Antinociception, function

There is evidence that in cerebral ischaemia adenosine may have protective effects, since it inhibits the release of many excitatory neurotransmitters, such as glutamate, and it also stabilises the membrane potential. Unfortunately, adenosine has an extremely short half-life, but recently nucleoside (adenosine) transport inhibitors, e.g. draflazine, have been developed that prevent the endothelial uptake and breakdown of adenosine and prolong its beneficial effects. Nucleoside transport inhibitors also have myocardial protective properties and may have a role in organ preservation prior to transplantation. Adenosine also has an antinociceptive function and various adenosine analogues have antinociceptive activity, which correlates with their affinity for the A1 receptors (Lipkowski and co-workers 1996). 

Considerable evidence for opioid-chemokine interactions comes from studies of pain and inflammation, where the inherent relationships between pain, inflammation, and the counteracting antinociceptive influences of opioids have considerable biomedical implications. The adaptive changes in immune and nervous system function with chronic inflammation and pain further reveal the inherent interrelatedness between opioids (Ossipov et al. 2003 Evans 2004 Roy et al. 2006 Christie 2008)... 

Like many other neuropeptides, NT serves a dual function as a neurotransmitter or neuromodulator in the central nervous system and as a local hormone in the periphery. When administered centrally, NT exerts potent effects including hypothermia, antinociception, and modulation of dopamine neurotransmission. When administered into the peripheral circulation, it causes vasodilation, hypotension, increased vascular permeability, increased secretion of several anterior pituitary hormones, hyperglycemia, inhibition of gastric acid and pepsin secretion, and inhibition of gastric motility. It also exerts effects on the immune system. 

However, due to the ubiquitous expression of K+ channels in virtually all excitable cells the general question arises how can they be exploited as targets for drug therapy of painful states To put it in other words, what is required to ascertain a specific antinociceptive action when modulating K+ channel functioning ... 

MRZ-2/576 has been demonstrated to cross the blood -brain barrier rapidly and to function centrally as a glycineB antagonist after systemic administration of doses within the relevant antinociceptive dose range. However, the compound is only short-acting within the CNS because of a relatively short half-life within this compartment (Parsons et al., 1997). The compound has antinociceptive properties and shows exceptionally good efficacy in a visceral pain model (McClean et al., 1998 Olivar et al., 1999). 

The exo position of the chloropyridine is essential for the antinociceptive potency of epibatidine - its racemic endo diastereoisomer is inactive. Also inactive are amides derived from epibatidine through acylation of the secondary amine function (R = C(O)R ). On the other hand the potency of 7-methylepibatidine (R = Me) is comparable to epibatidine itself, so a basic nitrogen but not necessarily a secondary amine is needed for activity (Li et al., 1993). 

West, W. L., Yeomans, D. C. Proudfit, H. K. (1993). The function of noradrenergic neurons in mediating antinociception induced by electrical stimulation of the locus coeruleus in two different sources of sprague-dawley rats. Brain Res., 626,127-135. 

The 5-HT3 receptors are found in both the peripheral nervous system and central nervous system (CNS), where they mediate last synaptic transmission at synapses (3). In the CNS, they are located predominantly at intemeurones, where they modulate the release of a range of neurotransmitters (4-9). There is some evidence that 5-HT3 receptors play roles in brain reward mechanisms and in neurological phenomena such as anxiety, psychosis, nociception, and cognitive function (10,11), and in the first few years following the discovery of these receptors, there was also much interest in the therapeutic potential of 5-HT3 receptor antagonists for antipsychotic, antinociceptive, and other psychiatric disorders (12-15). This potential has not yet been realized, but there is still active research in this area (16), and their current major therapeutic target is against emesis in cancer chemotherapy and irritable bowel syndrome (17,18). 

---