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NEUROTRANSMITTERS AND DRUGS Nociceptive sensory information arriving from primary afferent fibres enters via the dorsal horn and on entering the spinal cord undergoes considerable convergence and modulation buy kamagra polo 100 mg with visa best erectile dysfunction vacuum pump. The spinal cord is an important site at which the various incoming nociceptive signalling systems undergo convergence and modulation and is under ongoing control by peripheral inputs, interneurons and descending controls. One consequence of this modulation is that the relationship between stimulus and response to pain is not always straightforward. The response of output cells could be greatly altered via the interaction of various neurotransmitter systems in the spinal cord, all of which are subject to plasticity and alterations during pathological conditions. 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 PAIN AND ANALGESIA 463 and while excitatory mechanisms are of importance, the role of controlling inhibitory transmitter systems is perhaps paramount. Since glutamate is the main excitatory neurotransmitter in the CNS it is not unexpected to find that the vast majority of primary afferents synapsing in the dorsal horn of the spinal cord, regardless of whether they are small or large diameter, utilise this transmitter. It has an excitatory effect on a number of receptors found on both postsynaptic spinal neurons, leading to a depolarisation via three distinct receptor subclasses, the a-amino-3-hydroxy 5-methyl-4-isoxazeloproprionic acid (AMPA) receptor, the N-methyl-D-aspartate (NMDA) receptors and the G-protein-linked meta- botropic family of receptors. In addition, presynaptic kainate receptors for glutamate have been described in the spinal cord. Most is known about the first two receptors, the AMPA and NMDA receptors, named after chemical analogues of glutamate with selective actions on these sites (see Chapter 11). Glutamate is released in response to both acute and more persistent noxious stimuli and it is fast AMPA-receptor activation that is responsible for setting the initial baseline level of activity in responses to both noxious inputs and tactile stimuli. However, if a repetitive and high-frequency stimulation of C-fibres occurs there is then an amplifica- tion and prolongation of the response of spinal dorsal horn neurons, so-called wind-up (Fig. This enhanced activity results from the activation of the NMDA-receptor. If there are only acute or low-frequency noxious or tactile inputs to the spinal cord the activation of the NMDA-receptor is not possible. The reason is that under normal physiological conditions the ion channel of this receptor is blocked by the normal levels of Mg2‡ found in nervous tissues. This unique Mg2‡ plug of the channel requires a repeated depolarisation of the membrane to be removed and allows the NMDA receptor-channel to be activated. Here it is likely that the co-release of the peptides such as substance P and CGRP that are found in C-fibres with glutamate is responsible for a prolonged slow depolarisation of the neurons and subsequent removal of the block. Not only do AMPA receptor antagonists have no effect on wind-up but the brief depolarisation produced by this receptor would not be expected to produce any pro- longed removal of the block, unlike the long-lasting slow (several seconds) activations caused by peptides. The lack of peptides in large Ab afferent fibres explains the lack of wind-up after low-threshold stimuli. This NMDA receptor activation has been clearly shown to play a key role in the hyperalgesia and enhancement of pain signalling seen in more persistent pain states including inflammation and neuropathic conditions. There are a number of antagonists at the multiple regulatory sites found on the NMDA receptor and its channel, including the licensed drugs, ketamine, a potent channel blocker, and the weaker agents, dextromethorphan and memantine. These drugs have been shown to be antinociceptive in a number of animal models of inflammation and nerve damage and there are also data from volunteer and clinical studies to support this. Overall, these studies indicate that it is likely that aberrant peripheral activity is amplified and enhanced by NMDA-receptor-mediated spinal mechanisms in tissue damage and neuropathic pain and that the receptor is critical for both the induction and maintenance of the pain. Although there is much good clinical evidence for the effectiveness of agents acting as antagonists at the NMDA-receptor complex, especially ketamine, and although some individual patients get good pain relief in nerve injury situations, the majority cannot achieve complete pain control. This is partly because adequate dosing is prevented by the narrow therapeutic window of the existing drugs. Note the increased response to a constant peripheral stimulus as the NMDA receptor is activated. These may include drugs acting on subtypes of the receptor (NR2B receptor antagonists are analgesic but side-effects have not been fully evaluated), drugs with different use-dependent block of the channel or more practically, use of low-dose NMDA blockers in combination with another agent. As neurons become more active, then ion channels, other than sodium channels, open in their membranes. There are a number of voltage-operated calcium channels (see Chapter 3) that are critical for both transmitter release and neuronal excitability. Successful results in animals with agents that block neuronal voltage-sensitive calcium channels would also suggest that there is an increase in central neuronal excitability after both inflammation and nerve damage. N-type channels, blocked by o-conotoxin, a marine snail toxin, have been shown to play a key role in behavioural allodynia and the neuronal responses to low- and high-threshold natural stimuli after nerve damage, and in the C-fibre-evoked central hyperexcitability that follows inflammation. Blockers of this channel (SNX-111 or o-conotoxin) are considerably more effective after nerve injury (spinal nerve ligation) and since the channel is voltage operated then these results again suggest increased excitability of the spinal cord after injury.

