Neuronal circuitry for pain processing in the dorsal horn (original) (raw)

• Sivilotti, L. & Woolf, C. J. The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord. J. Neurophysiol. 72, 169–179 (1994).
  CAS PubMed Google Scholar
• Yaksh, T. L. Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists. Pain 37, 111–123 (1989).
  CAS PubMed Google Scholar
• Rexed, B. The cytoarchitectonic organization of the spinal cord in the cat. J. Comp. Neurol. 96, 414–495 (1952).
  CAS PubMed Google Scholar
• Woodbury, C. J., Ritter, A. M. & Koerber, H. R. On the problem of lamination in the superficial dorsal horn of mammals: a reappraisal of the substantia gelatinosa in postnatal life. J. Comp. Neurol. 417, 88–102 (2000).
  CAS PubMed Google Scholar
• Dhaka, A., Earley, T. J., Watson, J. & Patapoutian, A. Visualizing cold spots: TRPM8-expressing sensory neurons and their projections. J. Neurosci. 28, 566–575 (2008).
  CAS PubMed PubMed Central Google Scholar
• Liu, Q. et al. Molecular genetic visualization of a rare subset of unmyelinated sensory neurons that may detect gentle touch. Nature Neurosci. 10, 946–948 (2007).
  CAS PubMed Google Scholar
• Seal, R. P. et al. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature 462, 651–655 (2009).
  CAS PubMed PubMed Central Google Scholar
• Lawson, S. N., Crepps, B. A. & Perl, E. R. Relationship of substance P to afferent characteristics of dorsal root ganglion neurones in guinea-pig. J. Physiol. 505, 177–191 (1997).
  CAS PubMed PubMed Central Google Scholar
• Snider, W. D. & McMahon, S. B. Tackling pain at the source: new ideas about nociceptors. Neuron 20, 629–632 (1998).
  CAS PubMed Google Scholar
• Taylor, A. M., Peleshok, J. C. & Ribeiro-da-Silva, A. Distribution of P2X(3)-immunoreactive fibers in hairy and glabrous skin of the rat. J. Comp. Neurol. 514, 555–566 (2009).
  CAS PubMed Google Scholar
• Bennett, D. L., Dmietrieva, N., Priestley, J. V., Clary, D. & McMahon, S. B. trkA, CGRP and IB4 expression in retrogradely labelled cutaneous and visceral primary sensory neurones in the rat. Neurosci. Lett. 206, 33–36 (1996).
  CAS PubMed Google Scholar
• Perry, M. J. & Lawson, S. N. Differences in expression of oligosaccharides, neuropeptides, carbonic anhydrase and neurofilament in rat primary afferent neurons retrogradely labelled via skin, muscle or visceral nerves. Neuroscience 85, 293–310 (1998).
  CAS PubMed Google Scholar
• Plenderleith, M. B. & Snow, P. J. The plant lectin Bandeiraea simplicifolia I-B4 identifies a subpopulation of small diameter primary sensory neurones which innervate the skin in the rat. Neurosci. Lett. 159, 17–20 (1993).
  CAS PubMed Google Scholar
• Zylka, M. J., Rice, F. L. & Anderson, D. J. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45, 17–25 (2005).
  CAS PubMed Google Scholar
• Cavanaugh, D. J. et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc. Natl Acad. Sci. USA 106, 9075–9080 (2009).
  CAS PubMed PubMed Central Google Scholar
• Lynn, B. Effect of neonatal treatment with capsaicin on the numbers and properties of cutaneous afferent units from the hairy skin of the rat. Brain Res. 322, 255–260 (1984).
  CAS PubMed Google Scholar
• Michael, G. J. et al. Nerve growth factor treatment increases brain-derived neurotrophic factor selectively in TrkA-expressing dorsal root ganglion cells and in their central terminations within the spinal cord. J. Neurosci. 17, 8476–8490 (1997).
  CAS PubMed PubMed Central Google Scholar
• Rethelyi, M., Light, A. R. & Perl, E. R. Synaptic complexes formed by functionally defined primary afferent units with fine myelinated fibers. J. Comp. Neurol. 207, 381–393 (1982).
  CAS PubMed Google Scholar
• Ribeiro-da-Silva, A. & Coimbra, A. Two types of synaptic glomeruli and their distribution in laminae I-III of the rat spinal cord. J. Comp. Neurol. 209, 176–186 (1982).
  CAS PubMed Google Scholar
• Ribeiro-da-Silva, A., Tagari, P. & Cuello, A. C. Morphological characterization of substance P-like immunoreactive glomeruli in the superficial dorsal horn of the rat spinal cord and trigeminal subnucleus caudalis: a quantitative study. J. Comp. Neurol. 281, 497–415 (1989).
  CAS PubMed Google Scholar
• Zoli, M., Jansson, A., Sykova, E., Agnati, L. F. & Fuxe, K. Volume transmission in the CNS and its relevance for neuropsychopharmacology. Trends Pharmacol. Sci. 20, 142–150 (1999).
  CAS PubMed Google Scholar
• Antal, M., Petko, M., Polgar, E., Heizmann, C. W. & Storm-Mathisen, J. Direct evidence of an extensive GABAergic innervation of the spinal dorsal horn by fibres descending from the rostral ventromedial medulla. Neuroscience 73, 509–518 (1996).
