brain. I. Spinal cord and lower medulla , 1977, Brain Research.

[12]  W. Sweet,et al.  Pain threshold alterations by brain stimulation in the monkey. , 1971, Journal of neurosurgery.

[13]  J. Besson,et al.  Opiate antagonist, naloxone, strongly reduces analgesia induced by stimulation of a raphe nucleus (centralis inferior) , 1977, Brain Research.

[14]  S. Snyder,et al.  Opiate receptor: autoradiographic localization in rat brain. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[15]  H. Akil,et al.  Monoaminergic mechanisms of stimulation-produced analgesia , 1975, Brain Research.

[16]  T. Yaksh,et al.  Sites of morphine induced analgesia in the primate brain: relation to pain pathways. , 1974 .

[17]  A. Pert,et al.  Afferents to brain stem nuclei (brain stem raphe, nucleus reticularis pontis caudalis and nucleus gigantocellularis) in the rat as demonstrated by microiontophoretically applied horseradish peroxidase , 1978, Brain Research.

[18]  S. Snyder,et al.  An endogenous morphine-like factor in mammalian brain. , 1975, Life sciences.

[19]  A. Lajtha,et al.  The periaqueductal gray: Site of morphine analgesia and tolerance as shown by 2-way cross tolerance between systemic and intracerebral injections , 1976, Brain Research.

[20]  H. Morris,et al.  Identification of two related pentapeptides from the brain with potent opiate agonist activity , 1975, Nature.

[21]  H. Fields,et al.  Some properties of spinal neurons projecting to the medial brain-stem reticular formation , 1975, Experimental Neurology.

[22]  G. Berntson,et al.  Effect of opiate receptor blockade on pain sensitivity in the rat , 1977, Brain Research Bulletin.

[23]  K. Tsou,et al.  STUDIES ON THE SITE OF ANALGESIC ACTION OF MORPHINE BY INTRACEREBRAL MICRO-INJECTION. , 1964, Scientia Sinica.

[24]  J. Dostrovsky,et al.  MORPHINE EFFECTS ON RAT RAPHE MAGNUS NEURONS , 1977 .

[25]  W. Willis,et al.  Inhibition of primate spinothalamic tract neurons by stimulation in the region of the nucleus raphe magnus , 1976, Brain Research.

[26]  K. Albus,et al.  Differentiation between spinal and supraspinal sites of action of morphine when inhibiting the hindleg flexor reflex in rabbits. , 1973, Neuropharmacology.

[27]  Donald D. Price,et al.  Antagonism of acupuncture analgesia in man by the narcotic antagonist naloxone , 1977, Brain Research.

[28]  T. Hökfelt,et al.  Immunohistochemical studies using antibodies to leucine-enkephalin: Initial observations on the nervous system of the rat , 1976, Neuroscience.

[29]  A I Basbaum,et al.  Brainstem control of spinal pain-transmission neurons. , 1978, Annual review of physiology.

[30]  P. Wall,et al.  Lack of effect of naloxone on pain perception in humans , 1976, Nature.

[31]  D. Price,et al.  Differential effects of spinal cord lesions on narcotic and non-narcotic supression of nociceptive reflexes: Further evidence for the physiologic multiplicity of pain modulation , 1978, Brain Research.

[32]  E. Valenstein,et al.  Attenuation of Aversive Properties of Peripheral Shock by Hypothalamic Stimulation , 1965, Science.

[33]  H. Kuypers,et al.  Retrograde axonal transport of horseradish peroxidase from spinal cord to brain stem cell groups in the cat , 1975, Neuroscience Letters.

[34]  D. V. Reynolds,et al.  Surgery in the Rat during Electrical Analgesia Induced by Focal Brain Stimulation , 1969, Science.

[35]  W. Willis,et al.  Inhibition of spinothalamic tract cells and interneurons by brain stem stimulation in the monkey. , 1977, Journal of neurophysiology.

[36]  Allan I. Basbaum,et al.  Three bulbospinal pathways from the rostral medulla of the cat: an autoradiographic study of pain modulating systems A.I. Basbaum, C.H. Clanton and H.L. Fields, J. comp. Neurol., 178 (1978) 209–224 , 1978, PAIN.

[37]  S. Snyder,et al.  The regional distribution of a morphine-like factor enkephalin in monkey brain , 1976, Brain Research.

[38]  S. Balagura,et al.  The analgesic effect of electrical stimulation of the diencephalon and mesencephalon. , 1973 .

[39]  E. Anderson,et al.  Morphine analgesia: Blockade by raphe magnus lesions , 1975, Brain Research.

[40]  J. McKenzie,et al.  The effects of morphine and pethidine on somatic evoked responses in the midbrain of the cat, and their relevance to analgesia , 1962 .

[41]  H. Fields,et al.  Opiate and stimulus-produced analgesia: functional anatomy of a medullospinal pathway. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[42]  G. Gebhart,et al.  Evaluation of the periaqueductal central gray (PAG) as a morphine-specific locus of action and examination of morphine-induced and stimulation-produced analgesia at coincident PAG loci , 1977, Brain Research.

[43]  A. Gol Relief of pain by electrical stimulation of the septal area. , 1967, Journal of the neurological sciences.

[44]  B Carder,et al.  Analgesia from Electrical Stimulation in the Brainstem of the Rat , 1971, Science.

[45]  H. Fields,et al.  Response of medullary raphe neurons to peripheral stimulation and to systemic opiates , 1977, Brain Research.

[46]  H. Fields,et al.  Somatosensory properties of spinoreticular neurons in the cat , 1977, Brain Research.

[47]  L. Conway,et al.  Structural changes of the intradural arteries following subarachnoid hemorrhage. , 1972, Journal of neurosurgery.

[48]  S. Snyder,et al.  Regional Distribution of Opiate Receptor Binding in Monkey and Human Brain , 1973, Nature.

[49]  S. Snyder,et al.  Phylogenetic distribution of a morphine-like peptide ‘enkephalin’ , 1976, Brain Research.

[50]  H. Takagi,et al.  Enhancement by morphine of the central descending inhibitory influence on spinal sensory transmission. , 1971, European journal of pharmacology.

[51]  F. Walberg,et al.  The raphe nuclei of the brain stem in the cat. I. Normal topography and cytoarchitecture and general discussion , 1960, The Journal of comparative neurology.

[52]  G GOERANSSON,et al.  THE METABOLISM OF FATTY ACIDS IN THE RAT. VI. ARACHIDONIC ACID. , 1965, Acta physiologica Scandinavica.

[53]  S. Irwin,et al.  The effects of morphine methadone and meperidine on some reflex responses of spinal animals to nociceptive stimulation. , 1951, The Journal of pharmacology and experimental therapeutics.

[54]  J. Oliveras,et al.  Effects induced by stimulation of the centralis inferior nucleus of the raphe on dorsal horn interneurons in cat's spinal cord , 1977, Brain Research.

[55]  T. Yaksh,et al.  Antagonism by methysergide and cinanserin of the antinociceptive action of morphine administered into the periaqueductal gray , 1976, Brain Research.

[56]  I. Engberg,et al.  Reticulospinal inhibition of transmission in reflex pathways , 1968, The Journal of physiology.

[57]  D. Mayer,et al.  Pain reduction by focal electrical stimulation of the brain: an anatomical and behavioral analysis , 1974, Pain.