The thalamic nucleus submedius and ventrolateral orbital cortex are involved in nociceptive modulation: A novel pain modulation pathway

Recently, a series of studies have given rise to and provided evidence for the hypothesis that the nucleus submedius (Sm) in the medial thalamus is involved in modulation of nociception. The Sm, ventrolateral orbital cortex (VLO) and the periaqueductal gray (PAG) constitute a pain modulatory pathway, activation of which leads to activation of the PAG-brainstem descending inhibitory system and depression of the nociceptive inputs in the spinal cord and trigeminal nucleus. Other studies have indicated that the Sm-VLO-PAG pathway plays an important role in the analgesia induced by electroacupuncture stimulation of the acupuncture point (acupoint) for exciting small diameter fiber (A-delta and C group) afferents. Opioid peptides, serotonin, dopamine, glutamate and their related receptors are involved in Sm- and/or VLO-mediated descending antinociception, and a GABAergic disinhibitory mechanism participates in mediating the antinociception induced by activation of mu-opioid receptors, serotonin 1(A) receptors, and dopamine D(2)-like receptors. This review describes these findings, which provide important new insights into the roles of the thalamus and cerebral cortex in descending pain modulation.

[1]  S. Jabbur,et al.  Continuous perfusion with morphine of the orbitofrontal cortex reduces allodynia and hyperalgesia in a rat model for mononeuropathy , 2004, Neuroscience Letters.

[2]  Yu-Feng Xie,et al.  The roles of different types of glutamate receptors involved in the mediation of nucleus submedius (Sm) glutamate-evoked antinociception in the rat , 2003, Brain Research.

[3]  J. Dostrovsky,et al.  Trigeminal projections to the nucleus submedius of the thalamus in the rat , 1991, The Journal of comparative neurology.

[4]  J. Dostrovsky,et al.  Responses of neurons in the rat thalamic nucleus submedius to cutaneous, muscle and visceral nociceptive stimuli , 1993, Pain.

[5]  J. Streltzer Textbook of Pain, 4th ed , 2001 .

[6]  Y. Khan,et al.  Cellular distribution of dopamine D1 and D2 receptors in rat medial prefrontal cortex , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[7]  Jing-shi Tang,et al.  Effect of stimulation and lesion of the thalamic nucleus submedius on formalin-evoked nociceptive behavior in rats. , 2007, Sheng li xue bao : [Acta physiologica Sinica].

[8]  C. Qu,et al.  D2-like but not D1-like dopamine receptors are involved in the ventrolateral orbital cortex-induced antinociception: A GABAergic modulation mechanism , 2009, Experimental Neurology.

[9]  P. Gaspar,et al.  D1 and D2 Receptor Gene Expression in the Rat Frontal Cortex: Cellular Localization in Different Classes of Efferent Neurons , 1995, The European journal of neuroscience.

[10]  Hong Jia,et al.  Involvement of the frontal ventrolateral orbital cortex in descending inhibition of nociception mediated by the periaqueductal gray in rats , 1997, Neuroscience Letters.

[11]  M. Baliki,et al.  Attenuation of neuropathic manifestations by local block of the activities of the ventrolateral orbito-frontal area in the rat , 2003, Neuroscience.

[12]  Allan I. Basbaum,et al.  Central nervous system mechanisms of pain modulation , 2006 .

[13]  P. Wall,et al.  Textbook of pain , 1989 .

[14]  J. Coffield,et al.  Immunoreactive enkephalin is contained within some trigeminal and spinal neurons projecting to the rat medial thalamus , 1987, Brain Research.

[15]  H. Jia,et al.  Effects of thalamic nucleus submedius lesions on the tail flick reflex inhibition evoked by hindlimb electrical stimulation in the rat. , 1995, Neuroreport.

[16]  K. Kawakita,et al.  Inhibitory effects of acupuncture manipulation and focal electrical stimulation of the nucleus submedius on a viscerosomatic reflex in anesthetized rats. , 1997, The Japanese journal of physiology.

