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Biotech / Medical : Indications -- pain -- Ignore unavailable to you. Want to Upgrade?

To: tommysdad who wrote (55)	1/19/2007 5:08:29 PM
From: dr.praveen	Read Replies (1) \| Respond to of 101

Activation of the peroxisome proliferator-activated receptor-alpha (PPARalpha) leads to rapid, broad-spectrum analgesia suggesting that PPARalpha agonists may represent a novel class of analgesics. signaling-gateway.org Current analgesics do not effectively control many severe pain states, so there is a need for novel therapeutics that alleviate this debilitating condition. LoVerme and colleagues, writing in the Journal of Pharmacology and Experimental Therapeutics, have shown that the peroxisome proliferator-activated receptor-alpha (PPARalpha) might represent a novel analgesic target, because agonists acting at this receptor produce rapid, broad-spectrum analgesia. From a range of structurally diverse PPARalpha agonists, the authors identified compounds — GW7647, Wy-14643 and palmitoylethanolamide (PEA, a naturally occuring ligand) — that reduced early- and late-phase irritant-induced nociception. After intraplantar administration of PEA to mice, tissue levels of the drug were elevated in the injected paw but remained unchanged in the brain and spinal cord, indicating that PPARalpha agonists might inhibit pain behaviour through a peripheral mechanism. This was reinforced by the finding that intraplantar administration of GW7647 or PEA attenuated the sensitization of spinal-cord nociceptive neurons to peripheral noxious stimuli in rats. Although PPARalpha is traditionally considered a nuclear receptor, the antinociceptive effects of PPARalpha agonists occurred within minutes of administration, an effect too rapid to be transcription-dependent. To elucidate the mechanism of action of PPARalpha agonists, the authors focused on K+channels, which are involved in some actions of PEA and also in the regulation of pain sensitivity. By testing a series of K+ channel blockers to modulate PPARalpha-mediated antinociception, the authors found that large conductance (KCa1.1) and intermediate conductance (KCa3.1) calcium-activated K+ channels mediated the rapid antinociceptive response to PPARalpha agonists. LoVerme and colleagues then examined the role of PPARalpha agonists in three pain models. In a mouse model of neuropathic pain, administration of GW7647 or PEA caused a rapid reversal of mechanical and thermal hyperalgesia, which was absent in neuropathic PPARalpha-null mice. Furthermore, GW7647 and PEA suppressed mechanical and thermal hyperalgesia in experimental arthritis and paw oedema — two mouse models of chronic inflammation. Unlike opiate analgesics, the use of PEA was not associated with the development of analgesic tolerance. Although not all PPARalpha agonists demonstrated analgesic efficacy, this study suggests that certain PPARalpha agonists—many of which are currently in clinical development — could have potential therapeutic activity in chronic pain states. Charlotte Harrison