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).