Neuropeptide Receptors and Adrenergic Receptors

16 May

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.

Peripheral and Central Mechanisms of Pain Generation

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).

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