Dorsal horn

As a neurotransmitter in the sensory nervous system, high levels of substance P are found in the dorsal horn of the spinal cord as well as in peripheral sensory nerve terminals. However, substance P also plays a significant role as a neuromodulator in the central, sympathetic, and enteric nervous system. NKA and NKB are also localized selectively in the CNS. 

The locus cemleus is important for the regulation of attentional states and autonomic nervous system activity. It has also been implicated in the autonomic and stress-like effects of opiate withdrawal. A noradrenergic pathway originating from the locus cemleus which descends into the spinal cord is part of the descending inhibitory control system, which has an inhibitory effect on nociceptive transmission in the dorsal horn. 

Afferent input from cutaneous and visceral nociceptors is known to converge on spinal neurons, which accounts for the referral of pain between visceral and cutaneous structures (e.g. cardiac pain gets referred to the chest and left upper arm in patients suffering from angina pectoris). Projection neurons in the spinal dorsal horn project to cell nuclei in supraspinal areas such as the thalamus, brainstem and midbrain. Of these, the synaptic junctions in the thalamus play a very important role in the integration and modulation of spinal nociceptive and non-nociceptive inputs. Nociceptive inputs are finally conducted to the cortex where the sensation of pain is perceived (Fig. 1). The mechanisms via which the cortex processes nociceptive inputs are only poorly understood. 

P2X X CM CL Smooth muscle, platelets, cerebellum, dorsal horn spinal neurons a, 3-meATP = ATP = 2-MeSATP, L-p.y-meATP (rapid desensitization) TNP-ATP, lp5l, NF023, NF449 Intrinsic cation channel (Ca2+ and Na+)... 

The substantia gelatinosa is part of the dorsal horn of the spinal cord, also called lamina II . The substantia gelatinosa is made up almost exclusively of interneurons (both excitatory and inhibitory), some of which respond only to nociceptive inputs, while others respond also to non-noxious stimuli. 

Fig. 4.1 Hypothetical model of pathogenesis of pain in DSP. (1) Injury of peripheral nerve fibers due to multifocal inflammation and secreted macrophage activation products results in abnormal spontaneous activity of neighboring uninjured nociceptive fibers ( peripheral sensitization ). (2) Furthermore, the aberrant inflammatory response in DRG leads to alterations in neuronal sodium and calcium channel expression and ectopic impulse generation. (3) This results in central remodeling within the dorsal horn due to A-fiber sprouting and synaptic formation with pain fibers in lamina 11, and maintenance of neuropathic pain ( central sensitization ). Reproduced with permission from (Keswani et al. 2002)...

Figure 1.6 Presynaptic inhibition of the form seen in the dorsal horn of the spinal cord, (a) The axon terminal (i) of a local neuron is shown making an axo-axonal contact with a primary afferent excitatory input (ii). (b) A schematic enlargement of the synapse, (c) Depolarisation of the afferent terminal (ii) at its normal resting potential by an arriving action potential leads to the optimal release of neurotransmitter, (d) When the afferent terminal (ii) is already partially depolarised by the neurotransmitter released onto it by (i) the arriving acting potential releases less transmitter and so the input is less effective...

Figure 13.3 Whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs) from dorsal horn neurons of rat (prenatal P2-13) spinal cord slices. The normal evoked EPSC of about 160pA obtained by focal stimulation of nearby tissue was dramatically reduced by addition of a cocktail (CABS) of CNQX 10 pM, D-APV 50 pM, bicuculline 10 pM and strychnine 5 pM to block glutamate, GABAa and glycine receptors. The small residual EPSC shown was blocked by the ATP P2 receptor antagonist suramin and is therefore probably mediated by released ATP. (Prom Bardoni et al. 1997 and reproduced by permission of the Journal of Neuroscience)...

Bardoni, R, Goldstein, PA, Justin Lee, C, Gee, JG and MacDermott, AB (1997) ATP P2x receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord. J. Neurosci. 17 5297-5304. 