  CAS PubMed Google Scholar
• Kato, G. et al. Direct GABAergic and glycinergic inhibition of the substantia gelatinosa from the rostral ventromedial medulla revealed by in vivo patch-clamp analysis in rats. J. Neurosci. 26, 1787–1794 (2006).
  CAS PubMed PubMed Central Google Scholar
• Polgár, E. et al. Selective loss of spinal GABAergic or glycinergic neurons is not necessary for development of thermal hyperalgesia in the chronic constriction injury model of neuropathic pain. Pain 104, 229–239 (2003).
  PubMed Google Scholar
• Todd, A. J. & Sullivan, A. C. Light microscope study of the coexistence of GABA-like and glycine-like immunoreactivities in the spinal cord of the rat. J. Comp. Neurol. 296, 496–505 (1990).
  CAS PubMed Google Scholar
• Keller, A. F., Coull, J. A., Chery, N., Poisbeau, P. & De Koninck, Y. Region-specific developmental specialization of GABA-glycine cosynapses in laminas I-II of the rat spinal dorsal horn. J. Neurosci. 21, 7871–7880 (2001).
  CAS PubMed PubMed Central Google Scholar
• Yasaka, T. et al. Cell-type-specific excitatory and inhibitory circuits involving primary afferents in the substantia gelatinosa of the rat spinal dorsal horn in vitro. J. Physiol. 581, 603–618 (2007).
  PubMed PubMed Central Google Scholar
• Todd, A. J. et al. The expression of vesicular glutamate transporters VGLUT1 and VGLUT2 in neurochemically defined axonal populations in the rat spinal cord with emphasis on the dorsal horn. Eur. J. Neurosci. 17, 13–27 (2003).
  CAS PubMed Google Scholar
• Maxwell, D. J., Belle, M. D., Cheunsuang, O., Stewart, A. & Morris, R. Morphology of inhibitory and excitatory interneurons in superficial laminae of the rat dorsal horn. J. Physiol. 584, 521–533 (2007).
  CAS PubMed PubMed Central Google Scholar
• Yasaka, T., Tiong, S. Y. X., Hughes, D. I., Riddell, J. S. & Todd, A. J. Populations of inhibitory and excitatory interneurons in lamina II of the adult rat spinal dorsal horn revealed by a combined electrophysiological and anatomical approach. Pain 151, 475–488 (2010). A recent study that compared physiological and morphological properties of lamina II interneurons with neurotransmitter phenotype and showed that A-type potassium current firing patterns were largely restricted to glutamatergic cells.
  PubMed PubMed Central Google Scholar
• Graham, B. A., Brichta, A. M. & Callister, R. J. Moving from an averaged to specific view of spinal cord pain processing circuits. J. Neurophysiol. 98, 1057–1063 (2007). A review that highlights the heterogeneity of neurons in the superficial dorsal horn and emphasizes the need to identify functional populations.
  CAS PubMed Google Scholar
• Ruscheweyh, R. & Sandkuhler, J. Lamina-specific membrane and discharge properties of rat spinal dorsal horn neurones in vitro. J. Physiol. 541, 231–244 (2002).
  CAS PubMed PubMed Central Google Scholar
• Hu, H. J. et al. The kv4.2 potassium channel subunit is required for pain plasticity. Neuron 50, 89–100 (2006). This study showed that Kv4.2, which is a downstream target for phosphorylation by extracellular signal-regulated kinases, mediates the majority of the A-type potassium currents in the dorsal horn and plays a crucial role in pain plasticity.
  CAS PubMed Google Scholar
• Huang, H. Y. et al. Expression of A-type K channel α subunits Kv 4.2 and Kv 4.3 in rat spinal lamina II excitatory interneurons and colocalization with pain-modulating molecules. Eur. J. Neurosci. 22, 1149–1157 (2005).
  PubMed Google Scholar
• Grudt, T. J. & Perl, E. R. Correlations between neuronal morphology and electrophysiological features in the rodent superficial dorsal horn. J. Physiol. 540, 189–207 (2002). This combined physiological and morphological study developed the most widely used classification scheme for superficial dorsal horn neurons.
  CAS PubMed PubMed Central Google Scholar
• Hantman, A. W., van den Pol., A. N. & Perl, E. R. Morphological and physiological features of a set of spinal substantia gelatinosa neurons defined by green fluorescent protein expression. J. Neurosci. 24, 836–842 (2004).
  CAS PubMed PubMed Central Google Scholar
• Lu, Y. & Perl, E. R. A specific inhibitory pathway between substantia gelatinosa neurons receiving direct C-fiber input. J. Neurosci. 23, 8752–8758 (2003).
  CAS PubMed PubMed Central Google Scholar
• Lu, Y. & Perl, E. R. Modular organization of excitatory circuits between neurons of the spinal superficial dorsal horn (laminae I and II). J. Neurosci. 25, 3900–3907 (2005). One of a series of papers describing elegant studies in which paired recordings were used to investigate synaptic linkages in the superficial dorsal horn. In this case, a synaptic connection between glutamatergic vertical cells and NK1R-expressing lamina I projection neurons was revealed.
