Receptors for several neuropeptides have been identiﬁed in primary afferent neurons, including receptors for the excitatory neuropeptides SP (neurokinin 1 receptors) and CGRP, and receptors for inhibitory peptides, namely for opi- oids, somatostatin and neuropeptide Y (NPY) (for review see Bär et al. 2004; Brack and Stein 2004). These receptors could be autoreceptors because some of the neurons with these receptors also synthesize the corresponding neuropep- tide. It has been proposed that the activity or threshold of a neuron results from the balance between excitatory and inhibitory compounds. Many noci- ceptive neurons, for example, seem to be under the tonic inhibitory inﬂuence of somatostatin because the application of a somatostatin receptor antagonist enhances activation of the neurons by stimuli (Carlton et al. 2001; Heppelmann
and Pawlak 1999). The expression of excitatory neuropeptide receptors in the neurons can be increased under inﬂammatory conditions (Carlton et al. 2002; Segond von Banchet et al. 2000).
The normal afferent ﬁbre does not seem to be inﬂuenced by stimulation of the sympathetic nervous system. However, primary afferents from inﬂamed tissue may be activated by sympathetic nerve stimulation. The expression of adrenergic receptors may be particularly important in neuropathic pain states (see the following section).
Mechanisms Involved in the Generation of Ectopic Discharges After Nerve Injury
Different mechanisms may produce ectopic discharges. After nerve injury the expression of TTX-S Na+ channels is increased, and the expression of TTX-R Na+ channels is decreased. These changes are thought to alter the membrane properties of neurons such that rapid ﬁring rates (bursting ectopic discharges) are favoured (Cummins et al. 2000). Changes in the expression of potassium channels of the neurons have also been shown (Everill et al. 1999). Injured axons may be excited by inﬂammatory mediators, e.g. by bradykinin, NO (Michaelis
et al. 1998) and cytokines (Cunha and Ferreira 2003; Marchand et al. 2005). Sources of these mediators are white bloods cells and Schwann cells around the damaged nerve ﬁbres. Finally, the sympathetic nervous system does not activate primary afferents in normal tissue, but injured nerve ﬁbres may be- come sensitive to adrenergic mediators (Kingery et al. 2000; Lee et al. 1999; Moon et al. 1999). This cross-talk may occur at different sites. Adrenergic re- ceptors may be expressed at the sensory nerve ﬁbre ending. Direct connections between afferent and efferent ﬁbres (so-called “ephapses”) is considered. Sym- pathetic endings are expressed in increased numbers in the spinal ganglion after nerve injury, and cell bodies of injured nerve ﬁbres are surrounded by “baskets” consisting of sympathetic ﬁbres (Jänig et al. 1996).
Spinal Nociceptive Processing
The spinal cord is the lowest level of the central nociceptive system. The neuronal organization of the spinal cord determines characteristic features of pain, e.g. the projection of pain into particular tissues. The spinal cord actively ampliﬁes the spinal nociceptive processing because nociceptive spinal cord neurons change their excitability to inputs from the periphery under painful conditions. On the other hand the spinal cord is under the inﬂuence of descending inﬂuences. Figure 2 shows functionally important aspects of the nociceptive processing in the central nervous system.
Fig. 2 Schematic display of the nociceptive processing underlying inﬂammatory and neuro- pathic pain
Types of Nociceptive Spinal Neurons and Responses to Noxious
Stimulation of Normal Tissue
Nociceptive Aδ ﬁbres project mainly to lamina I (and II). Some Aδ ﬁbres have further projections into lamina V. Cutaneous C ﬁbres project mainly to lamina II, but visceral and muscular unmyelinated afferents project to lamina II and also to deeper laminae. Visceral afferents distribute to a wider area of the cord, but the number of terminals for each ﬁbre is much lower for visceral than for cutaneous ﬁbres (Sugiura et al. 1989). By contrast, non-nociceptive
primary afferents with Aβ ﬁbres project to lamina III and IV. However, not
only neurons in the superﬁcial dorsal horn receive direct inputs from primary afferent neurons; dendrites of deep dorsal horn may extend dorsally into the superﬁcial laminae and receive nociceptive inputs in superﬁcial layers (Willis and Coggeshall 2004).
