Plasticity of Nociceptive Processing in the Spinal Cord

16 May

Importantly,  spinal cord neurons  show changes of their response properties including the size of their receptive fields when the peripheral tissue is suffi- ciently activated by noxious stimuli, when thin fibres in a nerve are electrically stimulated, or when nerve fibres are damaged. In addition descending influ- ences contribute  to spinal nociceptive processing (see Sect. 4 and Fig. 2). In general it is thought that plasticity in the spinal cord contributes significantly to clinically relevant pain states.

Wind-Up, Long-Term Potentiation and Long-Term Depression

Wind-up is a short-term  increase of responses of a spinal cord neuron when electrical stimulation  of afferent  C fibres is repeated  at intervals  of about

1 s (Mendell and Wall 1965). The basis of wind-up is a prolonged excitatory post-synaptic  potential (EPSP) in the dorsal horn neuron  that builds up be- cause of a repetitive C fibre volley (Sivilotti et al. 1993). Wind-up disappears quickly when repetitive stimulation is stopped. It produces a short-lasting in- crease of responses to repetitive painful stimulation. Neurons may also show wind-down.

Long-term potentiation (LTP) and long-term  depression  (LTD) are long- lasting changes of synaptic activity after peripheral nerve stimulation (Randic et al. 1993; Rygh et al. 1999; Sandkühler and Liu 1998). LTP can be elicited at a short  latency after application  of a high-frequency  train  of electrical stimuli that are suprathreshold for C fibres, in particular  when descending inhibitory influences are interrupted. However, LTP can also be elicited with natural noxious stimulation,  although the time course is much slower (Rygh et al. 1999). By contrast,  LTD in the superficial  dorsal  horn  is elicited by

electrical stimulation  of Aδ fibres. It may be a basis of inhibitory  mecha- nisms that  counteract  responses  to noxious  stimulation  (Sandkühler  et al.



Central Sensitization (Spinal Hyperexcitability)

In the course of inflammation and nerve damage neurons in the superficial, the deep and the ventral cord show pronounced changes of their response prop- erties, a so-called central sensitization. This form of neuroplasticity has been observed during cutaneous inflammation,  after cutaneous capsaicin applica- tion and during inflammation in joint, muscle and viscera. Typical changes of responses of individual neurons are:

– Increased responses to noxious stimulation of inflamed tissue.

– Lowering of threshold  of nociceptive specific spinal cord neurons  (they change into wide dynamic range neurons).

– Increased responses to stimuli applied to non-inflamed tissue surrounding the inflamed site.

– Expansion of the receptive field.

In particular, the enhanced responses to stimuli applied to non-inflamed  tis- sue around  the inflamed zone indicate that the sensitivity of the spinal cord neurons  is enhanced so that a previously subthreshold  input is sufficient to

activate the neuron. After sensitization, an increased percentage of neurons in a segment respond to stimulation of an inflamed tissue. Central sensitization can persist for weeks, judging from the recording of neurons at different stages of acute and chronic inflammation  (for review see Dubner  and Ruda 1992; Mense 1993; Schaible and Grubb 1993).

Evidence for central sensitization  has been observed in neuropathic  pain states in which conduction in the nerve remains present and thus a receptive field of neurons can be identified. In these models more neurons show ongo- ing discharges and, on average, higher responses can be elicited by innocuous stimulation of receptive fields (Laird and Bennett 1993; Palacek et al. 1992a, b). In some models of neuropathy  neurons  with abnormal  discharge properties can be observed.

During inflammation  and neuropathy  a large number of spinal cord neu- rons express C-FOS, supporting the finding that a large population of neurons

is activated. At least at some time points  metabolism  in the spinal cord is enhanced during inflammation  and neuropathy  (Price et al. 1991; Schadrack

et al. 1999).