  CAS PubMed PubMed Central Google Scholar
• Todd, A. J. & McKenzie, J. GABA-immunoreactive neurons in the dorsal horn of the rat spinal cord. Neuroscience 31, 799–806 (1989).
  CAS PubMed Google Scholar
• Albuquerque, C., Lee, C. J., Jackson, A. C. & MacDermott, A. B. Subpopulations of GABAergic and non-GABAergic rat dorsal horn neurons express Ca2+-permeable AMPA receptors. Eur. J. Neurosci. 11, 2758–2766 (1999).
  CAS PubMed Google Scholar
• Zheng, J., Lu, Y. & Perl, E. R. Inhibitory neurones of the spinal substantia gelatinosa mediate interaction of signals from primary afferents. J. Physiol. 588, 2065–2075 (2010).
  CAS PubMed PubMed Central Google Scholar
• Hantman, A. W. & Perl, E. R. Molecular and genetic features of a labeled class of spinal substantia gelatinosa neurons in a transgenic mouse. J. Comp. Neurol. 492, 90–100 (2005).
  CAS PubMed Google Scholar
• Han, Z. S., Zhang, E. T. & Craig, A. D. Nociceptive and thermoreceptive lamina I neurons are anatomically distinct. Nature Neurosci. 1, 218–225 (1998).
  CAS PubMed Google Scholar
• Lima, D. & Coimbra, A. A Golgi study of the neuronal population of the marginal zone (lamina I) of the rat spinal cord. J. Comp. Neurol. 244, 53–71 (1986).
  CAS PubMed Google Scholar
• Prescott, S. A. & De Koninck, Y. Four cell types with distinctive membrane properties and morphologies in lamina I of the spinal dorsal horn of the adult rat. J. Physiol. 539, 817–836 (2002).
  CAS PubMed PubMed Central Google Scholar
• Al Ghamdi, K. S., Polgar, E. & Todd, A. J. Soma size distinguishes projection neurons from neurokinin 1 receptor-expressing interneurons in lamina I of the rat lumbar spinal dorsal horn. Neuroscience 164, 1794–1804 (2009).
  CAS PubMed Google Scholar
• Antal, M. et al. Different populations of parvalbumin- and calbindin-D28k-immunoreactive neurons contain GABA and accumulate 3H-D-aspartate in the dorsal horn of the rat spinal cord. J. Comp. Neurol. 314, 114–124 (1991).
  CAS PubMed Google Scholar
• Todd, A. J. & Spike, R. C. The localization of classical transmitters and neuropeptides within neurons in laminae I–III of the mammalian spinal dorsal horn. Prog. Neurobiol. 41, 609–645 (1993).
  CAS PubMed Google Scholar
• Polgár, E., Furuta, T., Kaneko, T. & Todd, A. Characterization of neurons that express preprotachykinin B in the dorsal horn of the rat spinal cord. Neuroscience 139, 687–697 (2006).
  PubMed Google Scholar
• Laing, I., Todd, A. J., Heizmann, C. W. & Schmidt, H. H. Subpopulations of GABAergic neurons in laminae I–III of rat spinal dorsal horn defined by coexistence with classical transmitters, peptides, nitric oxide synthase or parvalbumin. Neuroscience 61, 123–132 (1994).
  CAS PubMed Google Scholar
• Mori, M., Kose, A., Tsujino, T. & Tanaka, C. Immunocytochemical localization of protein kinase C subspecies in the rat spinal cord: light and electron microscopic study. J. Comp. Neurol. 299, 167–177 (1990).
  CAS PubMed Google Scholar
• Polgár, E., Fowler, J. H., McGill, M. M. & Todd, A. J. The types of neuron which contain protein kinase C gamma in rat spinal cord. Brain Res. 833, 71–80 (1999).
  PubMed Google Scholar
• Spike, R. C., Todd, A. J. & Johnston, H. M. Coexistence of NADPH diaphorase with GABA, glycine, and acetylcholine in rat spinal cord. J. Comp. Neurol. 335, 320–333 (1993).
  CAS PubMed Google Scholar
• Burstein, R., Dado, R. J. & Giesler, G. J., Jr The cells of origin of the spinothalamic tract of the rat: a quantitative reexamination. Brain Res. 511, 329–337 (1990).
  CAS PubMed Google Scholar
• Hylden, J. L., Anton, F. & Nahin, R. L. Spinal lamina I projection neurons in the rat: collateral innervation of parabrachial area and thalamus. Neuroscience 28, 27–37 (1989).
  CAS PubMed Google Scholar
• Lima, D. & Coimbra, A. The spinothalamic system of the rat: structural types of retrogradely labelled neurons in the marginal zone (lamina I). Neuroscience 27, 215–230 (1988).
  CAS PubMed Google Scholar
• Lima, D., Mendes-Ribeiro, J. A. & Coimbra, A. The spino-latero-reticular system of the rat: projections from the superficial dorsal horn and structural characterization of marginal neurons involved. Neuroscience 45, 137–152 (1991).
  CAS PubMed Google Scholar
• Spike, R. C., Puskar, Z., Andrew, D. & Todd, A. J. A quantitative and morphological study of projection neurons in lamina I of the rat lumbar spinal cord. Eur. J. Neurosci. 18, 2433–2448 (2003).