Neurons with nociceptive response properties are located in the superﬁcial and deep dorsal and in the ventral horn. Both wide dynamic range neurons
and nociceptive-speciﬁc neurons encode the intensity of a noxious stimulus applied to a speciﬁc site. Wide dynamic range neurons receive inputs from Aβ, Aδ and C ﬁbres and respond in a graded fashion to innocuous and noxious stimulus intensities. Nociceptive-speciﬁc neurons respond only to Aδ and C ﬁbre stimulation and noxious stimulus intensities.
A proportion of neurons receive only inputs from the skin or from deep tissue such as muscle and joint. However, many neurons exhibit convergent inputs from skin and deep tissue, and all neurons that receive inputs from the viscera also receive inputs from skin (and deep tissue). This uncertainty in the message of a neuron could in fact be the reason why, during disease in viscera, pain is felt as occurring in a cutaneous or subcutaneous area; the pain is projected into a so-called Head zone. Another encoding problem is that, in particular, wide dynamic range neurons often have large receptive ﬁelds, and a stimulus of a deﬁned intensity may elicit different intensities of responses when applied to different sites of the receptive ﬁeld. Quite clearly, the precise location of a noxious stimulus, its intensity and character cannot be encoded by a single nociceptive neuron. Presumably, encoding of a noxious stimulus is only achieved by a population of nociceptive neurons (see Price et al. 2003). By contrast, other authors propose that only lamina I neurons with smaller receptive ﬁelds are able to encode noxious stimuli, thus forming labelled lines from spinal cord to the cortex (for review see Craig 2003).
The response of a spinal cord neuron is dependent on its primary affer- ent input, its spinal connections and on descending inﬂuences. Evidence has been provided that loops of neurons involving the brain stem inﬂuence the re-
sponses of nociceptive neurons. These loops may mainly originate in neurons in projection neurons in lamina I (see the following section) and facilitate, via descending ﬁbres from the brain stem, neurons in superﬁcial and deep
dorsal horn (Suzuki et al. 2002). In addition, descending inhibition inﬂuences responses of neurons (see Sect. 4.1).
Samples of activated neurons can be mapped by visualizing FOS protein in
neurons (Willis and Coggeshall 2004). Noxious heat stimulation, for example, evokes expression of C-FOS within a few minutes in the superﬁcial dorsal horn, and causes staining shifts to deeper laminae of the dorsal horn thereafter (Menetréy et al. 1989; Williams et al. 1990). Noxious visceral stimulation evokes C-FOS expression in laminae I, V and X, thus resembling the projection area of visceral afferent ﬁbres, and injection of mustard oil into the muscle elicited C-FOS expression in laminae I and IV to VI (Hunt et al. 1987; Menetréy et al. 1989).
Projections of Nociceptive Spinal Cord Neurons to Supraspinal Sites
The axons of most dorsal horn neurons terminate in the same or adjacent laminae, i.e. they are local interneurons. However, a proportion of neurons projects to supraspinal sites. Ascending pathways in the white matter of the ventral quadrant of the spinal cord include the spinothalamic tract (STT), the spinoreticular tract (SRT), and the spinomesencephalic tract (SMT). Axons of the STT originate from neurons in lamina I (some lamina I STT cells may ascend in the dorsolateral funiculus), lamina V and deeper. Many STT cells project to the thalamic ventral posterior lateral (VPL) nucleus, which is part of the lateral thalamocortical system and is involved in encoding of sensory stimuli (see Sect. 5). Some STT cells project to thalamic nuclei that are not involved in stimulus encoding, and they have collaterals to the brain stem. Axons of the SRT project to the medial rhombencephalic reticular formation, the lateral and dorsal reticular nucleus, the nucleus reticularis gigantocellu- laris and others. SRT cells are located in laminae V, VII, VIII and X, and they have prominent responses to deep input. SMT neurons are located in laminae I, IV, V, VII and VIII and project to the parabrachial nuclei and the periaqueductal grey and others. The parabrachial projection reaches in part to neurons that project to the central nucleus of amygdala. STT, SRT and SMT cells are either low-threshold, wide dynamic range or nociceptive- speciﬁc.
In addition, several spinal projection paths have direct access to the limbic system, namely the spinohypothalamic tract, the spino-parabrachio-amygdalar pathway, the spino-amygdalar pathway and others. In some species there is
a strong spino-cervical tract (SCT) ascending in the dorsolateral funiculus. SCT neurons process mainly mechano-sensory input, but some additionally receive nociceptive inputs (Willis and Coggeshall 2004). Finally, there is sub-
stantial evidence that nociceptive input from the viscera is processed in neurons that ascend in the dorsal columns (Willis 2005).