The mechanisms of central sensitization are complex, and it is likely that different pain states are characterized at least in part by specific mechanisms, although some of the mechanisms are involved in all types of central sensiti- zation. It may be crucial whether central sensitization is induced by increased inputs  in sensitized but otherwise normal  fibres (such as in inflammation), or whether structural  changes such as neuronal  loss contribute  (discussed for neuropathic  pain, see Campbell and Meyer 2005). Mechanisms of central sensitization are discussed in Sect. 3.5.

Synaptic Transmission of Nociceptive Input in the Dorsal Horn

Numerous transmitters and receptors mediate the processing of noxious in- formation  arising from noxious stimulation  of normal  tissue, and they are involved in plastic changes of spinal cord neuronal responses during periph- eral inflammation  and nerve damage (see Sect. 3.5). Transmitter  actions have either fast kinetics (e.g. action of glutamate and ATP at ionotropic receptors) or slower kinetics (in particular  neuropeptides that act through  G protein- coupled metabotropic receptors). Actions at fast kinetics evoke immediate and short effects on neurons, thus encoding the input to the neuron, whereas ac- tions at slow kinetics modulate synaptic processing (Millan 1999; Willis and Coggeshall 2004).

Glutamate is a principal transmitter of primary afferent and dorsal horn neurons.  It activates ionotropic  S-alpha-amino-3-hydroxy-5-methyl-4-isoxa- zolepropionic acid (AMPA)/kainate [non-N -methyl-d-aspartate (NMDA)] and

NMDA receptors. In particular  in the substantia  gelatinosa, evoked synaptic activity is mainly blocked by antagonists  at non-NMDA receptors  whereas

NMDA receptor  antagonists  usually cause a small reduction  of mainly later EPSP components. Both non-NMDA and NMDA receptors are involved in the synaptic activation  of neurons  by noxious stimuli (cf. Fundytus  2001; Mil- lan 1999; Willis and Coggeshall 2004). ATP has been implicated in synaptic transmission  of innocuous  mechano-receptive  and nociceptive input  in the superficial dorsal horn. Purinergic ATP receptors are expressed in dorsal horn neurons and in DRG cells, mediating enhanced release of glutamate (cf. Willis and Coggeshall 2004).

Excitatory neuropeptides are co-localized with glutamate. Neuropeptide- mediated EPSPs usually occur after a latency of seconds and are long-lasting.

They may not be sufficient to evoke action potential generation but act syn- ergistically with glutamate (Urban et al. 1994). SP is released mainly in the superficial dorsal horn  by electrical stimulation  of unmyelinated  fibres and

during noxious mechanical, thermal or chemical stimulation  of the skin and deep tissue. Neurokinin-1 (NK-1) receptors for SP are mainly located on den- drites and cell bodies of dorsal horn neurons in laminae I, IV–VI and X. Upon

strong activation by SP, NK-1 receptors are internalized. Mice with a deletion of the preprotachykinin A have intact  responses  to mildly noxious  stimuli but reduced responses  to moderate  and intense noxious stimuli. Mice with a deleted gene for the production of NK-1 receptors respond to acutely painful

stimuli but lack intensity coding for pain and wind-up. In addition, neurokinin A (NKA) is found in small DRG cells and in the dorsal horn and spinally re- leased upon noxious stimulation.  CGRP is often colocalized with substance

P in DRG neurons. It is spinally released by electrical stimulation  of thin fi- bres and noxious mechanical and thermal  stimulation.  CGRP binding sites are located in lamina I and in the deep dorsal horn. CGRP enhances actions

of SP by inhibiting  its enzymatic degradation  and potentiating  its release. CGRP activates nociceptive dorsal horn  neurons;  blockade of CGRP effects reduces nociceptive responses. Other excitatory neuropeptides in the dorsal horn are vasoactive intestinal polypeptide (VIP), neurotensin, cholecystokinin

(CCK, antinociceptive effects of CCK have also been described), thyrotropin- releasing hormone (TRH), corticotropin-releasing hormone (CRH) and pitu- itary adenylate cyclase-activating polypeptide (PACAP) (for review see Willis

and Coggeshall 2004).

