Molecular Events Involved in Spinal Hyperexcitability

16 May

Molecular Events Involved in Spinal Hyperexcitability (Central Sensitization) A complex pattern  of events takes place in the spinal cord that changes sen- sitivity of spinal  nociceptive  processing  involving  pre-  and  post-synaptic mechanisms.  (1) During peripheral  inflammation  the spinal release of me- diators  such as glutamate, SP, neurokinin  A and CGRP from nociceptors  is increased  (Schaible 2005). (2) Spinal cord  neurons  are sensitized  by acti- vation  of NMDA receptors,  and  this process is supported  by activation  of metabotropic  glutamate, NK-1 and CGRP receptors, and brain-derived  neu- rotrophic  factor  plays a role as well (Woolf and  Salter 2000). Antagonists to the NMDA receptor  can prevent  central  sensitization  and reduce estab- lished hyperexcitability (Fundytus 2001). Antagonists at NK-1 and CGRP re- ceptors  attenuate  central  sensitization.  Ablation of neurons  with NK-1 re- ceptors  was shown to abolish central  sensitization  (Khasabov et al. 2002).

Important molecular steps of sensitization  are initiated  by Ca2+  influx into cells through  NMDA receptors  and voltage-gated calcium channels  (Woolf

and Salter 2000). Ca2+ activates Ca2+–dependent  kinases that e.g. phospho- rylate NMDA receptors.  (3) The subunits  NR1 and GluR1 of glutamate  re-

ceptors show an up-regulation  of the protein and an increase of phosphory- lation (also of the NR2B NMDA receptor  subunit)  thus enhancing  synaptic glutamatergic  transmission.  First changes  appear  within  10 min  after  in-

duction  of inflammation  and  correlate  well with behavioural  hyperalgesia (Dubner  2005). (4) Expression of genes that  code for neuropeptides is en- hanced. In particular,  increased gene expression of opioid peptides (dynor- phin and enkephalin) have become known, suggesting that inhibitory mech-

anisms are up-regulated  for compensation.  However, dynorphin  has both an inhibitory action via κ receptors and excitatory actions involving NMDA re- ceptors.  (5) Other  mediators  such as spinal  prostaglandins  and  cytokines modify central hyperexcitability. As mentioned  above, sources of these me-

diators  are neurons,  glia cells, or both (Marchand  et al. 2005; Watkins and Maier 2005). Spinal actions of prostaglandins  include increase of transmitter release (cf. Vanegas and Schaible 2001), inhibition  of glycinergic inhibition (Ahmadi et al. 2002) and direct depolarization  of dorsal horn neurons (Baba et al. 2001).

In the case of neuropathic  pain, loss of inhibition  is being discussed as a major mechanism  of spinal hyperexcitability.  Reduced inhibition  may be produced  by loss of inhibitory interneurons through excitotoxic actions and apoptosis (Dubner 2005, see, however, Polgár et al. 2004).

Descending Inhibition and Facilitation

4.1

Periaqueductal Grey and Related Brain Stem Nuclei

From brain  stem nuclei, impulses  “descend”  onto  the spinal  cord  and  in- fluence the transmission  of pain signals at the dorsal horn  (cf. Fields and Basbaum 1999; Ossipov and Porreca 2005). Concerning  descending  inhibi- tion, the periaqueductal  grey matter (PAG) is a key region. It projects to the rostral ventromedial  medulla (RVM), which includes the serotonin-rich nu- cleus raphe magnus (NRM) as well as the nucleus reticularis gigantocellularis pars alpha and the nucleus paragigantocellularis  lateralis (Fields et al. 1991), and it receives inputs from the hypothalamus, cortical regions and the limbic system (Ossipov and Porreca 2005). Neurons in RVM then project along the dorsolateral  funiculus (DLF) to the dorsal horn.  Exogenous opiates imitate endogenous  opioids and induce analgesia by acting upon PAG and RVM in addition to the spinal dorsal horn (Ossipov and Porreca 2005). RVM contains so-called on- and off-cells. Off-cells are thought to exert descending inhibition of nociception, because whenever their activity is high there is an inhibition of nociceptive transmission,  and because decreases in off-cell firing correlate with increased nociceptive transmission. On-cells instead seem to facilitate no- ciceptive mechanisms at the spinal dorsal horn. Thus, RVM seems to generate antinociception  and facilitation of pain transmission  (Gebhart 2004; Ossipov and Porreca 2005). Ultimately, spinal bulbospinal loops are significant in set- ting the gain of spinal processing (Porreca et al. 2002; Suzuki et al. 2002).

