Neurotransmitters, pain

In this maimer, capsaicin binds to the same group of nociceptors which lead to the sensation of pain, heat, and acid. Then lead for a reduction in pain and inflammation by depleting the neurotransmitter pain signaling [111]. This effect has been observed for example when an intraarticular injection of capsaicin is administrated to reduce the mechanical hyperalgesia induced in osteoarthritis [112]. Additionally, capsaicin appears to be effective in protecting bone from osteoarthritic damage, supporting the hypothesis that capsaicin-sensitive sensory neurons contribute to bone lesions. Therefore capsaicin may be useful for the development of new therapeutic approaches to pain control and prevention of osteoarthritis-dependent bone loss [113]. 

The surrounding redness caused by the vasodilatation of local blood vessels in the skin (hyperaemia). Histamine released at the site of contact acts on sensory nerve endings in the skin. Impluses travel along the axon to other peripheral branches of the same neuron to cause release of vasodilataory peptide neurotransmitters from nerve endings serving a wider area of skin than the initial contact point. Impluses reaching the CNS are interpreted as itch and pain. 

How the different neurotransmitters may be involved in the initiation and maintenance of some brain disorders, such as Parkinson s disease, epilepsy, schizophrenia, depression, anxiety and dementia, as well as in the sensation of pain, is then evaluated and an attempt made to see how the drugs which are used in these conditions produce their effect by modifying appropriate neurotransmitter function (section C). The final section (D) deals with how neurotransmitters are involved in sleep and consciousness and in the social problems of drug use and abuse. 

Tricyclic antidepressants (TCAs) such as amitriptyline and doxepin have been used with some success in the treatment of IBS-related pain (Table 18-5). They modulate pain principally through their effect on neurotransmitter reuptake, especially norepinephrine and serotonin. Their helpfulness in functional gastrointestinal disorders seems independent of mood-altering effects normally associated with these agents. Low-dose TCAs (e.g., amitriptyline, desipramine, or doxepin 10 to 25 mg daily) may help patients with IBS who predominantly experience diarrhea or pain. 

In the vertebrate CNS monoamines have been associated with a number of physiological functions (reviewed in Kandel et al., 1991). Serotonin has functions associated with mood, pain, sleep, learning, and memory. Dopamine has functions associated with schizophrenia, Parkinson s disease, and cocaine addiction. In vertebrates, dopamine is further metabolized into two additional neurotransmitters, norepinephrine and epinephrine. Norepinephrine increases the excitability of cells in response to sudden sensory input such as fear. Epinephrine has been identified in specific neurons of the brain, but the function of these cells is unknown. In addition, AADC has also been found in a class of neurons that do not have any of the four neurotransmitters discussed above (Jaeger et al., 1983). These neurons may use one of the trace amines, tyramine, tryptamine, or phenylethylamine, as a neurotransmitter. 

The endogenous analgesic system is a built-in neuronal system that suppresses transmission of nervous impulses in the pain pathway. It functions by way of the following neurotransmitters produced in the CNS ... 

Figure 8.2 The endogenous analgesic system. The three major components of the endogenous analgesic system include the periaqueductal gray matter in the midbrain nucleus raphe magnus in the medulla and pain inhibitory complex in the dorsal horns of the spinal cord. This system causes presynaptic inhibition of pain fibers entering the spinal cord. The binding of enkephalin to opioid receptors on the pain fibers prevents release of the neurotransmitter, substance P. As a result, the pain signal is terminated in the spinal cord and does not ascend to higher centers in the CNS.

Agonist drugs can also bind directly to the postsynaptic receptor, so mimicking the physiological effect of the neurotransmitter for example, morphine and heroin bind to the brain s opiate receptors and, thus, directly stimulate feelings of pleasure and pain... 

If opiates are such addictive and potentially lethal compounds, why does the body respond to them As with the cannabinoids (Chapter 7), it has been discovered that the body and brain possess numerous opiate-specific receptor sites. As many as nine receptor subtypes have been identified, with three of them being the most important p (mu), k (kappa) and 8 (delta). The finding that the distribution of opiate receptors did not parallel the distribution of any known neurotransmitter prompted the search for and identification of a number of endogenous compounds specific to these receptors. These enkephalins and endorphins are manufactured within the brain and other body systems (especially the gut and intestines) and form the body s natural response to pain. They appear to be produced in bulk chains of amino acids called polypeptides , with each active neurotransmitter being composed of around five amino acid molecules. These active neurotransmitters are subsequently cleaved from the larger polypeptides at times of demand for example, it has been demonstrated that the plasma levels of these active compounds rise during childbirth, traumatic incidents and vigorous physical exercise. 

Substance P, an undecapeptide, is abundant both in the periphery and in the central nervous system. It is usually co-localized with one of the classical neurotransmitters, most commonly serotonin. Substance P is thought to have a role in the regulation of pain, asthma, psoriasis, inflammatory bowel disease and, in the CNS, emesis, migraine, schizophrenia, depression and anxiety. The substance-P-preferring receptor neurokinin-1 has been focused on most intensively in drug development, and existing... 

The body modulates pain through several processes. The endogenous opiate system consists of neurotransmitters (e.g., enkephalins, dynorphins, and /1-endorphins) and receptors (e.g., fl, S, k) that are found throughout the CNS. Endogenous opioids bind to opioid receptors and modulate the transmission of pain impulses. 

The CNS also contains a descending system for control of pain transmission. This system originates in the brain and can inhibit synaptic pain transmission at the dorsal horn. Important neurotransmitters here include endogenous opioids, serotonin, norepinephrine, y-aminobutyric acid, and neurotensin. 

Communication between one neurone and another or between a neurone and an effector tissue such as muscle is mediated via neurotransmitters. Although the message, for example the sensation of pain, may be passed a long distance, neurotransmitters... 

The diagram below shows the pathway of pain transmission from the peripheral nerves to the cerebral cortex. There are three levels of neuronal involvement and the signals may be modulated at two points during their course to the cerebral cortex. Descending inhibitory pathways arise in the midbrain and pass to the dorsal horn as shown. Multiple different neurotransmitters are involved in the pathway and include gamma-aminobutyric acid (GABA), N-methyl-D-aspartate (NMDA), noradrenaline and opioids. 

Cannabinoid CBj Human cDNA Motor function, memory, analgesia, convulsion, Parkinson s disease, emesis, glaucoma, pain, cancer Modulation of neurotransmitter release, sleep disturbance, weight loss, antiemetic activity locomotor disfunction, bronchodilatation, neuroprotection, memory loss... 

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