PLAN DE GESTIÓN DE RESIDUOS HOSPITALARIOS Y SIMILARES COMPONENTE INTERNO

whereas the non-peptidergic IB4-positive population distribute to Hi. Lamina I contains nociceptive-specific (mechanical, heat and cold) and WDR dorsal horn neurones, the majority o f which project to the SCT, STT and spinoreticular tract (SRT) as w ell as the periaqueductal grey (PAG), PEN and nucleus submedius. In contrast, the cells o f laminae II only project locally to surrounding segments and not

laminae, such as the WDR neurones in V. Morphologically they can be distinguished into excitatory ‘stalk’ cells found in IIo and the inhibitory GAB A neurotransmitter containing ‘islet’ cells found in Hi. Furthermore neurones o f IIo receive input from high-threshold and thermoreceptive afferents and those o f Hi receive low-threshold mechanical information (see Sorkin & Carlton, 1997).

Anatomically, and thus functionally, there exists a considerable amount o f convergence within the dorsal horn o f the spinal cord, and this is largely mediated by the WDR neurones located predominantly in lamina V (also IV, VI and some superficially). Non-noxious and noxious primary afferent inputs, directly from Ap- fibres and via a multi-synaptic pathway from AÔ- and C-fibres, all terminate upon these multireceptorial cells. WDR neurones display a dynamic response over a wide stimulus range such that they can encode stimulus intensity. WDR cells o f lamina V then project to STT, SMT, SRT, SCT, SHT and PSDC. The supraspinal targets o f these ascending tracts are all important in the transmission o f nociceptive information. In particular the STT terminates in the thalamus, which is a very important in encoding type, temporal pattern, intensity and topographical information regarding pain before relay to the cortex. Via interactions with cortical and limbic regions it is also responsible for sensory-discriminative and emotional facets o f pain perception (see Craig & Dostrovsky, 1997, for further discussion).

1.3.2.3 Abnormal Dorsal Horn Reorganization

Damage to peripheral nerve can impact upon the anatomical organization o f primary afferent termination patterns within the dorsal horn o f the spinal cord such that abnormal changes arise that may underlie some o f the experienced neuropathic pain symptoms and characteristics. As might be expected it is likely that peripheral nerve injury results in loss o f primary afferent input into the dorsal horn, indeed after peripheral nerve transection a substantial loss o f C-fibre terminals has been observed in lamina II (Castro-Lopes et aL, 1990). Further to this deafferentation, nociceptive input to dorsal horn neurones is reduced, which could underlie the occurrence o f sensory deficits experienced by neuropathic pain patients (Fields et aL, 1998).

Contrary to this, deafferentation has the ability to induce primary afferent regeneration and repair activity, as observed in the periphery. Whilst this can be beneficial in restoring original circuitry, more often than not in the development o f neuropathic pain, aberrant re-wiring may underlie the positive neuropathic pain symptoms such as allodynia. It has been demonstrated by the use o f cholera toxin B- conjugated (CB)-HRP tracing that the central projections o f intact AP-fibres within the deep dorsal horn, that convey non-noxious information, may make abnormal dorsal-oriented sprouts into lamina II after axotomy (W oolf et aL, 1992). This is also evident after SNL (Lekan et aL, 1996) and CCI (Nakamura & Myers, 1999). Alongside the previously mentioned induction o f substance P expression in AP- fibres, sprouting may permit innocuous input to reach the superficial dorsal horn, a region synonymous with pain transmission, whereby their terminations may activate nociceptive-specific spinal cord neurones (see W oolf et aL, 1995). This appears a rational mechanism for touch-evoked pain however it is difficult to prove clinically.

N ew evidence has come to light, which may support a role for anatomical sprouting in the dorsal horn. After nerve crush-induced neuropathic pain innocuous stimulation o f the target tissue evoked c-fos, an immediate early gene product expressed after noxious neuronal activation, in superficial dorsal horn neurones and activated PBN neurones, a major supraspinal termination site in the rat for nociceptive-specific superficial dorsal horn neurones (Bester et aL, 2000). Innocuously activated Ap-fibres, could activate nociceptive specific neurones in the superficial dorsal horn if their termination pattern extended dorsally. Additionally or alternatively, activation o f superficially terminating, low-threshold mechanoreceptive C-fibres could be involved (Vallbo et aL, 1999). Also, low-threshold stimulation has been demonstrated to evoke synaptic potentials in lamina II neurones 3 weeks after nerve injury (Kohama et aL, 2000), an area which normally only responds to high threshold stimuli.

AP-fibre sprouting could possibly be triggered by the physical absence o f normal C-fibre afferent terminals in lamina II after their degeneration. (Doubell et aL, 1997), yet dorsal rhizotomy produced lamina II vacancy was shown not to induce

factors and chemoattractants, yet this is still yet to be proven. Suggestions include a possible upregulation o f growth related proteins, such as GAP-43 (W oolf et aL,

1990), and injured C-fibre terminal secretion o f an Ap-fibre attractant (Doubell et aL, 1997; Mannion et aL, 1998). AP-fibre sprouting after axotomy has been demonstrated to be inhibited by application o f NGF, but since large diameter DRG cells to not express the appropriate TrkA receptor, the familiar explanation o f ‘disrupted axonal transport o f peripherally-derived NG F’ seems unfeasible as a causal mechanism.

Certain doubts surround the phenomena o f AP-fibre sprouting and its functional contribution to neuropathic pains. Some discrepancies have come to light concerning the specificity o f CB-HRP utilized to identify Ap-fibres and their sprouting. It has been proposed that after axotomy, small nociceptive neurones express novel cell membrane glycoconjugates that mediate the uptake o f CB, evident as an altered neuronal labelling profile after nerve injury (Tong et aL, 1999). This might imply that CB-HRP labelling in superficial laminae following peripheral nerve damage may not represent Ap-fibre sprouting. However others do not describe injury-induced alterations in DRG neuronal cell size distribution o f CB-HRP (Bennett et aL, 1996). As to the functional relevance o f sprouting, it cannot be the sole mediator o f allodynia for several reasons. Electrophysiological studies have shown that established behaviourally antiallodynic drugs have little impact upon the Ap-fibre-evoked response (Chapman et aL, 1998a; Suzuki et aL, 1999). Furthermore, the time scale o f functional reorganization o f AP-fibre terminals does not correlate with the rapidity with which allodynia can be manifest. Allodynia is observed 2 days after nerve injury (Bennett & Xie, 1988; Shir & Seltzer, 1990; Kim & Chung, 1992), yet CB-HRP labelling (W oolf et aL, 1995) and low threshold evoked neuronal activity (Kohama et aL, 2000) is not observed in lamina II until one and three weeks, respectively. Structural reorganization as a basis for allodynia cannot be responsible for the induction o f allodynia yet it may have relevance to its maintenance since sprouting demonstrated by CB-HRP labelling is maximal two weeks after nerve injury and still apparent at six months (W oolf et aL, 1995).