A particular form of descending inhibition of wide dynamic range (WDR) neurons is the “diffuse noxious inhibitory control” (DNIC). When a strong nox- ious stimulus is applied to a given body region, nociceptive neurons with input from that body region send impulses to structures located in the caudal medulla (caudal to RVM), and this triggers a centrifugal inhibition (DNIC) of nocicep- tive WDR neurons located throughout the neuraxis (Le Bars et al. 1979a, b).

4.2

Changes of Descending Inhibition and Facilitation During Inflammation

In models of inflammation, descending inhibition predominates  over facilita- tion in pain circuits with input from the inflamed tissue, and thus it attenuates primary hyperalgesia. This inhibition  descends from RVM, LC and possibly other supraspinal  structures,  and spinal serotonergic (from RVM) and nora- drenergic (from LC) mechanisms are involved. By contrast, descending facilita- tion predominates over inhibition in pain circuits with input from neighbour- ing tissues, thus facilitating secondary hyperalgesia. Reticular nuclei located dorsally to RVM also participate in facilitation of secondary hyperalgesia. Le-

sion of these nuclei completely prevents secondary hyperalgesia (Vanegas and

Schaible 2004).

In the RVM, excitatory amino acids mediate descending modulation in re- sponse to transient noxious stimulation and early inflammation, and they are involved in the development of RVM hyperexcitability associated with persis- tent pain (Heinricher  et al. 1999; Urban and Gebhart 1999). As in the spinal cord, increased gene and protein expression and increased phosphorylation of NMDA and AMPA receptors take place in RVM (Dubner 2005; Guan et al. 2002).

A hypothesis is that messages from the inflamed tissue are amplified and relayed until they reach the appropriate brain stem structures.  These in turn

send descending impulses to the spinal cord, dampen  primary hyperalgesia and cause secondary hyperalgesia. It is also possible that the “secondary neu- ronal pool” becomes hyperexcitable as a result of intraspinal mechanisms and

that  descending  influences mainly play a contributing,  yet significant, role in secondary hyperalgesia. Thus, during inflammation  descending influences are both  inhibitory  and  facilitatory, but  the mix may be different  for pri-

mary and secondary hyperalgesia and may change with time (Vanegas and

Schaible 2004).

4.3

Changes of Descending Inhibition and Facilitation During Neuropathic Pain

Peripheral nerve damage causes primary hyperalgesia and allodynia that seem to develop autonomously at the beginning but need facilitation from RVM for their maintenance. CCKB receptor activation, as well as excitation of neurons that express μ-opioid receptors in RVM, is essential for maintaining hyperex- citability in the primary neuronal pool (Porreca et al. 2002; Ossipov and Porreca

2005; Vanegas and Schaible 2004). “Secondary neuronal pools” are subject to a descending inhibition that is induced by the nerve damage and stems from the PAG. In contrast  with inflammation,  facilitation prevails in the primary while inhibition prevails in the secondary pool (Vanegas and Schaible 2004).

Generation of the Conscious Pain Response in the Thalamocortical System

The conscious pain response is produced by the thalamocortical system (Fig. 2). Electrophysiological data and brain imaging in humans have provided insights into which parts of the brain are activated upon noxious stimulation. As pointed out earlier, pain is an unpleasant sensory and emotional experience, and these different components of the pain response are produced by different networks. The analysis of the noxious stimulus for its location, duration  and intensity is the sensory-discriminative aspect of pain. This is produced  in the lateral thalamocortical  system consisting of relay nuclei in the lateral thalamus and

the areas SI and SII in the post-central gyrus. In these regions innocuous and noxious stimuli are discriminated (Treede et al. 1999).