  CAS PubMed Google Scholar
• Todd, A. J., McGill, M. M. & Shehab, S. A. Neurokinin 1 receptor expression by neurons in laminae, I., III and IV of the rat spinal dorsal horn that project to the brainstem. Eur. J. Neurosci. 12, 689–700 (2000).
  CAS PubMed Google Scholar
• Almarestani, L., Waters, S. M., Krause, J. E., Bennett, G. J. & Ribeiro-da-Silva, A. Morphological characterization of spinal cord dorsal horn lamina I neurons projecting to the parabrachial nucleus in the rat. J. Comp. Neurol. 504, 287–297 (2007).
  CAS PubMed Google Scholar
• Bernard, J. F., Dallel, R., Raboisson, P., Villanueva, L. & Le Bars, D. Organization of the efferent projections from the spinal cervical enlargement to the parabrachial area and periaqueductal gray: a PHA-L study in the rat. J. Comp. Neurol. 353, 480–505 (1995).
  CAS PubMed Google Scholar
• Feil, K. & Herbert, H. Topographic organization of spinal and trigeminal somatosensory pathways to the rat parabrachial and Kolliker-Fuse nuclei. J. Comp. Neurol. 353, 506–528 (1995).
  CAS PubMed Google Scholar
• Gauriau, C. & Bernard, J. F. A comparative reappraisal of projections from the superficial laminae of the dorsal horn in the rat: the forebrain. J. Comp. Neurol. 468, 24–56 (2004).
  PubMed Google Scholar
• Slugg, R. M. & Light, A. R. Spinal cord and trigeminal projections to the pontine parabrachial region in the rat as demonstrated with Phaseolus vulgaris leucoagglutinin. J. Comp. Neurol. 339, 49–61 (1994).
  CAS PubMed Google Scholar
• Al-Khater, K. M. & Todd, A. J. Collateral projections of neurons in laminae, I., III, and IV of rat spinal cord to thalamus, periaqueductal gray matter, and lateral parabrachial area. J. Comp. Neurol. 515, 629–646 (2009).
  PubMed PubMed Central Google Scholar
• Al-Khater, K. M., Kerr, R. & Todd, A. J. A quantitative study of spinothalamic neurons in laminae, I, III, and IV in lumbar and cervical segments of the rat spinal cord. J. Comp. Neurol. 511, 1–18 (2008).
  PubMed PubMed Central Google Scholar
• Polgár, E., Wright, L. L. & Todd, A. J. A quantitative study of brainstem projections from lamina I neurons in the cervical and lumbar enlargement of the rat. Brain Res. 1308, 58–67 (2010).
  PubMed PubMed Central Google Scholar
• Zhang, E. T. & Craig, A. D. Morphology and distribution of spinothalamic lamina I neurons in the monkey. J. Neurosci. 17, 3274–3284 (1997).
  CAS PubMed PubMed Central Google Scholar
• Zhang, E. T., Han, Z. S. & Craig, A. D. Morphological classes of spinothalamic lamina I neurons in the cat. J. Comp. Neurol. 367, 537–549 (1996).
  CAS PubMed Google Scholar
• Andrew, D. Sensitization of lamina I spinoparabrachial neurons parallels heat hyperalgesia in the chronic constriction injury model of neuropathic pain. J. Physiol. 587, 2005–2017 (2009).
  CAS PubMed PubMed Central Google Scholar
• Bester, H., Chapman, V., Besson, J. M. & Bernard, J. F. Physiological properties of the lamina I spinoparabrachial neurons in the rat. J. Neurophysiol. 83, 2239–2259 (2000).
  CAS PubMed Google Scholar
• Ruscheweyh, R., Ikeda, H., Heinke, B. & Sandkuhler, J. Distinctive membrane and discharge properties of rat spinal lamina I projection neurones in vitro. J. Physiol. 555, 527–543 (2004).
  CAS PubMed Google Scholar
• Zhang, X. & Giesler, G. J. Jr. Response characterstics of spinothalamic tract neurons that project to the posterior thalamus in rats. J. Neurophysiol. 93, 2552–2564 (2005).
  PubMed Google Scholar
• Willis, W. D., Trevino, D. L., Coulter, J. D. & Maunz, R. A. Responses of primate spinothalamic tract neurons to natural stimulation of hindlimb. J. Neurophysiol. 37, 358–372 (1974).
  CAS PubMed Google Scholar
• Salter, M. W. & Henry, J. L. Responses of functionally identified neurones in the dorsal horn of the cat spinal cord to substance P, neurokinin A and physalaemin. Neuroscience 43, 601–610 (1991).
  CAS PubMed Google Scholar
• Mantyh, P. W. et al. Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278, 275–279 (1997). By selectively ablating NK1R-expressing dorsal horn neurons in vivo , the authors demonstrated that these cells play a pivotal part in the development of hyperalgesia.
  CAS PubMed Google Scholar
• Nichols, M. L. et al. Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 286, 1558–1561 (1999).
  CAS PubMed Google Scholar
• Littlewood, N. K., Todd, A. J., Spike, R. C., Watt, C. & Shehab, S. A. The types of neuron in spinal dorsal horn which possess neurokinin-1 receptors. Neuroscience 66, 597–608 (1995).
