Highlights
- •Electrolytic model of spinal cord injury (SCI) produces features of pain after SCI (SCI-Pain).
- •SCI-Pain abolishes tonic activation of presynaptic GABAB autoreceptors in posterior thalamus.
- •SCI-Pain abolishes GABAB receptor mediated presynaptic regulation of glutamatergic terminals.
Abstract
Pain after spinal cord injury (SCI-Pain) is one of the most debilitating sequelae
of spinal cord injury, characterized as relentless, excruciating pain that is largely
refractory to treatments. Although it is generally agreed that SCI-Pain results from
maladaptive plasticity in the pain processing pathway that includes the spinothalamic
tract and somatosensory thalamus, the specific mechanisms underlying the development
and maintenance of such pain are yet unclear. However, accumulating evidence suggests
that SCI-Pain may be causally related to abnormal thalamic disinhibition, leading
to hyperactivity in the posterior thalamic nucleus (PO), a higher-order nucleus involved
in somatosensory and pain processing. We previously described several presynaptic
mechanisms by which activity in PO is regulated, including the regulation of GABAergic
as well as glutamatergic release by presynaptic metabotropic gamma-aminobutyric acid
(GABAB) receptors. Using acute slices from a mouse model of SCI-Pain, we tested whether
such mechanisms are affected by SCI-Pain. We reveal 2 abnormal changes in presynaptic
signaling in the SCI-Pain condition. The substantial tonic activation of presynaptic
GABAB receptors on GABAergic projections to PO—characteristic of normal animals—was absent
in mice with SCI-Pain. Also absent in mice with SCI-Pain was the normal presynaptic
regulation of glutamatergic projections to the PO by GABAB receptors. The loss of these regulatory presynaptic mechanisms in SCI-Pain may be
an element of maladaptive plasticity leading to PO hyperexcitability and behavioral
pain, and may suggest targets for development of novel treatments.
Perspective
This report presents synaptic mechanisms that may underlie the development and maintenance
of SCI-Pain. Because of the difficulty in treating SCI-Pain, a better understanding
of the underlying neurobiological mechanisms is critical, and may allow development
of better treatment modalities.
Key words
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References
- The role of the thalamus in modulating pain.Malays J Med Sci. 2006; 13: 11-18
- Plasticity of pain-related neuronal activity in the human thalamus.Prog Brain Res. 2006; 157: 353-364
- Blockade of neurotransmitter-activated K+ conductance by QX-314 in the rat hippocampus.Eur J Pharmacol. 1991; 199: 259-262
- GABAergic neurons in mammalian thalamus: A marker of thalamic complexity.Brain Res Bull. 1997; 42: 27-37
- Central synapses, quantal mechanisms and plasticity (human frontier workshop reports, workshop IV).Human Frontier Science Program, Strasbourg, France1998
- Pharmacological management of neuropathic pain following spinal cord injury.CNS Drugs. 2008; 22: 455-475
- Label-free quantification of membrane-ligand interactions using backscattering interferometry.Nat Biotechnol. 2011; 29: 357-360
- GABAergic neurons are present in the dorsal column nuclei but not in the ventroposterior complex of rats.Brain Res. 1986; 382: 305-326
- Chronic restraint stress induces mechanical and cold allodynia, and enhances inflammatory pain in rat: Relevance to human stress-associated painful pathologies.Behav Brain Res. 2009; 205: 360-366
- Selective GABAergic innervation of thalamic nuclei from zona incerta.Eur J Neurosci. 2002; 16: 999-1014
- Cortical control of zona incerta.J Neurosci. 2007; 27: 1670-1681
- Astrocytes as gatekeepers of GABAB receptor function.J Neurosci. 2010; 30: 15262-15276