The second component of the pain sensation is the affective aspect, i.e. the noxious stimulus is unpleasant and causes aversive reactions. This component is produced in the medial thalamocortical system, which consists of relay nu- clei in the central and medial thalamus, the anterior  cingulate cortex (ACC), the insula and the prefrontal cortex (Treede et al. 1999; Vogt 2005). These brain structures  are part of the limbic system, and the insula may be an interface of the somatosensory  and the limbic system. Even when destruction  of the somatosensory cortex impairs stimulus localization, pain affect is not altered. It should be noted that limbic regions are not only involved in pain processing. In particular the ACC is activated during different emotions including sadness and happiness, and parts of the ACC are also involved in the generation of au- tonomic responses (they have projections to regions that command autonomic output  systems). Other cingulate regions are involved in response selection (they have projections to the spinal cord and the motor cortices) and the ori- entation of the body towards innocuous and noxious somatosensory stimuli. A role of the ACC in the process of memory formation/access  has also been put forward (Vogt 2005).

References

Ahmadi S, Lippross S, Neuhuber WL, Zeilhofer HU (2002) PGE2 selectively blocks inhibitory glycinergic neurotransmission onto rat superficial dorsal horn neurons. Nat Neurosci

5:34–40

Akopian AN, Souslova V, England S, Okuse K, Ogata N, Ure J, Smith A, Kerr BJ, McMahon SB, Boyce S, Hill R, Stanfa LC, Dickenson AH, Wood JN (1999) The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 2:541–548

Baba H, Kohno T, Moore KA, Woolf CJ (2001) Direct activation of rat spinal dorsal horn neurons by prostaglandin E2. J Neurosci 21:1750–1756

Bär KJ, Schurigt U, Scholze A, Segond von Banchet G, Stopfel N, Bräuer R, Halbhuber KJ, Schaible HG (2004) The expression and localisation of somatostatin  receptors in dorsal root ganglion neurons of normal and monoarthritic rats. Neuroscience 127:197–206

Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, PatapoutianA (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and brady- kinin. Neuron 41:849–857

Banik RK, Kozaki Y, Sato J, Gera L, Mizumura K (2001) B2 receptor-mediated enhanced

bradykinin sensitivity of rat cutaneous C-fiber nociceptors during persistent inflamma- tion. J Neurophysiol 86:2727–2735

Belmonte C, Cervero E (1996) Neurobiology of nociceptors. Oxford University Press, Oxford

Brack A, Stein C (2004) Potential links between leukocytes and antinociception. Pain 111:1–2

Brock JA, McLachlan EM, Belmonte C (1998) Tetrodotoxin-resistant impulses  in single nociceptor nerve terminals in guinea-pig cornea. J Physiol 512:211–217

Campbell JN, Meyer RA (2005) Neuropathic  pain: from the nociceptor to the patient. In: Merskey H, Loeser JD, Dubner R (eds) The paths of pain 1975–2005. IASP Press, Seattle, pp 229–242

Carlton SM, Coggeshall RE (2002) Inflammation-induced up-regulation  of neurokinin  1 receptors in rat glabrous skin. Neurosci Lett 326:29–36

Carlton SM, Du J, Zhou S, Coggeshall RE (2001) Tonic control  of peripheral  cutaneous nociceptors by somatostatin  receptors. J Neurosci 21:4042–4049

Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzen- burg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313

Cervero F, Laird JMA (1991) One pain or many pains? A new look at pain mechanisms.

News Physiol Sci 6:268–273

Chapman  CR, Gavrin  J (1999) Suffering: the  contributions of persistent  pain.  Lancet

353:2233–2237

Craig AD (2003) Pain mechanisms: labeled lines versus convergence in central processing.