  CAS PubMed Google Scholar
• Yu, X. H. et al. NK-1 receptor immunoreactivity in distinct morphological types of lamina I neurons of the primate spinal cord. J. Neurosci. 19, 3545–3555 (1999).
  CAS PubMed PubMed Central Google Scholar
• Todd, A. J. et al. Projection neurons in lamina I of rat spinal cord with the neurokinin 1 receptor are selectively innervated by substance P-containing afferents and respond to noxious stimulation. J. Neurosci. 22, 4103–4113 (2002). This article demonstrated a strong monosynaptic input from substance P-containing (nociceptive) primary afferents to lamina I projection neurons that express the NK1R.
  CAS PubMed PubMed Central Google Scholar
• Polgár, E., Al Ghamdi, K. S. & Todd, A. J. Two populations of neurokinin 1 receptor-expressing projection neurons in lamina I of the rat spinal cord that differ in AMPA receptor subunit composition and density of excitatory synaptic input. Neuroscience 167, 1192–1204 (2010). This recent report identifies two populations of NK1R-expressing lamina I projection neurons that differ in their AMPAR subunit expression and in the density of excitatory synapses that they receive. It also provides evidence that GluA-containing receptors in the superficial dorsal horn are largely restricted to projection neurons.
  PubMed Google Scholar
• Polgár, E., Al-Khater, K. M., Shehab, S., Watanabe, M. & Todd, A. J. Large projection neurons in lamina I of the rat spinal cord that lack the neurokinin 1 receptor are densely innervated by VGLUT2-containing axons and possess GluR4-containing AMPA receptors. J. Neurosci. 28, 13150–13160 (2008).
  PubMed PubMed Central Google Scholar
• Puskár, Z., Polgár, E. & Todd, A. J. A population of large lamina I projection neurons with selective inhibitory input in rat spinal cord. Neuroscience 102, 167–176 (2001).
  PubMed Google Scholar
• Naim, M., Spike, R. C., Watt, C., Shehab, S. A. & Todd, A. J. Cells in laminae III and IV of the rat spinal cord that possess the neurokinin-1 receptor and have dorsally directed dendrites receive a major synaptic input from tachykinin-containing primary afferents. J. Neurosci. 17, 5536–5548 (1997).
  CAS PubMed PubMed Central Google Scholar
• Polgár, E., Campbell, A. D., MacIntyre, L. M., Watanabe, M. & Todd, A. J. Phosphorylation of ERK in neurokinin 1 receptor-expressing neurons in laminae III and IV of the rat spinal dorsal horn following noxious stimulation. Mol. Pain 3, 4 (2007).
  PubMed PubMed Central Google Scholar
• Naim, M. M., Shehab, S. A. & Todd, A. J. Cells in laminae III and IV of the rat spinal cord which possess the neurokinin-1 receptor receive monosynaptic input from myelinated primary afferents. Eur. J. Neurosci. 10, 3012–3019 (1998).
  CAS PubMed Google Scholar
• Sakamoto, H., Spike, R. C. & Todd, A. J. Neurons in laminae III and IV of the rat spinal cord with the neurokinin-1 receptor receive few contacts from unmyelinated primary afferents which do not contain substance P. Neuroscience 94, 903–908 (1999).
  CAS PubMed Google Scholar
• Polgár, E., Shehab, S. A., Watt, C. & Todd, A. J. GABAergic neurons that contain neuropeptide Y selectively target cells with the neurokinin 1 receptor in laminae III and IV of the rat spinal cord. J. Neurosci. 19, 2637–2646 (1999).
  PubMed PubMed Central Google Scholar
• Uta, D. et al. TRPA1-expressing primary afferents synapse with a morphologically identified subclass of substantia gelatinosa neurons in the adult rat spinal cord. Eur. J. Neurosci. 31, 1960–1973 (2010).
  PubMed PubMed Central Google Scholar
• Neumann, S., Braz, J. M., Skinner, K., Llewellyn-Smith, I. J. & Basbaum, A. I. Innocuous, not noxious, input activates PKCγ interneurons of the spinal dorsal horn via myelinated afferent fibers. J. Neurosci. 28, 7936–7944 (2008).
  CAS PubMed PubMed Central Google Scholar
• Hughes, D. I., Scott, D. T., Todd, A. J. & Riddell, J. S. Lack of evidence for sprouting of Abeta afferents into the superficial laminas of the spinal cord dorsal horn after nerve section. J. Neurosci. 23, 9491–9499 (2003).
  CAS PubMed PubMed Central Google Scholar
• Santos, S. F., Rebelo, S., Derkach, V. A. & Safronov, B. V. Excitatory interneurons dominate sensory processing in the spinal substantia gelatinosa of rat. J. Physiol. 581, 241–254 (2007).
  CAS PubMed PubMed Central Google Scholar
• Hughes, D. I. et al. P boutons in lamina IX of the rodent spinal cord express high levels of glutamic acid decarboxylase-65 and originate from cells in deep medial dorsal horn. Proc. Natl Acad. Sci. USA 102, 9038–9043 (2005).