γ-Aminobutyric acid (GABA)ergic inhibitory neurons are located through- out the spinal cord. They can be synaptically activated by primary  afferent

fibres. Both the ionotropic GABAA and the metabotropic  GABAB receptor are located pre-synaptically on primary afferent neurons or post-synaptically on dorsal horn neurons. Responses to both innocuous mechanical and noxious stimuli can be reduced by GABA receptor agonists. Some of the inhibitory ef- fects are due to glycine, and the ventral and the dorsal horn contain numerous glycinergic neurons. Glycine may be co-localized with GABA in synaptic termi- nals. Many DRG neurons and neurons in the dorsal horn express nicotinergic

and muscarinergic receptors for acetylcholine. Application of acetylcholine to

the spinal cord produces pro- or anti-nociception (cf. Willis and Coggeshall


The dorsal horn contains leu-enkephalin, met-enkephalin,  dynorphin  and endomorphins 1 and 2. Enkephalin-containing neurons  are particularly  lo- cated in laminae I and II, with dynorphin-containing neurons in laminae I, II and V. Endomorphin  2 has been visualized in terminals of primary afferent neurons in the superficial dorsal horn and in DRG, but also in post-synaptic neurons. Opiate receptors

(μ, δ, κ) are concentrated in the superficial dorsal horn, and in particular μ and δ receptors are located in interneurons and on primary afferent fibres. Opi-

oids reduce release of mediators from primary afferents (pre-synaptic effect), responses of neurons to (innocuous  and) noxious stimulation  and responses to ionophoretic  application of excitatory amino acids showing post-synaptic

effects of opioids (many dorsal horn neurons are hyperpolarized by opiates). In addition  to these “classical” opiate  receptors,  nociceptin  [orphanin  flu- oroquinolone  (FQ)] receptors  have been discovered. Nociceptin has similar

cellular actions as classical opioid peptides. However, pro-nociceptive effects have also been described. A related peptide is nocistatin. At present it is un- known at which receptor nocistatin acts. Somatostatin is expressed in primary afferent neurons, dorsal horn interneurons and axons that descend from the

medulla. It is released mainly in the substantia  gelatinosa, by heat stimula- tion. It is an intriguing question whether inhibitory somatostatin  is released in the spinal cord from primary afferent fibres or from interneurons. Galanin

is expressed in a subpopulation of small DRG neurons, and galanin binding sites are also expressed on DRG neurons. Both facilitatory and inhibitory ef- fects of galanin have been described in inflammatory  and neuropathic  pain

states. NPY is normally only expressed at very low levels in DRG neurons, but DRG neurons  express Y1 and Y2 receptors. It was proposed that Y1 and Y2 receptors contribute  to pre-synaptic  inhibition  (for review see Willis and Coggeshall 2004).

Spinal processing  is influenced  by numerous  other  mediators  including spinal prostaglandins, cytokines and neurotrophins. These mediators are pro- duced in neurons and/or glia cells (Marchand et al. 2005; Vanegas and Schaible

2001). They are particularly  important under pathophysiological  conditions (see the following section). In addition, synaptic transmission is influenced by transmitters of descending systems (see Sect. 4.1).

Transmitter release is dependent on Ca2+-influx into the pre-synaptic end- ing through voltage-dependent  calcium channels. In addition, Ca2+ regulates neuronal excitability. Important for the nociceptive processing are high-voltage activated N-type channels, which are mainly located pre-synaptically but also

on the post-synaptic side, and P/Q-type channels that are located on the pre- synaptic site. Blockers of N-type channels  reduce responses  of spinal cord neurons and behavioural responses to noxious stimulation of normal and in-

flamed tissue, and they reduce neuropathic pain. P/Q-type channels are mainly

involved in the generation of pathophysiological pain states. A role for high- voltage activated L-type channels and low-voltage activated T-type channels has also been discussed (Vanegas and Schaible 2000).

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