Annu Rev Neurosci 26:1–30

Cummins TR, Black JA, Dib-Hajj SD, Waxman SG (2000) Glial-derived neurotrophic factor upregulates expression of functional SNS and NaN sodium channels and their currents in axotomized dorsal root ganglion neurons. J Neurosci 20:8754–8761

Cunha  FQ, Ferreira  SH (2003) Peripheral  hyperalgesic  cytokines.  Adv Exp Med Biol

521:22–39

Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K, Hughes SA, Rance K, Grau E, Harper AJ, Pugh PL, Rogers DC, Bingham S, Randall A, Sheardown SA (2000) Vanilloid receptor-1 is essential for inflam- matory thermal hyperalgesia. Nature 405:183–187

Dubner  R (2005) Plasticity in central  nociceptive pathways. In: Merskey H, Loeser JD, Dubner R (eds) The paths of pain 1975–2005. IASP Press, Seattle, pp 101–115

Dubner R, Ruda MA (1992) Activity-dependent neuronal plasticity following tissue injury and inflammation. Trends Neurosci 15:96–103

Everill B, Kocsis JD (1999) Reduction in potassium currents in identified cutaneous afferent

dorsal root ganglion neurons after axotomy. J Neurophysiol 82:700–708

Fields HL, Basbaum AI (1999) Central nervous system mechanisms of pain modulation. In: Wall PD, Melzack R (eds) Textbook of pain. Churchill Livingstone, London, pp 309–329

Fields HL, Heinricher MM, Mason P (1991) Neurotransmitters in nociceptive modulatory circuits. Annu Rev Neurosci 14:219–245

Fundytus ME (2001) Glutamate receptors and nociception. CNS Drugs 15:29–58

Gebhart GF (2004) Descending modulation of pain. Neurosci Biobehav Rev 27:729–737

Gold MS (2005) Molecular basis of receptors. In: Merskey H, Loeser JD, Dubner R (eds) The paths of pain 1975–2005. IASP Press, Seattle, pp 49–67

Gold MS, Traub  JT (2004) Cutaneous  and colonic rat DRG neurons  differ with respect to both baseline and PGE2-induced changes in passive and active electrophysiological properties. J Neurophysiol 91:2524–2531

Guan Y, Terayama R, Dubner R, Ren K (2002) Plasticity in excitatory amino acid receptor- mediated  descending  pain  modulation  after  inflammation.  J Pharmacol  Exp Ther

300:513–520

Han HC, Lee DH, Chung JM (2000) Characteristics of ectopic discharges in a rat neuropathic pain model. Pain 84:253–261

Heinricher MM, McGaraughty S, Farr DA (1999) The role of excitatory amino acid trans- mission within the rostral ventromedial medulla in the antinociceptive actions of sys- temically administered  morphine. Pain 81:57–65

Heppelmann  B, Pawlak M (1999) Peripheral application of cyclo-somatostatin,  a somato- statin antagonist, increases the mechanosensitivity of the knee joint afferents. Neurosci Lett 259:62–64

Hong S, Wiley JW (2005) Early painful diabetic neuropathy  is associated with differential changes in the expression and function of vanilloid receptor 1. J Biol Chem 280:618–627

Hunt  SP, Pini A, Evan G (1987) Induction  of c-fos-like protein  in spinal  cord neurons following sensory stimulation. Nature 328:632–634

Jänig W, Levine JD, Michaelis M (1996) Interactions  of sympathetic and primary afferent neurons  following nerve injury and tissue trauma.  In: Kumazawa T, Kruger L, Mizu- mura K (eds) The polymodal receptor: a gateway to pathological pain. Progress in brain research, vol 113. Elsevier Science, Amsterdam, pp 161–184

Ji RR, Samad TA, Jin SX, Schmoll R, Woolf CJ (2002) p38 MAPK activation  by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron 36:57–68

Kendall NA (1999) Psychological approaches to the prevention of chronic pain: the low back paradigm. Baillieres Best Pract Res Clin Rheumatol 13:545–554