RVEDP cheap 100 mg kamagra polo with visa erectile dysfunction treatment in kolkata, right ventricular end-diastolic pressure; SVR, systemic vascular resistance. Small type represents compensatory changes that return variables toward the original values. These factors, together with neural and 30 minutes, a 10% loss of blood volume into the interstitial myogenic responses and the muscle and respiratory pumps, space can occur. This loss, coupled with the 550 mL dis- play a significant role during the seconds and minutes fol- placed by redistribution from the central blood volume into lowing standing (Fig. The combination of all of the legs, causes central blood volume to fall to a level so low these factors minimizes net capillary filtration, making it that reflex sympathetic nerve activity cannot maintain car- possible to remain standing for long periods. Diminished cerebral blood flow and a loss of consciousness (fainting) result. Arteriolar constriction due to the increased reflex sym- Long-Term Responses Defend Venous pathetic nerve activity tends to reduce capillary hydrostatic Return During Prolonged Upright Posture pressure. However, this alone does not bring capillary hy- In addition to the relatively short-term cardiovascular re- drostatic pressure back to normal because it does not affect sponses, there are equally important long-term adjustments the hydrostatic pressure exerted on the capillaries from the to orthostasis. The muscle pump is the most important factor bed (or astronauts not subject to the force of gravity). The people who are bedridden, intermittent upright posture alternate compression and filling of the veins as the muscle does not shift the distribution of blood volume from the pump works means the venous valves are closed most of the thorax to the legs. When the valves are closed, the hydrostatic column tral blood volume (and pressure) is greater than in a person of blood in the leg veins at any point is only as high as the who is periodically standing up in the presence of gravity. The average increase in central blood volume caused by ex- The myogenic response of arterioles to increased trans- mural pressure also acts to oppose filtration. As discussed earlier, raising the transmural pressure stretches vascular smooth muscle and stimulates it to contract. This is espe- Blood cially true for the myocytes of precapillary arterioles. The volume Atrial Arterial elevated transmural pressure associated with standing causes pressure volume a myogenic response and decreases the number of open cap- illaries. With fewer open capillaries, the filtration rate for a AVP ANP Medullary cardiovascular center: increased given capillary hydrostatic pressure imbalance is less. Blood loss in- fluences sodium and water excretion by the kidney via several pathways. All these pathways, combined with an increased intake of salt and water, restore the extracellular fluid FIGURE 18. These responses occur longed standing, capillary filtration reduces ve- later than those shown in Figures 18. Without the compensatory events that result in the pathways responsible for stimulating an increased intake of salt changes shown in small type, prolonged standing would in- and water are not shown. CHAPTER 18 Control Mechanisms in Circulatory Function 303 tended bed rest results in reduced activity of all of the path- Aldosterone acts on the distal nephron to cause in- ways that increase blood volume in response to standing. Aldosterone released from the adrenal cortex day and is quantitatively significant after a few days. Wa- point, standing becomes difficult because blood volume is ter intake is determined by thirst and the availability of not adequate to sustain a normal blood pressure. This Increased plasma osmolality, sensed by the hypothalamus, increase, proportioned between the extrathoracic and in- results in both thirst and increased AVP release. Thirst and trathoracic vessels, augments stroke volume during stand- AVP release are also increased by decreased stretch of ing. If blood volume is not maintained by intermittent erect baroreceptors and cardiopulmonary receptors. Renal arteriolar vasoconstric- The long-term regulation of blood volume is driven by tion associated with increased sympathetic nerve activ- changes in plasma volume accomplished by sympathetic ity produced by standing reduces the glomerular filtra- nervous system effects on the kidneys; hormonal changes, tion rate. This results in a decrease in filtered sodium and including RAAS, AVP, and ANP; and alterations in pressure tends to decrease sodium excretion. Regulation of the precise quantities of wa- control of extracellular fluid volume is determined by the bal- ter and sodium that are excreted maintains the correct ance between the intake and excretion of sodium and water. Sodium excre- The distribution of extracellular fluid between plasma tion is much more closely regulated than sodium intake. Ex- and interstitial compartments is determined by the balance cretion of sodium is determined by the glomerular filtration of hydrostatic and colloid osmotic forces across the capil- rate, the plasma concentrations of aldosterone and ANP, and lary wall. Retention of sodium and water tends to dilute a variety of other factors, including angiotensin II.

