Desensitisation

A condition in which a receptor is unresponsive despite the presence of agonist also referred to as a refractory state . Typically this state is the consequence of prolonged exposure to agonist, and occurs after receptor activation it is a built in mechanism to limit a receptor s effects. Mechanistically the desensitised state differs from the resting, closed state of a receptor because in the latter state, a receptor can respond to agonist. This difference predicts that these states are structurally distinct. The desensitised state may also be stabilised by very low concentrations of agonist, such that no measurable activation of the receptor precedes it. Desensitisation is an intrinsic property of many receptors but can also be influenced by other interactions or modifications, such as phosphorylation. 

Agonists activate nAChR by binding to the agonistbinding site (Fig. 1). They can remain bound (often with higher affinity) when the nAChR enters the desensitised state. 

Descending Inhibitory Pathway Desensitised State Desensitization Desmoplakin... 

Figure 3.4 Transmembrane topology of a 7-TM domain G-protein receptor such as the P-adrenoceptor. Agonist binding is predicted to be within the transmembrane domains. The extracellular structure is stabilised by the disulphide bond joining the first and second extracellular loop. The third intracellular loop is the main site of G-protein interaction while the third intracellular loop and carboxy tail are targets for phosphorylation by kinases responsible for initiating receptor desensitisation...

The GABAb receptors were the first G-protein-coupled receptors to be observed to form functional heterodimers (Bowery and Enna 2000) where two G-protein molecules come together to act as a dimer to enhance their combined response. A similar effect has recently also been described for dopamine and somatostatin receptors (Rocheville et al. 2000) and it is likely that this may occur with other G-protein-coupled receptors. The significance of this in terms of the pharmacology of the receptors is unclear, or indeed whether dimerisation affects mechanisms such as desensitisation. 

Heterologous desensitisation refers to the desensitisation of the response to one agonist by the application of a different agonist. For example, desensitisation of a response to adrenaline by application of 5-HT is mediated by protein kinase A or protein kinase C because these kinases can phosphorylate receptors which are not occupied by agonist. Phosphorylation disrupts the receptor-G-protein interaction and induces the binding of specific proteins, arrestins which enhance receptors internalisation via clathrin-coated pits. Thus desensitisation of G-protein-coupled receptors results in a decrease in the number of functional receptors on the cell surface. 

What the overall physiological consequences of either an increase or decrease in 5-HT transmission in any brain region might be is beyond the scope of this chapter. However, it is certain that the diverse cocktail of 5-HT receptors in every brain region gives scope for flexibility and refinement in the 5-HT response that would not be possible if there were only the two receptors identified by Gaddum. This flexibility applies not only to the qualitative features of the response but also its duration. Another dimension of sophistication is added by the different affinities of 5-HT for each of its receptors and differences in their rates of desensitisation. An interesting discussion of how all these variables could affect overall 5-HT transmission in the brain can be found in Uphouse (1997). 

The reason for this disappointing response is uncertain but may be due to desensitisation of the GABAa receptors, or the actual inhibition of GABA inhibitory neurons through somatic autoreceptors which could disrupt the precise timing of physiological inhibition. Activation of the GABAb receptor with baclofen has no... 

Figure 20.6 Schematic representation of the effects of 5-HT reuptake inhibitors on serotonergic neurons, (a) 5-HT is released at the somatodendritic level and by proximal segments of serotonergic axons within the Raphe nuclei and taken up by the 5-HT transporter. In these conditions there is little tonic activation of somatodendritic 5-HTia autoreceptors. At nerve terminals 5-HTib receptors control the 5-HT synthesis and release in a local manner, (b) The blockade of the 5-HT transporter at the level of the Raphe nuclei elevates the concentration of extraneuronal 5-HT to an extent that activates somatodendritic autoreceptors (5-HTia). This leads to neuronal hyperpolarisation, reduction of the discharge rate and reduction of 5-HT release by forebrain terminals, (c) The exposure to an enhanced extracellular 5-HT concentration produced by continuous treatment with SSRIs desensitises Raphe 5-HTia autoreceptors. The reduced 5-HTia function enables serotonergic neurons to recover cell firing and terminal release. Under these conditions, the SSRI-induced blockade of the 5-HT transporter in forebrain nerve terminals results in extracellular 5-HT increases larger than those observed after a single treatment with SSRIs. (Figure and legend taken from Hervas et al. 1999 with permission)...

More importantly for this discussion is the finding that chronic administration of an antidepressant produces a similar increase in the concentration of extracellular 5-HT in the terminal field together with recovery of neuronal firing. Presumably this is because the prolonged elevation of extracellular 5-HT around the neurons in the Raphe causes progressive desensitisation of the somatodendritic 5-HTia receptors. At this point, inhibition of their firing does not occur and so more 5-HT is released in the cortex (see Hervas et al. 1999). 