Khasabov SG, Rogers SD, Ghilardi JR, Pertes CM, Mantyh PW, Simone DA (2002) Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci 22:9086–9098

Kingery WS, Guo TZ, Davies ME, Limbird L, Maze M (2000) The alpha(2A) adrenoceptor and

the sympathetic postganglionic neuron  contribute  to the development of neuropathic heat hyperalgesia in mice. Pain 85:345–358

Klede M, Handwerker  HO, Schmelz M (2003) Central  origin  of secondary  mechanical hyperalgesia. J Neurophysiol 90:353–359

Laird JMA, Bennett GJ (1993) An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy. J Neurophysiol 69:2072–

2085

Le Bars D, Dickenson AH, Besson JM (1979a) Diffuse noxious inhibitory controls (DNIC).

I. Effects on dorsal horn convergent neurons in the rat. Pain 6:283–304

Le Bars D, Dickenson AH, Besson JM (1979b) Diffuse noxious inhibitory controls (DNIC).

II. Lack of effect on non-convergent  neurones, supraspinal involvement and theoretical implications. Pain 6:305–327

Lee DH, Liu X, Kim HT, Chung K, Chung JM (1999) Receptor  subtype  mediating  the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. J Neurophysiol 81:2226–2233

Liang YF, Haake B, Reeh PW (2001) Sustained  sensitization  and  recruitment  of cuta- neous nociceptors by bradykinin  and a novel theory of its excitatory action. J Physiol

532:229–239

Liu CN, Michaelis M, Amir R, Devor M (2000) Spinal nerve injury enhances subthreshold membrane  potential oscillations in DRG neurons: relation to neuropathic  pain. J Neu- rophysiol 84:205–215

Lynn B (1996) Neurogenic inflammation  caused by cutaneous polymodal receptors. Prog

Brain Res 113:361–368

Marchand F, Perretti M, McMahon SB (2005) Role of the immune system in chronic pain.

Nat Rev Neurosci 6:521–532

McCleskey EW, Gold MS (1999) Ion channels of nociception. Annu Rev Physiol 61:835–856

Mendell LM, Wall PD (1965) Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibers. Nature 206:97–99

Menetréy D, Gannon  JD, Levine JD, Basbaum AI (1989) Expression of c-fos protein  in interneurons and  projection  neurons  of the rat  spinal  cord  in response  to noxious somatic, articular, and visceral stimulation. J Comp Neurol 285:177–195

Mense S (1993) Nociception from skeletal muscle in relation to clinical muscle pain. Pain

54:241–289

Michaelis M, Vogel C, Blenk KH, Arnarson  A, Jänig W (1998) Inflammatory  mediators sensitize acutely axotomized nerve fibers to mechanical stimulation in the rat. J Neurosci

18:7581–7587

Millan MJ (1999) The induction of pain: an integrative review. Prog Neurobiol 57:1–164

Moon DE, Lee DH, Han HC, Xie J, Coggeshall RE, Chung JM (1999) Adrenergic sensitivity of the sensory receptors modulating mechanical allodynia in a rat neuropathic pain model. Pain 80:589–595

Obreja O, Rathee PK, Lips KS, Distler C, Kress M (2002) IL-1β potentiates  heat-activated

currents  in rat sensory neurons: involvement of IL-1 RI, tyrosine kinase, and protein kinase C. FASEB J 16:1497–1503

Orstavik K, Weidner C, Schmidt R, Schmelz M, Hilliges M, Jørum E, Handwerker H, Toreb-

jörk HE (2003) Pathological C-fibres in patients with a chronic painful condition. Brain

126:567–578

Ossipov MH, Porreca F (2005) Descending modulation  of pain. In: Merskey H, Loeser JD, Dubner R (eds) The paths of pain 1975–2005. IASP Press, Seattle, pp 117–130