It is now known that the GABAA receptor comprises different combinations of subunits order 100 mg kamagra polo with visa erectile dysfunction treatment chandigarh, probably in a pentameric complex (see Chapter 11), and so it might even be possible to develop drugs that target different subunits, thereby increasing their functional specificity. One such compound has already been developed, the imidazopyridine zolpidem (Fig. Notwithstanding this selectivity, zolpidem turns out to be a potent hypnotic agent. Zopiclone is another hypnotic, available in the clinic; this drug displaces benzodiazepines from the GABAA receptor but lacks subunit selectivity and does not seem to target precisely the same binding domain as the benzodiazepines. If this was the case then other agents that augment GABAergic transmission such as inhibitors of GABA uptake (e. Indeed, there are reports of their anti-anxiety effects in patients receiving these treatments for relief of epilepsy. There is also some supporting evidence from preclinical studies but the behavioural effects of these drugs in animal models are less robust than are those of the benzodiazepines. It remains to be seen whether this is because they are just less effective anti-anxiety agents than the benzodiazepines or whether existing preclinical models show a bias that detects preferentially the anti-anxiety effects of benzodiazepines. This is regrettably confusing because this receptor has now been found in the brain also (Awad and Gavish 1987). These benzodiazepine receptors differ from those described above in a number of important respects, not least because they do not affect, nor are they affected by, GABA binding. They also have their own specific ligands: the isoquinolone, PK 11195, and the benzodiazepine, Ro 4864, neither of which binds to the GABAA receptor. Another difference is that these peripheral benzodiazepine receptors are located mainly intraneuronally, on mitochondrial outer membranes, rather than on the plasma membrane. In the brain, they are associated with glial cells but in the periphery they are found in a range of tissues, including mast cells and platelets. Their function is still a matter of intense debate but one possibility is that they regulate cholesterol uptake and, secondary to this, the synthesis of neurosteroids (Do Rego et al. Since neuro- steroids also have a binding domain on the GABAA receptor, there might be some indirect functional coupling between these two types of receptors after all. Other possible, albeit controversial, functions of these receptors are reviewed in Doble and Martin (1996). OTHER LIGANDS FOR THE BENZODIAZEPINE RECEPTOR Among the early indications that the benzodiazepines were not the only compounds to bind to the benzodiazepine receptor were findings that emerged from a search for an endogenous ligand for this receptor site. This effort produced a non-benzodiazepine ligand, ethyl-b-carboline-3-carboxylate (b-CCE), and this pointed the way to a whole family of compounds that are high-affinity ligands for this receptor. However, not all turned out to share the properties of the protypical benzodiazepines (anti-anxiety, anticonvulsant, etc. THE BENZODIAZEPINE RECEPTOR AGONIST/INVERSE AGONIST SPECTRUM The rich portfolio of compounds that bind to the benzodiazepine receptor includes many compounds which, despite not being benzodiazepines, share the properties of the prototypical benzodiazepines, chlordiazepoxide and diazepam. However, all these groups of compounds, including the benzodiazepines themselves, span the activity spectrum: from full inverse agonist to full agonist. In between these extremes are compounds which have either partial agonist or partial inverse agonist activity and some are antagonists (Fig. This spectrum of actions reflects the overall effects of these drugs on native receptors and is usually assessed in whole animals. However, the synthesis of receptors comprising different combinations of subunits has shown that the activity of these drugs depends greatly on subunit composition. For instance, GABAA receptors have been characterised to which diazepam does not bind at all (see Chapter 11). The first antagonist to be developed was the (imidazo)benzodiazepine, flumazenil. This compound blocks the actions of both agonists and inverse agonists in vitro. The subunit composition of the GABAA receptor could be one confounding factor in resolving this question. For instance, flumazenil has been reported to augment the action of GABA at cloned receptors comprising a4 b2 g2 subunits.

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