A related strategy would be to inactivate the 5-HTib/id autoreceptors which are found on serotonergic nerve terminals and so prevent feedback inhibition of 5-HT release in the terminal field. These drugs would not prevent the impact of indirect activation of 5-HTia receptors, and the reduced neuronal firing, by SSRIs (described above), but they would augment 5-HT release in the terminal field once the presynaptic 5-HTia receptors have desensitised. Selective 5-HTib/id antagonists have been developed only recently but will doubtless soon be tested in humans. 

Dilution or simple mixing with a stable compound is sufficient to stabilise an unstable substance. In the case of a simple mixture with a neutral substance, this stabilisation process is called desensitisation . Thus hardeners such as benzoyl peroxide are nomially in the form of suspensions in heavy esters or oils. This peroxide is mixed with 30% of water by weight. Dynamite is nitroglycerine stabilised with the help of a neutral material. In all these cases, heat that is produced by the potential beginning of decomposition is absorbed by the inert substance. 

An accident of the same nature happened when it was dried with diphosphorus pentoxide. In this case, it is unlikely that the reason for it is the formation of an acetylene salt. The author believes that, since water plays a desensitising role on this compound, it leads to a very unstable pure alcohol when it is removed by strong dehydrating agents. The temperature rise due to the dessicating agent hydration is sufficient to decompose the pure alcohol violently.This interpretation could also be applied to the previous case. 

RDX may be used alone in pressed charges, although for this purpose tetryl is a more general choice. For shell and bomb fillings it is too sensitive alone to initiation by impact and friction and is either desensitised with wax, or else used like PETN in admixture with TNT. RDX may also be compounded with mineral jelly and similar materials to give a useful plastic explosive. 

Simple mixtures of this type have little resistance to water and are suitable for use only under the driest conditions. Many methods have been used for giving water resistance to these explosives, particularly to the milled varieties which tend to be less satisfactory in this respect than the hot mixed compositions. A small proportion of wax may be used, particularly if mixed in hot, but this tends to desensitise the explosive. Greater success is achieved by the addition of calcium soaps such as calcium stearate, in finely divided form. These also cause some desensitisation, but to an extent which is less marked in proportion to the degree of waterproofness achieved. 

Another hazard is that cartridges fired early will cause compression in other holes and thus desensitise the explosive. To overcome this a sensitive explosive is required and one of semi-gelatine type is used in Britain. 

Further properties which a detonating fuse should have are the ability to initiate blasting explosives (tested with suitable relatively insensitive mixtures usually of TNT and ammonium nitrate) resistance to low temperatures without cracking on flexing and to hot storage without desensitisation and toughness to prevent damage from stones, etc. The fuse must always be waterproof and must often withstand diesel oil, which can separate from ANFO. 

Shell for penetrating armour have heavier steel bodies with at least the nose of specially hardened metal. The proportion of explosive is smaller and it must also be exceptionally resistant to detonation by impact, so that the shell can penetrate the armour before the explosive is detonated by the fuze. Suitable fillings are therefore TNT or desensitised TNT/RDX mixtures. The latest armour-piercing projectiles for anti-tank use contain no explosive, but have high density cores made of tungsten. 

In the simpler version of this method, a double based powder of small size is made by conventional solvent methods and thoroughly dried. The required amount of this powder is then placed in a beaker of cellulose acetate or ethyl cellulose and the voids are all filled with desensitised nitroglycerine. The curing process consists of heating to temperatures of the order of 80°C for a prolonged period and on cooling, the mass becomes a gelatinous body similar to cordite or ballistite. 

The effect of adding talc as an inert desensitiser upon the sensitivity of the acetylide has been studied. 

The shock-sensitive nitrate is desensitised by 1-2% of propane, butane, chloroform, dimethyl ether or diethyl ether. 

Gardner, D. L. et al J. Org. Chem., 1964, 29, 3738-3739 It is a dangerously sensitive oil which has exploded on storage, heating or contact with piperidine. Absorption in alumina was necessary to desensitise it to allow non-explosive analytical combustion. 

Three beakers containing lead styphnate were being heated in a laboratory oven to dry the explosive salt. When one of the beakers was moved, all 3 detonated. Other heavy metal salts of polynitrophenols are dangerously explosive when dry [1], The desensitising effect of presence of water upon the friction sensitivity of this priming explosive was studied. There is no effect up to 2% content and little at 5%. Even... 

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