[17]  RJ Dado,et al.  Afferent input to nucleus submedius in rats: retrograde labeling of neurons in the spinal cord and caudal medulla , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  M. Millan,et al.  Reciprocal Autoreceptor and Heteroreceptor Control of Serotonergic, Dopaminergic and Noradrenergic on Behalf Of: British Association for Psychopharmacology , 2022 .

[19]  F. Huang,et al.  Mu-Opioid Receptor in the Nucleus Submedius: Involvement in Opioid-Induced Inhibition of Mirror-Image Allodynia in a Rat Model of Neuropathic Pain , 2008, Neurochemical Research.

[20]  Yu-Feng Xie,et al.  Involvement of GABAergic modulation of the nucleus submedius (Sm) morphine-induced antinociception , 2004, Pain.

[21]  C. Qu,et al.  Involvement of GABAergic modulation of antinociception induced by morphine microinjected into the ventrolateral orbital cortex , 2006, Brain Research.

[22]  F. Huang,et al.  Microinjection of morphine into thalamic nucleus submedius depresses bee venom‐induced inflammatory pain in the rat , 2008 .

[23]  Jing-shi Tang,et al.  5-hydroxytryptamine 1A (5-HT1A) but not 5-HT3 receptor is involved in mediating the nucleus submedius 5-HT-evoked antinociception in the rat , 2005, Brain Research.

[24]  M. Chesselet,et al.  Expression of Mu opioid receptor mRNA in rat brain: An in situ hybridization study at the single cell level , 1994, The Journal of comparative neurology.

[25]  Jing-shi Tang,et al.  GABAergic modulation mediates antinociception produced by serotonin applied into thalamic nucleus submedius of the rat , 2005, Brain Research.

[26]  Trevor Sharp,et al.  A review of central 5-HT receptors and their function , 1999, Neuropharmacology.

[27]  J. Coffield,et al.  Enkephalin-like immunoreactivity in the nucleus submedius of the cat and rat thalamus. , 1988, Somatosensory research.

[28]  Jing-shi Tang,et al.  Response of neurons in the thalamic nucleus submedius (Sm) to noxious stimulation and electrophysiological identification of on- and off-cells in rats , 2002, PAIN.

[29]  E. Grantham Prefrontal lobotomy for relief of pain, with a report of a new operative technique. , 1951, Journal of neurosurgery.

[30]  C. Qu,et al.  Synaptic connections between GABAergic elements and serotonergic terminals or projecting neurons in the ventrolateral orbital cortex. , 2009, Cerebral cortex.

[31]  Jing-shi Tang,et al.  The roles of different subtypes of opioid receptors in mediating the nucleus submedius opioid-evoked antiallodynia in a neuropathic pain model of rats , 2006, Neuroscience.

[32]  Hong Jia,et al.  Inhibitory effects of electrically evoked activation of ventrolateral orbital cortex on the tail-flick reflex are mediated by periaqueductal gray in rats , 1997, PAIN.

[33]  W. K. Dong,et al.  The effect of thalamic nucleus submedius lesions on nociceptive responding in rats , 1994, Pain.

[34]  B. Lumb,et al.  The representation of prolonged and intense, noxious somatic and visceral stimuli in the ventrolateral orbital cortex of the cat , 1992, Pain.

[35]  F. Benes,et al.  Dopamnine‐Immunoreactive axon varicosities form nonrandom contacts with GABA‐immunoreactive neurons of rat medial prefrontal cortex , 1993 .

[36]  Jing-shi Tang,et al.  Inhibitory effects of glutamate‐induced activation of thalamic nucleus submedius are mediated by ventrolateral orbital cortex and periaqueductal gray in rats , 1998, European journal of pain.

[37]  J. Dostrovsky,et al.  Noxious stimuli excite neurons in nucleus submedius of the normal and arthritic rat , 1988, Brain Research.

[38]  F. Huang,et al.  The role of 5-HT receptor subtypes in the ventrolateral orbital cortex of 5-HT-induced antinociception in the rat , 2008, Neuroscience.

[39]  F. Bloom,et al.  The distribution and morphology of opioid peptide immunoreactive neurons in the cerebral cortex of rats , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[40]  Jing-shi Tang,et al.  Morphine applied to the thalamic nucleus submedius produces a naloxone reversible antinociceptive effect in the rat , 1999, Neuroscience Letters.

