Sensory excitation nerves

TRPVl also plays a central role in intercellular pro-inflammatory feedback loops. An important example is mast cells and sensory nerves. Mast cells release tryptase that, in turn, activates the protease-activated receptor PAR-2 activation of PAR-2 then opens TRPVl via PKC [50]. In keeping with this, PAR-2 agonists reduce the heat activation threshold of TRPVl from 42 °C to below body temperature [51]. Excited nerve endings release SP that, as a positive feedback, binds to neurokinin NKl receptors on mast cells. Mast cells also express TRPVl [52]. Consequently, endovanilloids can act in concert to stimulate mast cells and activate capsaicin-sensitive nerve endings. Of relevance is the finding that PAR-2 is up-regulated in the bladder during experimental cystitis [53]. 

The mechanisms by which pyrethroids alone are toxic are complex and become more complicated when they are co-formulated with piperonyl butoxide, an organ-ophosphorus insecticide, or both, as these compounds inhibit pyrethroid metabolism. The main effects of p3rethroids are on sodium and chloride channels. As a result, excitable (nerve and muscle) cells are the principal targets of pyrethroid toxicity, which is manifested as disordered function rather than structural damage. In that way, the major toxic effect of dermal exposure is paresthesia, supposable also due to hyperactivity of cutaneous sensory nerve fibers [12]. 

Chloride channels represent the only anionic channel of interest for analgesic development. These channels often play an important role in neural excitability and therefore are important in the roles of several neurotransmitters including GABA and glycine. Hyperpolarization of the post-synaptic cell body leads to a less excitable nerve fiber and the resultant loss of sensory transmission through select fibers. Through several 20 cascading events, interactions at the Cl" channel result in a hyperpolarization by the inward rush of Cl. 

These are a subset of sensory neurons having their cell bodies (small to medium size) in dorsal root and in cranial nerve ganglia and possessing nonmyelinated (C-type) or thinly myelinated (A-delta type) fibres. This subset of neurons express transient receptor potential vanilloid type 1 (TRPV1, or vanilloid, or capsaicin receptor) that is excited by capsaicin, the pungent ingredient of chilli. These neurons have been classified as polymodal nociceptors because they can be excited by various noxious stimuli. 

Hi-receptors in the adrenal medulla stimulates the release of the two catecholamines noradrenaline and adrenaline as well as enkephalins. In the heart, histamine produces negative inotropic effects via Hr receptor stimulation, but these are normally masked by the positive effects of H2-receptor stimulation on heart rate and force of contraction. Histamine Hi-receptors are widely distributed in human brain and highest densities are found in neocortex, hippocampus, nucleus accumbens, thalamus and posterior hypothalamus where they predominantly excite neuronal activity. Histamine Hrreceptor stimulation can also activate peripheral sensory nerve endings leading to itching and a surrounding vasodilatation ( flare ) due to an axonal reflex and the consequent release of peptide neurotransmitters from collateral nerve endings. 

Pain production is the most common injury inflicted on man. This noxious stimulus is perceived almost instantly after skin - tentacle contact. A subpopulation (30 - 40%) of visceral sensory C fibers denoting noscioception have been shown to be selectively excited experimentally in nerve ganglia preparations by a component of... 

In addition to changes within the nerve, sympathetic afferents become able to activate sensory afferents via as yet poorly characterised a-adrenoceptors. These interactions between adjacent sensory and autonomic nerve axons and between ganglion cells result in excitation spreading between different nerve fibres. These peripheral ectopic impulses can cause spontaneous pain and prime the spinal cord to exhibit enhanced evoked responses to stimuli, which themselves have greater effects due to increased sensitivity of the peripheral nerves. 

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. 

Interneurons are found in all areas of the spinal cord gray matter. These neurons are quite numerous, small, and highly excitable they have many interconnections. They receive input from higher levels of the CNS as well as from sensory neurons entering the CNS through the spinal nerves. Many intemeurons in the spinal cord synapse with motor neurons in the ventral hom. These interconnections are responsible for the integrative functions of the spinal cord including reflexes. 

Mechanism-specific adverse effects. Since local anesthetics block Na+ influx not only in sensory nerves but also in other excitable tissues, they are applied locally and measures are taken (p. 206) to impede their distribution into the body. Too rapid entry into the... 

The lethal oral dose in humans is probably around 100, but doses as low as 16 mg have reportedly been fatal whereas doses of 2 000 mg have been survived. After ingestion, effects usually occur within 10-30 minutes and include stiffness of the face and neck muscles and increased reflex excitability. Strychnine acts by altering nerve impulses in the spinal cord, resulting in a decreased threshold for stimulation, and, hence, a hyperexcitable state. Any sensory stimulus may produce a violent motor response that, in the early stages of intoxication, tends to be a coordinated extensor thrust and, in later stages, may be a tetanic convulsion with opisthotonos anoxia and cyanosis develop rapidly. Between convulsions, muscular relaxation is complete, breathing is resumed, and cyanosis lessens. Because sensation is unaffected, the convulsions are painful and lead to overwhelming fear. As many as 10 convulsions separated by intervals of 10-15 minutes may be experienced, but death often occurs after the second to fifth convulsion, and even the first convulsion may be fatal if sustained death is commonly due to asphyxia.If recovery occurs, it is remarkably prompt and complete despite the violence of the illness muscle soreness may persist for a number of days. ... 