The large diameter A/l-afferent fibre enters the dorsal horn of the spinal cord through the medial division of the dorsal root. It then descends through the medial region of lamina I or II, or alternatively, curves around the medial (central) edge of the dorsal horn down to the ventral horn. On reaching deeper laminae, laminae IV and V, the AjS-fibres ascend back up into laminae III and IV where they repeatedly subdivide and form a characteristic termination pattern. The densest arborisation appears to occur in lamina III. Axons originating from specialised muscle stretch receptors have collaterals that pass ventrally to make monosynaptic connections with neurons of laminae V, VI and VII. Some also extend to laminae VIII and IX of the ventral horn where they synapse directly onto motor neurons and form the basis of monosynaptic reflexes. 

The termination pattern exhibited by A -fibres is entirely different from that of large AjS-fibres. A -fibres travel extensively in Lissauer s tract, overlying the dorsal horn and their terminals form a plexus at the surface of the spinal cord A(5-fibres from high-threshold mechanoreceptors distributed to laminae I, II outer and V. Projections also appear to terminate on the contralateral side, in lamina V. A(5-fibre innervations from deep tissues (muscles and joint) have been shown to terminate exclusively in lamina I, or in laminae IV and V. 

SENSORY TRANSMISSION IN THE SPINAL CORD Morphology of the spinal cord dorsal horn... 

The spinal cord is classically divided into white and grey matter (Fig. 21.2). The grey matter can be organised into ten different laminae, which run continuously along the entire length of the spinal cord. Within a given section of a spinal cord, each lamina can be seen as a layer of functionally distinct cells. Laminae I to VI comprise the dorsal horn, laminae VII to IX the ventral horn, and lamina X is the substantia grisea centralis which surrounds the central canal. 

Lamina I forms the outer layer of the dorsal horn and contains the large marginal cells of Waldeyer and plays an important role in nociception since it is the layer in which... 

Lamina VI forms the base of the dorsal horn and can be found only in certain levels of the spinal cord, the cervical and lumbar regions. Few data have been reported on the cell composition of lamina VI. Cells of lamina VI are small compared to those of lamina V and some axons appear to contribute to the STT and SCT pathways. 

The arrival of action potentials in the dorsal horn of the spinal cord, carrying the sensory information either from nociceptors in inflammation or generated both from nociceptors and intrinsically after nerve damage, produces a complex response to pain. Densely packed neurons, containing most of the channels, transmitters and receptors found anywhere in the CNS, are present in the zones where the C-fibres terminate... 

Figure 21.3 Wind-up in a dorsal horn neuron. Note the increased response to a constant peripheral stimulus as the NMDA receptor is activated. (Unpublished data)...

Opioids act in the brain and within the dorsal horn of the spinal cord, where their actions are better understood. The actions of opioids important for analgesia and their side-effects involve pre- and postsynaptic effects (1) reduced transmitter release from nerve terminals so that neurons are less excited by excitatory transmitters, and (2) direct inhibitions of neuronal firing so that the information flow from the neuron is reduced but also inhibitions of inhibitory neurons leading to disinhibition. This dual action of opioids can result in a total block of sensory inputs as they arrive in the spinal cord (Fig. 21.5). Thus any new drug would have to equal this dual action in controlling both transmitter release and neuronal firing. 

The opiate receptors in the spinal cord are predominantly of the mu and delta type and are found in the C-fibre terminal zone (the substantia gelatinosa) in the superficial dorsal horn. Considerable numbers of ORL-1 receptors are also found in this area. Up to 75% of the opiate receptors are found presynaptically on the C-fibre terminals and when activated inhibit neurotransmitter release. The opening of potassium channels will reduce calcium flux in the terminal and so there will be a resultant decrease in... 

The cell bodies of second-order sensory neurons are found in the dorsal horn. These neurons receive input from afferent neurons (first-order sensory neurons) entering the CNS from the periphery of the body through the dorsal... 

As discussed, the first-order neuron is the afferent neuron that transmits impulses from a peripheral receptor toward the CNS. Its cell body is located in the dorsal root ganglion. This neuron synapses with the second-order neuron whose cell body is located in the dorsal horn of the spinal cord or in the medulla of the brainstem. The second-order neuron travels upward and synapses with the third-order neuron, whose cell body is located in the thalamus. Limited processing of sensory information takes place in the thalamus. Finally, the third-order neuron travels upward and terminates in the somatosensory cortex where more complex, cortical processing begins. 

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