- Chronic neuropathic pain in patients with spinal cord injury. What is the efficacy of regional interventions? Sympathetic blocks, nerve blocks and intrathecal drugs.Ann Phys Rehabil Med. 2009; 52: 142-148
- Central pain and dysesthesia syndrome.Neurol Clin. 1998; 16: 899-918
- Central dysesthesia syndrome in spinal cord injury patients.Pain. 1988; 34: 109-116
- The character of the muscarinic receptors in different regions of the rat brain.Proc R Soc Lond B Biol Sci. 1980; 207: 1-12
- Central pain.in: McMahon S. Koltzenburg M. Wall and Melzack's Textbook of Pain. Elsevier Health Systems, 2005: 1057-1074
- Selective GABAergic control of higher-order thalamic relays.Neuron. 2005; 45: 929-940
- History of pain concepts and pain therapy.Mt Sinai J Med. 1991; 58: 191-202
- GABAB receptor activation exacerbates spontaneous spike-and-wave discharges in DBA/2J mice.Seizure. 2010; 19: 226-231
- Termination of the central pain pathway in man: The conscious appreciation of pain.Brain. 1957; 80: 606-622
- Extrasynaptic GABA(A) receptors: Their function in the CNS and implications for disease.Neuron. 2012; 73: 23-34
- The action of new potent GABAB receptor antagonists in the hemisected spinal cord preparation of the rat.Eur J Pharmacol. 1993; 235: 153-155
- Unit analysis of nociceptive mechanisms in the thalamus of the awake squirrel monkey.J Neurophysiol. 1966; 29: 727-750
- Quantitative assessment of tactile allodynia in the rat paw.J Neurosci Methods. 1994; 53: 55-63
- Thalamic processing of vibrissal information in the rat: II. Morphological and functional properties of medial ventral posterior nucleus and posterior nucleus neurons.J Comp Neurol. 1991; 314: 217-236
- Decreased spinothalamic and dorsal column medial lemniscus-mediated function is associated with neuropathic pain after spinal cord injury.J Neurotrauma. 2012; 29: 2706-2715
- Characterization of chronic pain and somatosensory function in spinal cord injury subjects.Pain. 2001; 89: 253-263
- Selective T-type calcium channel block in thalamic neurons reveals channel redundancy and physiological impact of I(T)window.J Neurosci. 2010; 30: 99-109
- Identification of spinal circuits transmitting and gating mechanical pain.Cell. 2014; 159: 1417-1432
- Tonic activation of presynaptic GABA(B) receptors on thalamic sensory afferents.Neuroscience. 1996; 72: 689-698
- Sensory perception in complete spinal cord injury.Acta Neurol Scand. 2004; 109: 194-199
- A prospective study of pain and psychological functioning following traumatic spinal cord injury.Spinal Cord. 2016; 54: 816-821
- Sensory function above lesion level in spinal cord injury patients with and without pain.Somatosens Mot Res. 2003; 20: 71-76
- Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy.Pain. 2004; 109: 150-161
- Thalamic connectivity of the second somatosensory area and neighboring somatosensory fields of the lateral sulcus of the macaque.J Comp Neurol. 1986; 252: 348-373
- Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.J Med Chem. 1995; 38: 3297-3312
- Posterior triangular thalamic neurons convey nociceptive messages to the secondary somatosensory and insular cortices in the rat.J Neurosci. 2004; 24: 752-761
- The main source of ambient GABA responsible for tonic inhibition in the mouse hippocampus.J Physiol. 2007; 582: 1163-1178
- Changes in electrophysiological properties and sodium channel Nav1.3 expression in thalamic neurons after spinal cord injury.Brain. 2005; 128: 2359-2371
- Thalamic inhibition: Diverse sources, diverse scales.Trends Neurosci. 2016; 39: 680-693
- Pirenzepine distinguishes between different subclasses of muscarinic receptors.Nature. 1980; 283: 90-92
- Local circuit neurons in the rat ventrobasal thalamus–a GABA immunocytochemical study.Neuroscience. 1987; 21: 229-236
