Pain transmission

Endogenous opioid peptide released both in the central nervous system and in other apparatuses of the body that have many regulatory functions, including inhibition of pain transmission. 

The studies with PET and fMRI tell us that placebo analgesia and opioid analgesia share a common neural mechanism and that pain transmission is inhibited by placebos, but they do not allow to conclude that the placebo-activated descending network is an opioid... 

Cell penetrating PNA constmcts regulate galanin receptor levels and modify pain transmission in vivo. Nature Biotechnol. 

Direct attenuation of the excitability of neurons in the trigeminal nuclei, as 5-HTib/ 5-HTid receptors on pain transmission neurons in the trigeminal nucleus caudalis and in the upper cervical cord, are activated. Stimulation of these receptors is caused by second-generation triptans that cross the blood-brain barrier such as zolmitriptan, naratriptan, rizatriptan and eletriptan. 

Capsaicin achieves pain relief by depleting substance P from sensory neurons in the spine, thereby decreasing pain transmission. Capsaicin is not effective for acute pain up to 2 weeks may be necessary before pain relief is appreciated. Most patients experience a local burning sensation at the site of application. The discomfort usually does not result in... 

A critical cellular response to opiates is the potentiation of K+ currents [42]. Stimulation of n receptors in neurons causes an increase in K+ conductance and a reduction in cell firing. Prolonged administration of fi agonists diminishes the ability of the opiates to increase K+ conductance to inhibit neuronal firing and pain transmission is no longer attenuated. 

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. 

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. 

Thus, there are numerous neurochemical systems that participate in pain transmission and analgesia systems in the brain. Potentially, any drug that interferes with any of these systems could have analgesic effects. As will be demonstrated in this chapter, there are many plants with analgesic and anesthetic effects, working through a variety of pharmacological mechanisms (table 8.4). 

Local anesthetics preferentially block small fibers because the distance over which such fibers can passively propagate an electrical impulse is shorter. During the onset of local anesthesia, when short sections of a nerve are blocked, the small-diameter fibers are the first to fail to conduct electrical impulses. For myelinated nerves, at least two and preferably three successive nodes of Ranvier must be blocked by the local anesthetic to halt impulse propagation. Therefore, myelinated nerves tend to become blocked before unmyelinated nerves of the same diameter. For this reason, the preganglionic fibers are blocked before the smaller unmyelinated C fibers involved in pain transmission. 

Another important reason for preferential blockade of sensory fibers follows directly from the state- and use-dependent mechanism of action of local anesthetics. Blockade by these drugs is more marked at higher frequencies of depolarization. Sensory (pain) fibers have a high firing rate and a relatively long action potential duration. Motor fibers fire at a slower rate and have a shorter action potential duration. Type A delta and C fibers are smaller-diameter fibers that participate in high-frequency pain transmission. Therefore, these fibers are blocked earlier and with lower concentrations of local anesthetics than are the large A alpha fibers. 

Analgesic efficacy and clinical use Tramadol HCI (Friderichs et al., 1978 Raffa and Friderichs, 1996) is a centrally-acting analgesic with a p-opioid and non-opioid component of action (Raffa et al., 1992). The non-opioid component induces inhibition of spinal pain transmission via inhibition of noradrenaline (NA) and serotonin (5HT) re-uptake (Driessen and Reimann, 1992 Driessen et al. 1993) Tramadol is a racemate and uptake inhibition and opioid properties are differentially distributed between the enantiomers (Raffa et al., 1993) and the active O-desmethyl metabolite. p-Opioid receptor binding, NA uptake inhibition and 5HT uptake inhibition are regarded as the relevant (Desmeules et al., 1996 Raffa and Friderichs, 1996) components of the complex analgesic action profile of the compound (+)-0-desmethyl-tramadol mainly contributes to p-activity, (-)-tramadol to NA uptake inhibition and (+)-tramadol to 5HT uptake inhibition, respectively. 

Adenosine deaminase catalyzes the hydrolytic deamination of adenosine and 2 -deoxyadenosine to inosine and 2 -deoxyinosine respectively. Inhibition of adenosine deaminase leads to an accumulation of its substrates which results in adenosine receptor-mediated effects. Most inhibitors are not reported to have antinociceptive properties, but 2 -deoxycoformycin was proven to have an inhibitory effect on pain transmission (Poon and Sawynok, 1999), and Fujisawa Pharmaceuticals claim adenosine deaminase inhibitors to be active against chronic pain. 

SP from primary afferents has a number of other effects on target cells besides pain transmission, e.g. vasodilatation, plasma protein extravasation, mast cell degranulation, recruitment of inflammatory cells, stimulation of secretion and muscle contraction (Maggi, 1997). The role of SP as an endogenous vasodilator in cerebral circulation and resulting effects on pain production have been discussed by Beattie et al. (1995a). 

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