Both somatic and autonomic effectors may be re-flexly excited by nerve impulses arising from the same sensory end organs. For example, when the body is exposed to cold, heat loss is minimized by vasoconstriction of blood vessels in the skin and by the curling up of the body. At the same time, heat production is increased by an increase in skeletal muscle tone and shivering and by an increase in metabolism owing in part to secretion of epinephrine. 

The unique form of needle-free injection of powders into the epidermis or mucosa has been developed by researchers at the University of Oxford and Powderject Pharmaceuticals PLC (now PowderMed Ltd., United Kingdom). Drugs in microparticulate form are accelerated to sufficient velocities to enter the skin or mucosa and achieve a therapeutic effect (Burkoth et al. 1999). Provided the drug particles are sufficiently small to avoid skin lesions and pain, the concept has been shown to be clinically effective, pain-free, and applicable to a range of therapies. Use is pain-free because the penetration depth of the particles is typically less than 100 J,m into the epidermis, and thus the sensory nerve endings lying in the papillary dermis usually are not excited (Fig. 8.15). 

Many substances of widely different chemical structure abolish the excitability of nerve fibers on local application in concentrations that do not cause permanent injury and that may not affect other tissues. Sensory nerve fibers are most susceptible, so that these agents produce a selective sensory paralysis, which is utilized especially to suppress the pain of surgical operation. This property was first discovered in cocaine, but because of its toxicity and addiction liability, it has been largely displaced by synthetic chemicals. The oldest of these, procaine (novocaine), is still the most widely used. Its relatively low toxicity renders it especially useful for injections, but it is not readily absorbed from intact mucous membranes and is therefore not very effective for them. Many of its chemical derivatives are also used. They differ in penetration, toxicity, irritation, and local injury as well as in duration of action and potency. Absolute potency is not so important for practical use as is its balance with the other qualities. If cocaine is absorbed in sufficient quantity, it produces complex systemic actions, involving stimulation and paralysis of various parts of the CNS. These are mainly of toxicological and scientific interest. Its continued use leads to the formation of a habit, resembling morphinism. This is not the case with the other local anesthetics. 

Even the most severe acute pain (that lasting hours to days) can usually be well controlled—with significant but tolerable adverse effects—with currently available analgesics, especially the opioids. Chronic pain (lasting weeks to months), however, is not very satisfactorily managed with opioids. It is now known that in chronic pain, presynaptic receptors on sensory nerve terminals in the periphery contribute to increased excitability of sensory nerve endings (peripheral sensitization). 

Laxatives in this group exert an irritant action on the enteric mucosa (A). Consequently, less fluid is absorbed than is secreted. The increased filling of the bowel promotes peristalsis excitation of sensory nerve endings elicits enteral hypermotility. According to the site of irritation, one distinguishes the small-bowel irritant castor oil from the large-bowel irritants anthraqui-none and diphenylmethane derivatives (for details see p.178). 

Pyrethroids can be classified as type I or type II depending on their effects on sensory neurons in American cockroaches. Type I compounds induce repetitive discharges in sensory neurons in vitro but not neurotransmitter release, so these processes are not related to the toxic action of pyrethroids. In contrast, type II pyrethroids, which typically contain the cyano group, do not induce repetitive discharges. Type II pyrethroids cause slow depolarization of nerve membrane, which reduces the amplitude of the action potential, leading to a loss of electrical excitability (Bloomquist, 1999). In addition, type I pyrethroids exhibit a negative temperature coefficient of toxicity, i.e., they are more toxic at low temperatures than at high temperatures, whereas type II pyrethroids exhibit a positive temperature coefficient of toxicity (Corbett et al., 1984 Matsumura, 1985). 

Another example of an effect apparently unrelated to ChE Inhibition Is found in studies of the actions of ChE Inhibitors on ionic conductances of electrically excitable membranes. When single frog nerve fibers were used, physostlgraine (1-10 mM) attenuated action potential and current, markedly prolonged the duration of the current, and slowed conduction. This mechanism might be involved in functional sensory deficit and—If selective for Inhibitory fibers, as Is the case with local anesthetics (65)--might play a role In generation of facilitation before depression. 

Skeletal muscles are controlled by large nerves in the spinal cord. The nerve cell or neuron is part of the spinal cord, but its projections, the axon and the many dendrites course outward to connect to muscle cells. The nerve axon is a sensory device that senses the muscle cells current condition. The dendrites are motor fibers that deliver the instructions to change its state to the muscle fiber. The area at which the muscle and nerve connect is called the neuromuscular junction. It is here that the end releases a chemical called a neurotransmit-ter that crosses the microscopic space between the nerve and muscle and causes the desired response. Five such neurotransmitters have been described acetylcholine, serotonin, norepinephrine, glycine, and gamma-ammi-nobutyric acid or GABA. Of these, the functions of three are known. Acetylcholine excites muscle activity and glycine and GABA inhibit it. 

Neurotransmitters affect receptors in two basic ways. Some bind to receptors which are said to have ionic effects. These receptors, when activated, operate to open tiny pores (ion-channels), allowing electrically charged particles (ions) to enter the nerve cell. When numerous ionic receptors are activated, this can result in either an excitation of the nerve cell (action potential) or, conversely, a calming of the nerve cell (hyperpolarization, which makes it less likely that the cell will fire). Excitation or inhibition depends on which specific type of channel is activated. This phenomenon is responsible for eliciting immediate and transient changes in neuronal excitability (for example, this occurs when a motor neuron is activated and there is corresponding activation of a muscle, or when sensory events are perceived). 

---