  CAS PubMed PubMed Central Google Scholar
• Todd, A. J. GABA and glycine in synaptic glomeruli of the rat spinal dorsal horn. Eur. J. Neurosci. 8, 2492–2498 (1996).
  CAS PubMed Google Scholar
• Watson, A. H., Hughes, D. I. & Bazzaz, A. A. Synaptic relationships between hair follicle afferents and neurones expressing GABA and glycine-like immunoreactivity in the spinal cord of the rat. J. Comp. Neurol. 452, 367–380 (2002).
  CAS PubMed Google Scholar
• Mantyh, P. W. et al. Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268, 1629–1632 (1995).
  CAS PubMed Google Scholar
• Ding, Y. Q. et al. Two major distinct subpopulations of neurokinin-3 receptor-expressing neurons in the superficial dorsal horn of the rat spinal cord. Eur. J. Neurosci. 16, 551–556 (2002).
  PubMed Google Scholar
• Seybold, V. S. et al. Relationship of NK3 receptor-immunoreactivity to subpopulations of neurons in rat spinal cord. J. Comp. Neurol. 381, 439–448 (1997).
  CAS PubMed Google Scholar
• Todd, A. J., Spike, R. C. & Polgar, E. A quantitative study of neurons which express neurokinin-1 or somatostatin sst2a receptor in rat spinal dorsal horn. Neuroscience 85, 459–473 (1998).
  CAS PubMed Google Scholar
• Kemp, T., Spike, R. C., Watt, C. & Todd, A. J. The mu-opioid receptor (MOR1) is mainly restricted to neurons that do not contain GABA or glycine in the superficial dorsal horn of the rat spinal cord. Neuroscience 75, 1231–1238 (1996).
  CAS PubMed Google Scholar
• Brumovsky, P. et al. The neuropeptide tyrosine Y1R is expressed in interneurons and projection neurons in the dorsal horn and area X of the rat spinal cord. Neuroscience 138, 1361–1376 (2006).
  CAS PubMed Google Scholar
• Zhang, X., Tong, Y. G., Bao, L. & Hokfelt, T. The neuropeptide Y Y1 receptor is a somatic receptor on dorsal root ganglion neurons and a postsynaptic receptor on somatostatin dorsal horn neurons. Eur. J. Neurosci. 11, 2211–2225 (1999).
  CAS PubMed Google Scholar
• Abe, K. et al. Responses to 5-HT in morphologically identified neurons in the rat substantia gelatinosa in vitro. Neuroscience 159, 316–324 (2009).
  CAS PubMed Google Scholar
• Lu, Y. & Perl, E. R. Selective action of noradrenaline and serotonin on neurones of the spinal superficial dorsal horn in the rat. J. Physiol. 582, 127–136 (2007).
  CAS PubMed PubMed Central Google Scholar
• Gassner, M., Ruscheweyh, R. & Sandkuhler, J. Direct excitation of spinal GABAergic interneurons by noradrenaline. Pain 145, 204–210 (2009).
  CAS PubMed Google Scholar
• Sandkuhler, J. Models and mechanisms of hyperalgesia and allodynia. Physiol. Rev. 89, 707–758 (2009). This review provides a detailed and systematic account of the mechanisms that have been proposed to underlie abnormal pain states.
  PubMed Google Scholar
• Torsney, C. & MacDermott, A. B. Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. J. Neurosci. 26, 1833–1843 (2006).
  CAS PubMed PubMed Central Google Scholar
• Moore, K. A. et al. Partial peripheral nerve injury promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord. J. Neurosci. 22, 6724–6731 (2002).
  CAS PubMed PubMed Central Google Scholar
• Coull, J. A. et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424, 938–942 (2003).
  CAS PubMed Google Scholar
• Eaton, M. J., Plunkett, J. A., Karmally, S., Martinez, M. A. & Montanez, K. Changes in GAD- and GABA- immunoreactivity in the spinal dorsal horn after peripheral nerve injury and promotion of recovery by lumbar transplant of immortalized serotonergic precursors. J. Chem. Neuroanat. 16, 57–72 (1998).
  CAS PubMed Google Scholar
• Ibuki, T., Hama, A. T., Wang, X. T., Pappas, G. D. & Sagen, J. Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts. Neuroscience 76, 845–858 (1997).
  CAS PubMed Google Scholar
• Azkue, J. J., Zimmermann, M., Hsieh, T. F. & Herdegen, T. Peripheral nerve insult induces NMDA receptor-mediated, delayed degeneration in spinal neurons. Eur. J. Neurosci. 10, 2204–2206 (1998).
  CAS PubMed Google Scholar
• Scholz, J. et al. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of inhibition in lamina II of the dorsal horn after peripheral nerve injury. J. Neurosci. 25, 7317–7323 (2005).
  CAS PubMed PubMed Central Google Scholar
• Whiteside, G. T. & Munglani, R. Cell death in the superficial dorsal horn in a model of neuropathic pain. J. Neurosci. Res. 64, 168–173 (2001).
  CAS PubMed Google Scholar
• Polgár, E., Hughes, D. I., Arham, A. Z. & Todd, A. J. Loss of neurons from laminas I–III of the spinal dorsal horn is not required for development of tactile allodynia in the spared nerve injury model of neuropathic pain. J. Neurosci. 25, 6658–6666 (2005).