[41]  M. Peschanski,et al.  Fine structure of the dorsal part of the nucleus submedius of the rat thalamus: An anatomical study with reference to possible pain pathways , 1988, Neuroscience.

[42]  Jing-shi Tang,et al.  Inhibitory effects of electrical stimulation of thalamic nucleus submedius on the nociceptive responses of spinal dorsal horn neurons in the rat , 1996, Brain Research.

[43]  E. Richfield,et al.  Comparative distributions of dopamine D‐1 and D‐2 receptors in the cerebral cortex of rats, cats, and monkeys , 1989, The Journal of comparative neurology.

[44]  Hong Jia,et al.  Inhibitory effects of electrical stimulation of ventrolateral orbital cortex on the rat jaw-opening reflex , 1998, Brain Research.

[45]  J. Wang,et al.  Roles of different subtypes of opioid receptors in mediating the ventrolateral orbital cortex opioid-induced inhibition of mirror-neuropathic pain in the rat , 2007, Neuroscience.

[46]  Reshetniak Vk,et al.  [Effects of the removal of the orbito-frontal cortex on the development of reflex analgesia]. , 1989 .

[47]  F. Huo,et al.  Thalamic nucleus submedius receives GABAergic projection from thalamic reticular nucleus in the rat , 2005, Neuroscience.

[48]  G. Sperk,et al.  GABAA receptors: immunocytochemical distribution of 13 subunits in the adult rat brain , 2000, Neuroscience.

[49]  Jing-shi Tang,et al.  Inhibitory effects of electrical stimulation of thalamic nucleus submedius area on the rat tail flick reflex , 1995, Brain Research.

[50]  H. Jia,et al.  Electrically-evoked inhibitory effects of the nucleus submedius on the jaw-opening reflex are mediated by ventrolateral orbital cortex and periaqueductal gray matter in the rat , 1999, Neuroscience.

[51]  H. Burton,et al.  Spinal and medullary lamina I projection to nucleus submedius in medial thalamus: a possible pain center. , 1981, Journal of neurophysiology.

[52]  A. Craig,et al.  Responses of spinothalamic lamina I neurons to maintained noxious mechanical stimulation in the cat. , 2002, Journal of neurophysiology.

[53]  Responses of neurons in the ventrolateral orbital cortex to noxious cutaneous stimulation in a rat model of peripheral mononeuropathy , 1994, Brain Research.

[54]  R. Zukin,et al.  Neuroanatomical patterns of the mu, delta, and kappa opioid receptors of rat brain as determined by quantitative in vitro autoradiography. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[55]  R. Oades,et al.  Ventral tegmental (A10) system: neurobiology. 1. Anatomy and connectivity , 1987, Brain Research Reviews.

[56]  Y. Hurd,et al.  D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain , 2001, Journal of Chemical Neuroanatomy.

[57]  H. Groenewegen,et al.  The prefrontal cortex and the integration of sensory, limbic and autonomic information. , 2000, Progress in brain research.

[58]  A. Craig,et al.  The thalamo‐cortical projection of the nucleus submedius in the cat , 1982, The Journal of comparative neurology.

[59]  Mei Zhao,et al.  μ- but not δ- and κ-opioid receptors in the ventrolateral orbital cortex mediate opioid-induced antiallodynia in a rat neuropathic pain model , 2006, Brain Research.

[60]  K. Kawakita,et al.  Effects of electrical stimulation of thalamic nucleus submedius and periaqueductal gray on the visceral nociceptive responses of spinal dorsal horn neurons in the rat , 1999, Brain Research.

[61]  E. Perl,et al.  Spinal neurons specifically excited by noxious or thermal stimuli: marginal zone of the dorsal horn. , 1970, Journal of neurophysiology.

[62]  K. Follett,et al.  Electrical stimulation of thalamic Nucleus Submedius inhibits responses of spinal dorsal horn neurons to colorectal distension in the rat , 2003, Brain Research Bulletin.

