Inhibition of antinociception

In further support of a pro-nociceptive role of CX3CL1 are data showing that the direct injection of CX3CL1 in the periaqueductal grey, a brain region mostly involved with analgesic responses, albeit un-effective by itself, results in inhibition of the antinociceptive effects induced by p, 5, and k opioid agonists (Chen et al. 2(X)7). 

As mentioned above, inhibition of adenosine kinase increases extracellular adenosine concentrations. Interest in enhancement of the neuroprotective, antinociceptive, and anti-inflammatory actions of adenosine has encouraged development of systemically applicable adenosine kinase inhibitor drugs. For example, it was found recently that the specific adenosine kinase inhibitor ABT-702, when given intraperitoneally, increases sleep and slow wave EEG activity of rats (Radek et al, 2004), a finding that encourages further research into the hypnogenic effect of this type of drug. 

Gogas, K. R. and Hough, L. B. Inhibition of naloxone-resistant antinociception by centrally-administered H2 antagonists. /. Pharmacol. Exp. Ther. 248 262-267,1989. 

Nonpeptide receptors Adenosine Aj Human cDNA Cardiac arrhythmia, asthma, myocardial ischemia, obesity, pain, renal disease, sleep apnea, stroke, cancer, inflammation, glaucoma, cystic fibrosis, Alzheimer s disease, Parkinson s disease Bradycardia, lipolysis inhibition, reduction of glomerular filtration and natriuresis, tubero-glomerular feedback, antinociception, renal vasodilatation-constriction, reduction of central cholinergic and noradrenergic nerve activity, presynaptic inhibition of excitatory neuro transmission... 

The leaves of Aleurites moluccana contain 2"-C-rhamnosylswertisin and swertisin. The antinociceptive effect of both compounds was evaluated by the writhing test in mice. " The results indicated that the first derivative inhibits, dose dependently, the abdominal constrictions caused by acetic acid with an ID50 value of 6.9 to 10.2 pM/kg and maximal inhibition of 92%. When compared with aspirin ID5o= 133 pM/kg, the C-glycosylflavone was about 16-fold more potent. On the other hand, the swertisin alone did not show any effect. 

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. 

Compounds with moderate p-affinities are very potent in a variety of pain models in mice and rats. In addition to antinociceptive efficacy in models of acute pain (tail flick, writhing) these compounds inhibit acute and persistent inflammatory pain (Randall Selitto, formalin test). Furthermore, they show strong inhibition of acute visceral pain (colorectal distension) and of tactile and cold allodynia in models of neuropathic pain (spinal nerve ligation (Chung), chronic constriction injury (Bennett)). The data suggest these compounds to be potential candidates for the management of clinical pain indications. Somatic and visceral pain with and without inflammatory conditions as well as neuropathic pain might be addressed with this approach. 

Ghelardini, C., Galeotti, N., Bartolini, A. Loss of muscarinic antinociception by antisense inhibition of M1 receptors, Br. J. Pharmacol. 2000, 129, 1633-1640. 

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. 

Tan-No, K., Taira, A., Sakurada, T., Inoue, M., Sakurada, S., Tadano, T., Sato, T., Sakurada, C., Nylander, I., Silberring, J., Terenius, L., and Kisara, K. (1996). Inhibition of dynorphin-converting enzymes prolongs the antinociceptive effect of intrathecally administered dynorphin in the mouse formalin test. Eur.J. Pharmacol. 314, 61-67. 

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