Analgesic profile of the nicotinic acetylcholine receptor agonists, (+)-epibatidine and ABT-594 in models of persistent inflammatory and neuropathic pain.

The anti-nociceptive and locomotor effects of the nicotinic acetylcholine receptor (nAChR) agonists (+)-epibatidine and ABT-594 were compared in the rat. Acute thermal nociception was measured using the tail flick test. Mechanical hyperalgesia was measured as paw withdrawal threshold (PWT) in response to a mechanical stimulus in two animal models of persistent pain; (1) 24 h following subplantar injections of Freund's complete adjuvant (FCA) into the left hind paw or (2) 11-15 days following a partial ligation of the left sciatic nerve. Disruption of locomotor function was assessed using an accelerating rotarod device. In all tests, (+)-epibatidine was significantly more potent than ABT-594. Both (+)-epibatidine and ABT-594 dose-dependently increased tail flick latencies but only at doses that also disrupted performance in the rotarod test. On the other hand, (+)-epibatidine and ABT-594 dose-dependently reversed inflammatory and neuropathic hyperalgesia at significantly lower doses than that needed to disrupt performance in the rotarod test. In summary, ABT-594 is less potent than (+)-epibatidine in assays of acute and persistent pain and in the rotarod assay. However, ABT-594 displayed a clearer separation between its motor and anti-hyperalgesic effects. This shows that nicotinic agonists with improved selectivity between the nicotinic receptor subtypes could provide strong analgesic effects with a much improved therapeutic window.

Selective neurokinin-1 receptor antagonists are anti-hyperalgesic in a model of neuropathic pain in the guinea-pig.

Neuropathic pain is poorly managed by conventional analgesic therapy, such as non-steroidal anti-inflammatory drugs and opiates. The development of animal models of peripheral neural damage has aided in our understanding of the pathology and pharmacology of neuropathic pain. This report is the first clear demonstration using selective neurokinin-1 receptor antagonists of a potentially novel therapeutic approach to the treatment of neuropathic pain resulting from peripheral nerve damage in a guinea-pig model. The neurokinin-1 receptor antagonists, SDZ NKT 343 and LY 303,870 significantly reduced mechanical hyperalgesia following oral and intrathecal administration. (R,R)-SDZ NK T343, the enantiomer of SDZ NKT 343 did not show anti-hyperalgesic activity. RPR 100,893 showed significant anti-hyperalgesic activity only following intrathecal administration suggesting poor absorption or low level penetration of the blood-brain barrier. These results imply that neurokinin-1 receptor antagonists offer a new class of anti-hyperalgesic drugs with a largely central site of action in neuropathic pain.

Comparison of the effects of diltiazem and its analogue siratiazem on contractility in arteries, ileum and cardiac muscle.

1. The aim of this study was to compare the abilities of diltiazem and siratiazem to inhibit concentration-response curves for contractile responses to calcium in arterial and intestinal smooth muscle and cardiac muscle. 2. Diltiazem and siratiazem inhibited, in a concentration-dependent manner, the maximum contraction produced by cumulative addition of calcium chloride to rabbit mesenteric artery, ileum and paced atria in vitro. The order of potency, as indicated by the IC25 values (with 95% confidence intervals) for siratiazem was ileum, 0.33 microM (0-0.63) > mesenteric artery, 0.75 microM (0.32-1.01) and for diltiazem was ileum 0.1 microM (0.007-0.14) = mesenteric artery 0.13 microM (0-0.22). 3. In rabbit atria, the IC25 was of the order of 10 microM for both siratiazem and diltiazem. 4. Both drugs also inhibited calcium concentration-response curves in sheep cerebral arteries and in this tissue the IC25 values were 1.18 (0.37-1.63) and 0.89 (0-1.36) microM for siratiazem and diltiazem, respectively. 5. It is concluded that siratiazem, like diltiazem, blocks entry of calcium via voltage-operated channels with a similar potency to diltiazem on rabbit ileum and cardiac muscle and sheep cerebral arteries but is less potent on rabbit mesenteric arteries.