- Chronic spinal cord injury induced changes in the responses of thalamic neurons.Exp Neurol. 2006; 197: 177-188
- All thalamocortical neurones possess a T-type Ca2+ ‘window’ current that enables the expression of bistability-mediated activities.J Physiol. 1999; 517: 805-815
- Cholecystokinin inhibits endocannabinoid-sensitive hippocampal IPSPs and stimulates others.Neuropharmacology. 2008; 54: 117-128
- Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors.Nature. 1997; 386: 239-246
- How to do random allocation (randomization).Clin Orthop Surg. 2014; 6: 103-109
- Kinetics of GABAB autoreceptor-mediated suppression of GABA release in rat insular cortex.J Neurophysiol. 2012; 107: 1431-1442
- Target cell-specific modulation of neuronal activity by astrocytes.Proc Natl Acad Sci U S A. 2006; 103: 10058-10063
- A call for transparent reporting to optimize the predictive value of preclinical research.Nature. 2012; 490: 187-191
- VPM and PoM nuclei of the rat somatosensory thalamus: Intrinsic neuronal properties and corticothalamic feedback.Cereb Cortex. 2007; 17: 2853-2865
- Therapeutic use of release-modifying drugs.Handb Exp Pharmacol. 2008; : 561-573
- Feedforward inhibitory control of sensory information in higher-order thalamic nuclei.J Neurosci. 2005; 25: 7489-7498
- GABAA receptor-mediated IPSCs in rat thalamic sensory nuclei: Patterns of discharge and tonic modulation by GABAB autoreceptors.J Physiol. 1997; 502: 91-104
- Channel-mediated tonic GABA release from glia.Science. 2010; 330: 790-796
- Differential projection of the posterior paralaminar thalamic nuclei to the amygdaloid complex in the rat.Exp Brain Res. 2000; 134: 520-532
- Convergent and complementary projections of the caudal paralaminar thalamic nuclei to rat temporal and insular cortex.Cereb Cortex. 2000; 10: 753-771
- Effects of intrathecal baclofen on chronic spinal cord injury pain.J Pain Symptom Manage. 1996; 12: 241-247
- Motor cortex stimulation reduces hyperalgesia in an animal model of central pain.Pain. 2011; 152: 1398-1407
- Chronic pain following spinal cord injury.in: Jandial R. Chen M. Chen B. Ciacci J. Regenerative Biology of the Spine and Spinal Cord. Landes Bioscience, New York, NY2012: 74-88
- Zona incerta: A role in central pain.J Neurophysiol. 2009; 102: 181-191
- Cholinergic regulation of the posterior medial thalamic nucleus.J Neurophysiol. 2006; 96: 2265-2273
- Assessing nociception in murine subjects.in: Kruger L. Methods in Pain Research. CRC Press, Boca Raton, FL2001: 11-39
- Abnormal anterior pretectal nucleus activity contributes to central pain syndrome.J Neurophysiol. 2010; 103: 3044-3053
- The slow inhibitory postsynaptic potential in rat hippocampal CA1 neurones is blocked by intracellular injection of QX-314.Neurosci Lett. 1990; 110: 309-313
- GABA-containing neurons in the thalamus and pretectum of the rodent: An immunocytochemical study.Anat Embryol (Berl). 1984; 170: 197-207
- Presynaptic and extrasynaptic regulation of posterior nucleus of thalamus.J Neurophysiol. 2017; 118: 507-519
- Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury.AJNR Am J Neuroradiol. 2002; 23: 901-905
- Somatic stimuli exciting spinothalamic projections to thalamic neurons in cat and monkey.Exp Neurol. 1961; 3: 256-296
- Intrathecal baclofen: Effects on spasticity, pain, and consciousness in disorders of consciousness and locked-in syndrome.Curr Pain Headache Rep. 2015; 19: 466
- A study of the functional contributions of the lemniscal and spinothalamic systems to somatic sensibility. Central nervous mechanisms in pain.Bull Johns Hopkins Hosp. 1960; 106: 266-316
- Evidence for a large projection from the zona incerta to the dorsal thalamus.J Comp Neurol. 1999; 404: 554-565
- Chronic pain after SCI. A patient survey.Spinal Cord. 2000; 38: 611-614