[63]  R. Myers,et al.  Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. , 1991, Science.

[64]  K. Bowen,et al.  Retrograde tracing of projections between the nucleus submedius, the ventrolateral orbital cortex, and the midbrain in the rat , 1992, The Journal of comparative neurology.

[65]  J. Dostrovsky,et al.  The afferent and efferent connections of the nucleus submedius in the rat , 1992, The Journal of comparative neurology.

[66]  Jing-shi Tang,et al.  Morphine microinjections into the rat nucleus submedius depress nociceptive behavior in the formalin test , 2002, Neuroscience Letters.

[67]  A. Craig,et al.  Quantitative response characteristics of thermoreceptive and nociceptive lamina I spinothalamic neurons in the cat. , 2001, Journal of neurophysiology.

[68]  Activation of mu-opioid receptors in thalamic nucleus submedius depresses bee venom–evoked spinal c-Fos expression and flinching behavior , 2009, Neuroscience.

[69]  Mei Zhao,et al.  The effects of microinjection of morphine into thalamic nucleus submedius on formalin-evoked nociceptive responses of neurons in the rat spinal dorsal horn , 2006, Neuroscience Letters.

[70]  L. Jasmin,et al.  An Opioidergic Cortical Antinociception Triggering Site in the Agranular Insular Cortex of the Rat that Contributes to Morphine Antinociception , 1996, The Journal of Neuroscience.

[71]  S. Cooper,et al.  Anaesthetisation of prefrontal cortex and response to noxious stimulation , 1975, Nature.

[72]  J. Dostrovsky,et al.  Ventrolateral orbital cortex and periaqueductal gray stimulation-induced effects on on- and off-cells in the rostral ventromedial medulla in the rat , 1996, Neuroscience.

[73]  Jing-shi Tang,et al.  Inhibitory effects of 5-hydroxytryptamine microinjection into thalamic nucleus submedius on rat tail flick reflex are mediated by 5-HT2 receptors , 1999, Neuroscience Letters.

[74]  A. Craig,et al.  Electron microscopic identification of lamina I axon terminations in the nucleus submedius of the cat thalamus , 1992, Brain Research.

[75]  H. Uylings,et al.  Qualitative and quantitative comparison of the prefrontal cortex in rat and in primates, including humans. , 1990, Progress in brain research.

[76]  C. Qu,et al.  GABAergic modulation is involved in the ventrolateral orbital cortex 5-HT1A receptor activation-induced antinociception in the rat , 2008, PAIN.

[77]  G. Leichnetz,et al.  Frontal cortical projections to the periaqueductal gray in the rat: A retrograde and orthograde horseradish peroxidase study , 1981, Neuroscience Letters.

[78]  A. Craig,et al.  Pain mechanisms: labeled lines versus convergence in central processing. , 2003, Annual review of neuroscience.

[79]  N. Mizuno,et al.  Serotoninergic projections from the dorsal raphe nucleus to the nucleus submedius in the rat and cat , 1993, Neuroscience.

[80]  Jing-shi Tang,et al.  Morphine applied to the ventrolateral orbital cortex produces a naloxone-reversible antinociception in the rat , 2001, Neuroscience Letters.

[81]  T. Tzschentke Pharmacology and behavioral pharmacology of the mesocortical dopamine system , 2001, Progress in Neurobiology.

[82]  F. Huo,et al.  μ but not δ and κ opioid receptor involvement in ventrolateral orbital cortex opioid-evoked antinociception in formalin test rats , 2004, Neuroscience.

[83]  M. Herkenham,et al.  Autoradiographic localization of μ- and δ-opiate receptors in the forebrain of the rat , 1986, Brain Research.

[84]  H. Akil,et al.  Autoradiographic differentiation of mu, delta, and kappa opioid receptors in the rat forebrain and midbrain , 1987 .

[85]  G. Koob,et al.  The origin and distribution of dopamine-containing afferents to the rat frontal cortex , 1978, Brain Research.

[86]  Tao Chen,et al.  GABAergic neurons express μ-opioid receptors in the ventrolateral orbital cortex of the rat , 2005, Neuroscience Letters.