LA CIRCULACIÓN EN LOS SERES HUMANOS

In the previous section, one o f the most evident changes in the periphery follow ing nerve injury is the development o f ectopic activity. Since action potential generation is

dependent upon ion channel activity interest in the changes in the expression o f ion

channels arose. Perhaps one o f the first indications that the expression o f ion channels changed follow ing nerve injury was observed by M eiri et al. (1981). They reported that the membrane properties at the regenerating tip o f injured axons were different from normal membrane properties and there was an increase in the Na"^, Ca^"^ and

conductance o f the resting membrane (Meiri et al. 1981).

Sodium channels

Voltage-gated sodium channels elicit an inward transmembrane current, which

depolarises the cell membrane and therefore are vital to action potential generation. To date, ten distinct sodium channels have been identified and different genes encode them. A ll sodium channel a-subunits consist o f four hom ologous domains, which form a

single, voltage-gated aqueous pore and are associated with ^-subunits that can m odify '

channel properties and interact with extracellular matrix proteins (W ood and Baker 2001). D R G neurones have been shown to have multiple different sodium currents that can be distinguished by their various voltage dependencies, kinetics and sensitivity to tetrodotoxin (TTX), providing evidence for the existence o f several types o f V G SC s on D R G neurones (Black et al. 2001). In fact, 8 o f the 10 sodium channels are detectable in D R G neurones (see Table 1.4.3). Furthermore, D R G and trigeminal neurones are the only neuronal cell types to express significant m R N A levels o f three sodium channels: N a v l.7 /P N 1 channels are expressed on almost all D R G neurones, N a v l.8/S N S

(sensory-neurone-specific)/PN3 are preferentially expressed in small and m edium DR G neurones and N a v l.9 /N a N sodium channels are m ainly found on small DRG neurones for (references see Black et al. 2001).

Table 1.4.3 Voltage-gated Na'^ channel a -subunits o f sensoiy neurones - adapted from (Wood and Baker 2001) TTX -s, TTX sensitive; TTX -r, TTX resistant

N a v l.l Type I TTX-S Present

Nav 1.2 Type II TTX-S Present

Nav 1.3 Type III TTX-s U pregulated after nerve injury

N a v l.4 SkM TTX-s Absent

N avl.5 Cardiac TTX -r Absent

N av l.6 N aC h6 TTX -s Abundant

Nav 1.7 P N l TTX-s Abundant

Nav 1.8 SN S /P N 3 TTX -r Abundant

Nav 1.9 N aN TTX -r Abundant

Nax N aG 7 Present

N erve injury causes the disruption of axonal transport, thus abnorm al accum ulations of sodium channels have been found at the tips of injured axons (D evor et al. 1989; England et al. 1994; England et al. 1996) and found to be N av i.3/T ype III and N avl.S /S N S (Novakovic et al. 1998; Black et al. 1999). This accum ulation of sodium channels is thought to cause a decrease in the action potential threshold and hence spontaneous ectopic activity. Following nerve injury, both N avl.8/S N S m RNA and Nav 1.9/NaN m RN A are dow nregulated in the D R G (Dib-H ajj et al. 1996; Dib-Hajj et al. 1998; Dib-Hajj et al. 1999). Furthermore, N av 1.3/Type III m RNA , which is normally only expressed developm entally, is upregulated follow ing nerve injury (W axman et al.

1994; Dib-Hajj et al. 1999). As yet there are no specific antagonists are available for the sodium channel subtypes, how ever selective knock-dow n of N avl.8/S N S reversed allodynia in SN L rats (Porreca et al. 1999).

Calcium channels

Several calcium channel subtypes have been identified; low-voltage activated T-type and high-voltage activated N-, L-, P/Q- and R-types. H igh-voltage activated calcium channels

consist o f an a , subunit that forms the pore o f the channel with P and y subunits

that modulate the subunit (Walker and D e Waard 1998). Alternative splicing o f the

gene generates P- and Q-type channels, encodes N -type, and a^p

encodes L-type channels and Œjq, and form T-type channels. The gene

responsible for R-type channels may be but this has not been firmly established

(Snutch et al. 2001). L-type calcium channels do not have a major role in nociception and L-type channel blockers are used in the treatment o f cardiovascular disease (Snutch et al. 2001). T-type calcium channels have been found in the dorsal hom and sensory ganglia (Talley et al. 1999) but currently lack specific pharmacological agents. However, an anticonvulsant euthosuximide, is a relatively specific T-type antagonist and was shown to inhibit dorsal hom neurones in a similar manner both before and after nerve injury (Matthews and Dickenson 2001a). P/Q-type channels are found in the dorsal hom and have been implicated in inflammation (Sluka 1998). H owever, selective block o f P/Q-type channels by (o-agatoxin IV A had the same effect in normal and neuropathic

rats (Matthews and Dickenson 2001b). The m ost influential calcium channel follow ing neuropathy appears to be the N-type calcium channel (Dickenson et al. 2001). N-type

channels are found in the superficial dorsal hom and follow ing nerve injury the a , g and