Palacek J, Dougherty PM, Kim SH, Paleckova V, Lekan V, Chung JM, Carlton SM, Willis WD (1992a) Responses of spinothalamic  tract  neurons  to mechanical and thermal  stim- uli in an experimental  model of peripheral  neuropathy  in primates.  J Neurophysiol

68:1951–1966

Palacek J, Paleckova V, Dougherty PM, Carlton SM, Willis WS (1992b) Responses of spinotha- lamic tract cells to mechanical and thermal stimulation of skin in rats with experimental peripheral neuropathy. J Neurophysiol 67:1562–1573

Papapoutian A, Peier AM, Story GM, Viswanath V (2003) ThermoTRP channels and beyond:

mechanisms of temperature sensation. Nat Rev Neurosci 4:529–539

Peier AM, Moqrich  A, Hergarden  AC, Reeve AJ, Andersson  DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S, Patapoutian  A (2002) A TRP channel that senses cold stimuli and menthol. Cell 108:705–715

Polgár E, Gray S, Riddell JS, Todd AJ (2004) 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

Porreca F, Ossipov MH, Gebhart GF (2002) Chronic pain and medullary descending facili-

tation. Trends Neurosci 25:319–325

Price DD, Mao J, Coghill RC, d’Avella D, Cicciarello R, Fiori MG, Mayer DJ, Hayes RL (1991) Regional changes in spinal cord glucose metabolism in a rat model of painful neuropathy. Brain Res 564:314–318

Price DD, Greenspan JD, Dubner R (2003) Neurons involved in the exteroceptive function

of pain. Pain 106:215–219

Randic M, Jiang MC, Cerne R (1993) Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord. J Neurosci 13:5228–5241

Rashid MH, Inoue M, Bakoshi S, Ueda H (2003) Increased expression of vanilloid receptor

1 on myelinated primary afferent neurons contributes  to the antihyperalgesic effect of capsaicin cream in diabetic neuropathic pain in mice. J Pharmacol Exp Ther 306:709–717

Ringkamp M, Peng B, Wu G, Hartke TV, Campbell JN, Meyer RA (2001) Capsaicin responses in heat-sensitive and heat-insensitive A-fiber nociceptors. J Neurosci 21:4460–4468

Russo CM, Brose WG (1998) Chronic pain. Annu Rev Med 49:123–133

Rygh LJ, Svendson F, Hole K, Tjolsen A (1999) Natural noxious stimulation  can induce long-term increase of spinal nociceptive responses. Pain 82:305–310

Sandkühler J, Liu X (1998) Induction of long-term potentiation at spinal synapses by noxious stimulation or nerve injury. Eur J Neurosci 10:2476–2480

Schadrack J, Neto FL, Ableitner A, Castro-Lopes JM, Willoch F, Bartenstein B, Zieglgäns- berger W, Tölle TR (1999) Metabolic activity changes in the rat  spinal cord during adjuvant monoarthritis. Neuroscience 94:595–605

Schaible HG (2005) Basic mechanisms of deep somatic tissue. In: McMahon SB, Koltzen- burg M (eds) Textbook of pain. Elsevier, London, pp 621–633

Schaible HG, Grubb BD (1993) Afferent and spinal mechanisms of joint pain. Pain 55:5–54

Schaible HG, Richter F (2004) Pathophysiology of pain. Langenbecks Arch Surg 389:237–243

Schaible HG, Schmidt RF (1988) Time course of mechanosensitivity  changes in articular afferents during a developing experimental arthritis. J Neurophysiol 60:2180–2195

Schaible HG, Del Rosso A, Matucci-Cerinic M (2005) Neurogenic aspects of inflammation.

