Laminae It was the Swedish anatomist, Bror Rexed (1952), who established that the cells of the spinal cord are arranged in layers or laminae.
There are six laminae in the dorsal (Lamina I–VI);
three in the ventral horn (Lamina VII–IX) and an additional column of cells clustered around the central canal known as Lamina X (Fig. 6.4).
At the outer part of the dorsal horn there is a clear zone visible to the naked eye and it was because of this appearance that the Italian anatomist Luigi Rolando (1773–1831) in 1824 named it the substan-tia gelatinosa. Some neurophysiologists (Wall 1990) state that the substantia gelatinosa includes both Lamina I and II, whilst others (Bowsher 1990, Fields 1987, p. 44) call Lamina II the substantia gelatinosa and Lamina I the marginal zone.
The thin unmyelinated C nociceptive afferents terminate mainly in Laminae I and II where their axon terminals secrete either Substance P or vasoactive intestinal polypeptide (VIP) according to whether they arise from somatic structures or visceral ones respectively (Thompson 1988).
The medium-sized myelinated A-delta noci-ceptive afferents terminate chiefly in Laminae I, II and V.
In contrast to this, most of the large diameter myelinated A-beta low-threshold mechano-receptive afferent fibres, on entering the spinal cord, pass directly up the dorsal column to end in the medulla oblongata’s gracile and cuneate nuclei.
Axons from these nuclei then form the medial lemi-niscus and this, after decussating in the medulla, terminates principally in the ventrobasal thalamus.
However, what is of particular importance, as far as the pain modulating effect of A-beta afferent activity is concerned, is that the medial leminiscus is con-nected, via the anterior pretectal nucleus, to the peri-aqueductal grey area in the midbrain at the upper end of the opioid peptide mediated serotinergic descending inhibitory system (see p. 61).
Therefore, as a result of these connections, A-beta afferent activity is enabled to block the C afferent input to the spinal cord by promoting activity in this descending system (Bowsher 1991). In addition, Todd & Mackenzie (1989) have shown that large diameter A-beta nerve fibres, on entering the spinal cord, give off branches which make contact with gamma-aminobutyric acid mediated interneurons (GABA-ergic interneurons) in Lamina II. These also exert an inhibitory effect on the C afferent input to the cord.
It therefore follows that high-frequency, low-intensity transcutaneous nerve stimulation (TENS), which exerts its pain modulating effect by recruit-ing A-beta nerve fibres (Ch. 9), achieves this effect partly by these fibres, when stimulated, evoking activity in the opioid peptide-mediated descend-ing inhibitory system, and partly by them evokdescend-ing activity in dorsal horn GABA-ergic interneurons (Fig. 6.5).
Dorsal horn transmission cells The neurons in the dorsal horn responsible for transmitting sensory afferent information to the brain are of three main types – low-threshold mechanoreceptor cells, nociceptive-specific cells, and wide dynamic range cells.
Low-threshold mechanoreceptor cells, found chiefly in Laminae III and IV, transmit to the brain information received via large diameter low-threshold A-beta afferents that have become
Frontal cortex
Post-central gyrus of the parietal lobe (somatosensory cortex)
Link between NST pathway and PAG Periaqueductal grey area (PAG) of midbrain Red nucleus
Laterally situated NST pathway Medially situated PSRD pathway
Nucleus raphé magnus in medulla
D L Funiculus
DH
A-delta fibres C-afferent fibres VIIth nucleus
Vth nucleus
Limbic system
Thalamus
I II III IV V
VI VII
VIII IX IX
X
Figure 6.4 Diagramatic representation of the course taken by the two ascending ‘pain’ pathways – the neospinothalamic (NST) pathway carrying A-delta ‘pin prick’ information, and the paleo-spino-reticulo-diencephalic pathway carrying C
‘tissue damage’ information. It also shows the descending inhibitory pathway – the dorsolateral funiculus (DLF) which links the periaqueductal grey area (PAG) and the nucleus raphé magnus (NRM) with the dorsal horn (DH).
To thalamus
Pretectal nucleus
PAG
NST pathway
DLF
SG SG
G
ENK ENK
C NRM
A-beta
A-delta DCN ML
Figure 6.5 Tissue damage nociceptive information reaches the substantia gelatinosa (SG) vis C afferent fibres.