  PubMed PubMed Central Google Scholar
• Polgár, E., Gray, S., Riddell, J. S. & Todd, A. J. Lack of evidence for significant neuronal loss in laminae I–III of the spinal dorsal horn of the rat in the chronic constriction injury model. Pain 111, 144–150 (2004).
  PubMed Google Scholar
• Polgár, E. & Todd, A. J. Tactile allodynia can occur in the spared nerve injury model in the rat without selective loss of GABA or GABA(A) receptors from synapses in laminae I–II of the ipsilateral spinal dorsal horn. Neuroscience 156, 193–202 (2008).
  PubMed Google Scholar
• Hwang, J. H. & Yaksh, T. L. The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain 70, 15–22 (1997).
  CAS PubMed Google Scholar
• Malan, T. P., Mata, H. P. & Porreca, F. Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain. Anesthesiology 96, 1161–1167 (2002).
  CAS PubMed Google Scholar
• Schoffnegger, D., Heinke, B., Sommer, C. & Sandkuhler, J. Physiological properties of spinal lamina II GABAergic neurons in mice following peripheral nerve injury. J. Physiol. 577, 869–878 (2006).
  CAS PubMed PubMed Central Google Scholar
• Bailey, A. L. & Ribeiro-da-Silva, A. Transient loss of terminals from non-peptidergic nociceptive fibers in the substantia gelatinosa of spinal cord following chronic constriction injury of the sciatic nerve. Neuroscience 138, 675–690 (2006).
  CAS PubMed Google Scholar
• Castro-Lopes, J. M., Coimbra, A., Grant, G. & Arvidsson, J. Ultrastructural changes of the central scalloped (C1) primary afferent endings of synaptic glomeruli in the substantia gelatinosa Rolandi of the rat after peripheral neurotomy. J. Neurocytol 19, 329–337 (1990).
  CAS PubMed Google Scholar
• Ikeda, H., Heinke, B., Ruscheweyh, R. & Sandkuhler, J. Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299, 1237–1240 (2003).
  CAS PubMed Google Scholar
• Ikeda, H. et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312, 1659–1662 (2006). The second of two studies from these authors that demonstrates a form of LTP in lamina I projection neurons — in this case, induced by activation of C fibres at a rate that occurs in physiological conditions.
  CAS PubMed Google Scholar
• Bredt, D. S. & Nicoll, R. A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).
  CAS PubMed Google Scholar
• Esteban, J. A. et al. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nature Neurosci. 6, 136–143 (2003).
  CAS PubMed Google Scholar
• Nagy, G. G. et al. Widespread expression of the AMPA receptor GluR2 subunit at glutamatergic synapses in the rat spinal cord and phosphorylation of GluR1 in response to noxious stimulation revealed with an antigen-unmasking method. J. Neurosci. 24, 5766–5777 (2004).
  CAS PubMed PubMed Central Google Scholar
• Larsson, M. & Broman, J. Translocation of GluR1-containing AMPA receptors to a spinal nociceptive synapse during acute noxious stimulation. J. Neurosci. 28, 7084–7090 (2008).
  CAS PubMed PubMed Central Google Scholar
• Randic, M., Jiang, M. C. & Cerne, R. Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord. J. Neurosci. 13, 5228–5241 (1993).
  CAS PubMed PubMed Central Google Scholar
• Ji, R. R., Baba, H., Brenner, G. J. & Woolf, C. J. Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nature Neurosci. 2, 1114–1119 (1999).
  CAS PubMed Google Scholar
• Woolf, C. J., Shortland, P. & Coggeshall, R. E. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 355, 75–78 (1992).
  CAS PubMed Google Scholar
• Tong, Y. G. et al. Increased uptake and transport of cholera toxin B-subunit in dorsal root ganglion neurons after peripheral axotomy: possible implications for sensory sprouting. J. Comp. Neurol. 404, 143–158 (1999).
  CAS PubMed Google Scholar
• Shehab, S. A., Spike, R. C. & Todd, A. J. Evidence against cholera toxin B subunit as a reliable tracer for sprouting of primary afferents following peripheral nerve injury. Brain Res. 964, 218–227 (2003).
  CAS PubMed Google Scholar
• Woodbury, C. J., Kullmann, F. A., McIlwrath, S. L. & Koerber, H. R. Identity of myelinated cutaneous sensory neurons projecting to nocireceptive laminae following nerve injury in adult mice. J. Comp. Neurol. 508, 500–509 (2008).
  PubMed PubMed Central Google Scholar
• Neumann, S., Doubell, T. P., Leslie, T. & Woolf, C. J. Inflammatory pain hypersensitivity mediated by phenotypic switch in myelinated primary sensory neurons. Nature 384, 360–364 (1996).
  CAS PubMed Google Scholar
• Noguchi, K., Dubner, R., De Leon, M., Senba, E. & Ruda, M. A. Axotomy induces preprotachykinin gene expression in a subpopulation of dorsal root ganglion neurons. J. Neurosci. Res. 37, 596–603 (1994).
  CAS PubMed Google Scholar
• Malcangio, M., Ramer, M. S., Jones, M. G. & McMahon, S. B. Abnormal substance P release from the spinal cord following injury to primary sensory neurons. Eur. J. Neurosci. 12, 397–399 (2000).