- Short-term presynaptic plasticity.Cold Spring Harb Perspect Biol. 2012; 4: a005702
- Extracellular GABA in the ventrolateral thalamus of rats exhibiting spontaneous absence epilepsy: A microdialysis study.J Neurochem. 1995; 65: 1674-1680
- Inhibition of constitutive inward rectifier currents in cerebellar granule cells by pharmacological and synaptic activation of GABA receptors.Eur J Neurosci. 2006; 24: 419-432
- Indication, efficiency and complications of intrathecal pump supported baclofen treatment in spinal spasticity.Acta Neurol (Napoli). 1992; 14: 187-194
- On the repeatability of brush-evoked allodynia using a novel semi-quantitative method in patients with peripheral neuropathic pain.Pain. 2007; 130: 40-46
- Functional Connections of Cortical Areas: A New View from the Thalamus.The MIT Press, Cambridge, MA2013
- A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury.Pain. 2003; 103: 249-257
- The Intact and Sliced Brain. A Bradford Book.MIT Press, Cambridge, MA2001
- Intrathecal baclofen in cerebral palsy. A retrospective study of 25 wheelchair-assisted adults.Ann Phys Rehabil Med. 2010; 53: 483-498
- Acute brain slice methods for adult and aging animals: Application of targeted patch clamp analysis and optogenetics.Methods Mol Biol. 2014; 1183: 221-242
- State-dependent gating of sensory inputs by zona incerta.J Neurophysiol. 2006; 96: 1456-1463
- Reducing the uncertainty: Gating of peripheral inputs by zona incerta.J Neurosci. 2004; 24: 8911-8915
- Minimal alterations in T-type calcium channel gating markedly modify physiological firing dynamics.J Physiol. 2011; 589: 1707-1724
- Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mal-like epilepsy.Neurosci Lett. 1984; 44: 91-94
- Effects of intrathecal morphine, baclofen, clonidine and R-PIA on the acute allodynia-like behaviours after spinal cord ischaemia in rats.Eur J Pain. 2001; 5: 1-10
- Maladaptive homeostatic plasticity in a rodent model of central pain syndrome: Thalamic hyperexcitability after spinothalamic tract lesions.J Neurosci. 2008; 28: 11959-11969
- Treatments for chronic pain associated with spinal cord injuries: Many are tried, few are helpful.Clin J Pain. 2002; 18: 154-163
- Functional plasticity in primate somatosensory thalamus following chronic lesion of the ventral lateral spinal cord.Neuroscience. 2000; 101: 393-401
- Thalamic projections of spinothalamic pathways in monkey.Exp Neurol. 1961; 3: 240-255
- Pathological activity in mediodorsal thalamus of rats with spinal cord injury pain.J Neurosci. 2013; 33: 3915-3926
- Measuring pain in the (knockout) mouse: Big challenges in a small mammal.Behav Brain Res. 2001; 125: 65-73
- Reduced tonic inhibition in striatal output neurons from Huntington mice due to loss of astrocytic GABA release through GAT-3.Front Neural Circuits. 2013; 7: 188
- Enhancement of presynaptic glutamate release and persistent inflammatory pain by increasing neuronal cAMP in the anterior cingulate cortex.Mol Pain. 2008; 4: 40
- Pain following spinal cord injury: Pathophysiology and central mechanisms.Prog Brain Res. 2000; 129: 429-449
- M2 muscarinic acetylcholine receptors regulate long-term potentiation at hippocampal CA3 pyramidal cell synapses in an input-specific fashion.J Neurophysiol. 2012; 108: 91-100
- Short-term synaptic plasticity.Annu Rev Physiol. 2002; 64: 355-405
Article info
Publication history
Published online: February 23, 2018
Accepted:
February 12,
2018
Received in revised form:
January 29,
2018
Received:
September 7,
2017
Footnotes
Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R01NS051799 to A.K. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The authors have no conflicts of interest to declare.
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© 2018 by the American Pain Society