The onward transmission of this information is inhibited by enkephalinergic interneurons (ENK) which are activated via A-delta ‘pin prick’ fibres as they enter the cord and via serotinergic inhibitory fibres that descend in the dorsolateral funiculus (DLF) from the nucleus raphé magnus (NRM) in the medulla and periaqueductal grey area (PAG) in the midbrain (the descending inhibitory system). The descending inhibitory system is brought into action either via collaterals which link the neospinothalamic ‘A-delta pin prick’ ascending pathway (NST) with the PAG: or via collaterals which form a link between the PAG and the medial leminiscus (ML), which arises from dorsal column nuclei (DCN) connected to A-beta fibres in the dorsal column. The onward transmission of tissue damage nociceptive information in C afferent fibres is also inhibited by inhibitory GABA-ergic interneurons (G) which are activated by the A-beta fibres that enter the substantia gelatinosa.
(Based on Dr David Bowsher’s diagram in the Journal of the British Medical Acupuncture Society (1991). Reproduced with permission).
activated by some innocuous stimulus such as light touch to the skin.
Nociceptive-specific cells, principally present in Lamina I but also to a lesser extent in Lamina IV and V (Christensen & Perl 1970), as their name implies, are only excited by nociceptive primary afferents. Somewhat paradoxically, a study by Mayer et al (1975) suggests that interpretation of pain is related more closely to activity in wide dynamic range cells than it is to that in nociceptive-specific ones.
Wide dynamic range cells, which are present in all laminae but are mainly concentrated in Lamina V and to a lesser extent in Lamina I, transmit to higher centres information received via A-beta, A-delta and C afferents. The message they pass on to the higher centres therefore varies according to whether the peripherally applied stimulus is innocuous or noxious. It thus follows that the sensation ultimately experienced may be one of touch, or the brief local-ized pricking type of ‘first’ pain, or the persistent wide-spread aching type of ‘second’ pain.
The wide-dynamic range cells that receive small diameter afferents from the heart and abdominal organs also receive low-threshold afferents from the skin (Cervero 1983). Melzack & Wall (1988, p. 173) suggest that this may be the reason why pain from a pathological lesion in some internal structure may appear to be coming from the sur-face of the body and why in such circumstances the skin is liable to be tender.
It needs to be understood that none of these transmission cells possess physiological specificity, as they are capable of changing from one to another depending on the excitability of the spinal cord.
For example, animal experiments have shown that, under light barbiturate anaesthesia, nociceptive-specific cells become wide dynamic range ones (Collins & Ren 1987) and that under deeper anaes-thesia the latter become nociceptive specific (Dickhaus et al 1985).
Dorsal horn inhibitory interneurons In Laminae I and II there are interneurones that contain inhibitory neurotransmitters such as enkephalin and gamma-aminobutyric acid (Todd et al 1992).
Dorsal horn neuroplasticity From animal experi-ments it is clear that the effect of prolonged or
repetitious high-intensity stimulation of nocicep-tors is to bring about a progressive build-up of excitability in dorsal horn-situated nociceptive transmission neurons (wind-up) and the eventual sensitisation of them (central sensitisation).
Central sensitisation develops when these neurons’ N-methyl-D-aspartate (NMDA) recep-tors become activated. This is brought about as a result of the co-release of excitatory amino acids (glutamate and aspartate) and neuropeptides (SP and calcitonin gene-related peptide). The NMDA receptor channel is normally blocked by a magne-sium ‘plug’. The effect of activating these trans-mission neurons is to remove this ‘plug’ and by so doing allow an influx of calcium ions into them.
This in itself gives rise to considerable cell hyperex-citability. It also leads to the expression of onco-genes such as c-fos which brings about long-term changes in the responsiveness of these neurons;
to the production of nitrous oxide which is now believed to contribute to the maintenance of pain;
and to the activation of a number of secondary messengers including inositol triphosphate and diacylglycerol that further increase the excitability of the cells (Coderre et al 1993).
The effects of this central sensitisation are to increase the receptive fields of these dorsal horn nociceptive neurons; to bring about the develop-ment of large diameter A-beta sensory afferent-mediated hyperalgesia and allodynia; and to cause the nociceptive pain to persist (Cousins & Power 1999; Doubell et al 1999).
As will be discussed in Chapter 7 there are grounds for believing that central sensitisation not infrequently takes place in the myofascial pain syn-drome and invariably does so in the fibromyalgia syndrome.