  CAS PubMed Google Scholar
• Hughes, D. I., Scott, D. T., Riddell, J. S. & Todd, A. J. Upregulation of substance P in low-threshold myelinated afferents is not required for tactile allodynia in the chronic constriction injury and spinal nerve ligation models. J. Neurosci. 27, 2035–2044 (2007).
  CAS PubMed PubMed Central Google Scholar
• Baba, H., Doubell, T. P. & Woolf, C. J. Peripheral inflammation facilitates Abeta fiber-mediated synaptic input to the substantia gelatinosa of the adult rat spinal cord. J. Neurosci. 19, 859–867 (1999).
  CAS PubMed PubMed Central Google Scholar
• Schoffnegger, D., Ruscheweyh, R. & Sandkuhler, J. Spread of excitation across modality borders in spinal dorsal horn of neuropathic rats. Pain 135, 300–310 (2008).
  CAS PubMed Google Scholar
• Okamoto, M. et al. Functional reorganization of sensory pathways in the rat spinal dorsal horn following peripheral nerve injury. J. Physiol. 532, 241–250 (2001).
  CAS PubMed PubMed Central Google Scholar
• Kohno, T., Moore, K. A., Baba, H. & Woolf, C. J. Peripheral nerve injury alters excitatory synaptic transmission in lamina II of the rat dorsal horn. J. Physiol. 548, 131–138 (2003).
  CAS PubMed PubMed Central Google Scholar
• Schneider, S. P. Functional properties and axon terminations of interneurons in laminae III-V of the mammalian spinal dorsal horn in vitro. J. Neurophysiol. 68, 1746–1759 (1992).
  CAS PubMed Google Scholar
• Lima, D., Albino-Teixeira, A. & Tavares, I. The caudal medullary ventrolateral reticular formation in nociceptive-cardiovascular integration. An experimental study in the rat. Exp. Physiol. 87, 267–274 (2002).
  PubMed Google Scholar
• Boscan, P., Pickering, A. E. & Paton, J. F. The nucleus of the solitary tract: an integrating station for nociceptive and cardiorespiratory afferents. Exp. Physiol. 87, 259–266 (2002).
  PubMed Google Scholar
• Gauriau, C. & Bernard, J. F. Pain pathways and parabrachial circuits in the rat. Exp. Physiol. 87, 251–258 (2002).
  PubMed Google Scholar
• Heinricher, M. M., Tavares, I., Leith, J. L. & Lumb, B. M. Descending control of nociception: Specificity, recruitment and plasticity. Brain Res. Rev. 60, 214–225 (2009).
  CAS PubMed Google Scholar
• Gauriau, C. & Bernard, J. F. Posterior triangular thalamic neurons convey nociceptive messages to the secondary somatosensory and insular cortices in the rat. J. Neurosci. 24, 752–761 (2004).
  CAS PubMed PubMed Central Google Scholar
• Wall, P. D. et al. Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain 7, 103–111 (1979).
  CAS PubMed Google Scholar
• Decosterd, I. & Woolf, C. J. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87, 149–158 (2000).
  CAS PubMed Google Scholar
• Bennett, G. J. & Xie, Y. K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33, 87–107 (1988).
  CAS PubMed Google Scholar
• Kim, S. H. & Chung, J. M. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 50, 355–363 (1992).
  CAS Google Scholar
• Brown, A. G., Fyffe, R. E., Rose, P. K. & Snow, P. J. Spinal cord collaterals from axons of type II slowly adapting units in the cat. J. Physiol. 316, 469–480 (1981).
  CAS PubMed PubMed Central Google Scholar
• Light, A. R. & Perl, E. R. Spinal termination of functionally identified primary afferent neurons with slowly conducting myelinated fibers. J. Comp. Neurol. 186, 133–150 (1979).
  CAS PubMed Google Scholar
• Shortland, P., Woolf, C. J. & Fitzgerald, M. Morphology and somatotopic organization of the central terminals of hindlimb hair follicle afferents in the rat lumbar spinal cord. J. Comp. Neurol. 289, 416–433 (1989).
  CAS PubMed Google Scholar
• Lorenzo, L. E., Ramien, M., St. Louis, M., De Koninck, Y. & Ribeiro-da-Silva, A. Postnatal changes in the Rexed lamination and markers of nociceptive afferents in the superficial dorsal horn of the rat. J. Comp. Neurol. 508, 592–604 (2008).
  PubMed Google Scholar
• Todd, A. J. & Koerber, H. R. in Wall and Melzack's Textbook of Pain 5th Edition (Eds McMahon, S. & Koltzenburg, M.) 73–90 (Elsevier, Edinburgh, 2005).
  Google Scholar
• Todd, A. J. in Handbook of Clinical Neurology 3rd Series, Pain. (Eds Cervero, F. and Jensen, T. S.) 61–76 (Elsevier, Edinburgh, 2006).
  Google Scholar
• Todd, A. J. in Current Topics in Pain: 12th World Congress on Pain (Ed. Castro-Lopes, J.) 25–51 (IASP Press, Seattle, 2009).
  Google Scholar