Pinning Down Neuropathic Pain

RESEARCH HIGHLIGHTS

PAIN Pinning down neuropathic pain

Neuropathic pain, a widespread promotes chronic pain through its calcium channels, possibly by induc- chronic condition caused by injury agonist action at bradykinin recep- ing bradykinin receptor coupling to

to the nervous system, is one of the tors, could pave the way for new the Gs–cAMP–PKA pathway. most difficult syndromes to treat treatment options. Importantly, in vivo experiments successfully with Many experimental models of demonstrated that administration

drugs. New thera- chronic pain show significant and of dynorphin A2–13 into the spinal peutic approaches to time-dependent regional elevation canal of rats induced reversible the treatment of this of dynorphin A, where it is known hypersensitivity and hyperalgesia, condition require a to mediate inhibitory effects on an effect that was not observed in

better understanding pain regulation by binding to bradykinin-receptor-B2-knockout of the molecular opioid receptors. Dynorphin A also mice. In a model of neuropathic mechanisms mediates excitatory effects by an pain induced by spinal nerve that underlie its unknown mechanism. Now further ligation (SNL), the bradykinin

development. Lai receptors for dynorphin A have been B2 antagonist HOE 140 led to a and colleagues, discovered. A des-tyrosyl fragment of reversal of the chronic pain state.

reporting dynorphin A (dynorphin A2–13) with SNL induced time-dependent in Nature very low affinity for opioid receptors, upregulation of dynorphin, which Neuroscience, was shown to induce Ca2+ influx has a delayed onset and reached its

have now by binding to B1 and B2 bradykinin peak 7–10 days after injury. The uncovered an receptors in vitro in embryonic reversal with HOE 140 was similarly important piece of dorsal root ganglia (DRG) and in a time-dependent, with no effect at 2 the puzzle. The dis- model cell line for peripheral sensory days after SNL, but a complete block covery that dynorphin neurons. This led to the activation of of injury-induced pain 7 days post- A, an opioid neuropeptide, L-type and P/Q type voltage-sensitive SNL. Combined with the analysis

the injected paw but remained LoVerme and colleagues then ANALGESIA unchanged in the brain and spinal examined the role of PPARα agonists cord, indicating that PPARα agonists in three pain models. In a mouse model Fast-track to pain relief might inhibit pain behaviour through of neuropathic pain, administration of a peripheral mechanism. This was GW7647 or PEA caused a rapid reinforced by the finding that reversal of mechanical and thermal Current analgesics do not intraplantar administration of hyperalgesia, which was absent effectively control many severe GW7647 or PEA attenuated the in neuropathic PPARα-null mice. pain states, so there is a need for The sensitization of spinal-cord Furthermore, GW7647 and PEA novel therapeutics that alleviate this nociceptive neurons to peripheral suppressed mechanical and thermal debilitating condition. LoVerme and antinociceptive noxious stimuli in rats. hyperalgesia in experimental arthritis colleagues, writing in the Journal effects of Although PPARα is traditionally and paw oedema — two mouse models of Pharmacology and Experimental PPARα considered a nuclear receptor, the of chronic inflammation. Unlike opiate Therapeutics, have shown that the antinociceptive effects of PPARα analgesics, the use of PEA was not peroxisome proliferator-activated agonists agonists occurred within minutes of associated with the development of receptor-α (PPARα) might represent occurred administration, an effect too rapid analgesic tolerance. a novel analgesic target, because within to be transcription-dependent. To Although not all PPARα agonists agonists acting at this receptor elucidate the mechanism of action of demonstrated analgesic efficacy, produce rapid, broad-spectrum minutes of PPARα agonists, the authors focused this study suggests that certain analgesia. administration. on K+channels, which are involved PPARα agonists — many of which From a range of structurally in some actions of PEA and also in are currently in clinical development diverse PPARα agonists, the authors the regulation of pain sensitivity. — could have potential therapeutic identified compounds — GW7647, By testing a series of K+ channel activity in chronic pain states. Wy-14643 and palmitoylethanola- blockers to modulate PPARα-mediated Charlotte Harrison mide (PEA, a naturally occuring antinociception, the authors found that large conductance (K 1.1) and ligand) — that reduced early- Ca ORIGINAL RESEARCH PAPER LoVerme, J. et al.

and late-phase irritant-induced intermediate conductance (KCa3.1) Rapid broad-spectrum analgesia through nociception. After intraplantar calcium-activated K+ channels activation of peroxisome proliferator-activated α. mediated the rapid antinociceptive receptor- J. Pharmacol. Exp. Ther. 319, administration of PEA to mice, tissue 1051–1061 (2006) levels of the drug were elevated in response to PPARα agonists.