Rheum Dis Clin North Am 31:77–101

Segond von Banchet G, Petrow PK, Bräuer R, Schaible HG (2000) Monoarticular  antigen- induced arthritis  leads to pronounced  bilateral upregulation  of the expression of neu- rokinin 1 and bradykinin 2 receptors in dorsal root ganglion neurons of rats. Arthritis Res 2:424–427

Sivilotti LG, Thompson SWN, Woolf CJ (1993) The rate of rise of the cumulative depolar-

ization evoked by repetitive stimulation of small-calibre afferents is a predictor of action potential windup in rat spinal neurons in vitro. J Neurophysiol 69:1621–1631

Sommer C, Schröder JM (1995) HLA-DR expression in peripheral neuropathies: the role of Schwann cells, resident and hematogenous  macrophages, and endoneurial  fibroblasts. Acta Neuropathol (Berl) 89:63–71

Sugiura Y, Terui N, Hosoya Y (1989) Difference in the distribution  of central terminals between visceral and somatic unmyelinated (C) primary afferent fibres. J Neurophysiol

62:834–840

Sutherland SP, Benson CJ, Adelman JP, McCleskey EW (2001) Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc Natl Acad Sci USA 98:711–716

Suzuki R, Morcuende  S, Webber  M, Hunt  SP, Dickenson  AH (2002) Superficial NK1-

expressing neurons  control spinal excitability through  activation of descending path- ways. Nat Neurosci 5:1319–1326

Treede RD, Kenshalo DR, Gracely RH, Jones AKP (1999) The cortical representation of pain.

Pain 79:105–111

Urban  L, Thompson  SWN, Dray A (1994) Modulation  of spinal  excitability: coopera- tion  between  neurokinin  and  excitatory  amino  acid  transmitters. Trends  Neurosci

17:432–438

Urban MO, Gebhart GF (1999) Supraspinal contributions to hyperalgesia. Proc Natl Acad

Sci USA 96:7687–7692

Vanegas H, Schaible HG (2000) Effects of antagonists to high-threshold  calcium channels upon spinal mechanisms of pain, hyperalgesia and allodynia. Pain 85:9–18

Vanegas H, Schaible HG (2001) Prostaglandins and cyclooxygenases in the spinal cord. Prog

Neurobiol 64:327–363

Vanegas H, Schaible HG (2004) Descending control of persistent pain: inhibitory or facili- tatory? Brain Res Rev 46:295–309

Vogt BA (2005) Pain and emotion. Interactions  in subregions of the cingulate gyrus. Nat

Rev Neurosci 6:533–544

Watkins  LR, Maier SF (2005) Glia and  pain: past, present,  and  future.  In: Merskey H, Loeser JD, Dubner R (eds) The paths of pain 1975–2005. IASP Press, Seattle, pp 165–175

Weidner  C, Schmelz M, Schmidt R, Hansson  B, Handwerker  HO, Torebjörk  HE (1999) Functional attributes  discriminating  mechano-insensitive  and mechano-responsive  C nociceptors in human skin. J Neurosci 19:10184–10190

Williams S, Ean GL, Hunt SP (1990) Changing pattern of c-fos induction following thermal cutaneous stimulation in the rat. Neuroscience 36:73–81

Willis WD (2005) Physiology and anatomy of the spinal cord pain system. In: Merskey H,

Loeser JD, Dubner R (eds) The paths of pain 1975–2005. IASP Press, Seattle, pp 85–100

Willis WD, Coggeshall RE (2004) Sensory mechanisms of the spinal cord, 3rd edn. Kluwer

Academic/Plenum Publishers, New York

Wilson-Gerwing TD, Dmyterko MV, Zochodne DW, Johnston JM, Verge VM (2005) Neurotro- phin-3 suppresses thermal hyperalgesia associated with neuropathic pain and attenuates transient  receptor potential  vanilloid receptor-1 expression in adult sensory neurons. J Neurosci 25:758–767

Woolf CJ, Salter MW (2000) Neuronal  plasticity: increasing  the  gain in  pain.  Science

288:1765–1768

Wu G, Ringkamp M, Hartke TV, Murinson BB, Campbell JN, Griffin JW, Meyer RA (2001) Early onset of spontaneous  activity in uninjured  C-fiber nociceptors  after injury to neighbouring nerve fibers. J Neurosci 21 RC140:1–5

Random Posts

Comments are closed.