The α7 nicotinic ACh receptor agonist compound B and positive allosteric modulator PNU-120596 both alleviate inflammatory hyperalgesia and cytokine release in the rat.

Abstract

BACKGROUND AND PURPOSE:

Agonists selective for the α7 nicotinic acetylcholine (nACh) receptor produce anti-hyperalgesic effects in rodent models of inflammatory pain, via direct actions on spinal pain circuits and possibly via attenuated release of peripheral pro-inflammatory mediators. Increasingly, allosteric modulation of ligand-gated receptors is recognized as a potential strategy to obtain desired efficacy in the absence of the putative adverse effects associated with agonist activation.

EXPERIMENTAL APPROACH:

We compared the anti-hyperalgesic and anti-inflammatory effects of the α7 nACh receptor agonist compound B with the positive allosteric modulator (PAM) PNU-120596 and the standard non-steroidal anti-inflammatory drug (NSAID), diclofenac, in rats with hind paw inflammation induced by either formalin, carrageenan or complete Freund's adjuvant (CFA).

KEY RESULTS:

When administered before carrageenan, both diclofenac (30 mg·kg(-1) ) and PNU-120596 (30 mg·kg(-1) ) significantly reduced mechanical hyperalgesia and weight-bearing deficits for up to 4 h. Compound B (30 mg·kg(-1) ) also attenuated both measures of pain-like behaviour, albeit less robustly. Whereas compound B and PNU-120596 attenuated the carrageenan-induced increase in levels of TNF-α and IL-6 within the hind paw oedema, diclofenac only attenuated IL-6 levels. Established mechanical hyperalgesia induced by carrageenan or CFA was also partially reversed by compound B and PNU-120596. However, diclofenac was considerably more efficacious. Formalin-induced nocifensive behaviours were only reversed by compound B, albeit at doses which disrupted motor performance.

CONCLUSIONS AND IMPLICATIONS:

α7 nACh receptor PAMs could prove to be useful in the treatment of inflammatory pain conditions, which respond poorly to NSAIDs or in situations where NSAIDs are contra-indicated.

• Authors: G Munro, Rr Hansen, Hk Erichsen, Db Timmermann, Jk Christensen, Hh Hansen
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 167 Issue 2 Pg. 421-35 (Sep 2012) ISSN: 1476-5381 [Electronic] England
• PMID: 22536953 (Publication Type: Journal Article)
• Copyright: © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Chemical References

• 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea
• Anti-Inflammatory Agents, Non-Steroidal
• Azabicyclo Compounds
• Chrna7 protein, rat
• Cytokines
• Isoxazoles
• N-(1-azabicyclo(2.2.2)oct-3-yl)(5-(2-pyridyl)thiopene-2-carboxamide)
• Phenylurea Compounds
• Receptors, Nicotinic
• Thiophenes
• alpha7 Nicotinic Acetylcholine Receptor
• Diclofenac
• Carrageenan
• Freund's Adjuvant

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Azabicyclo Compounds (therapeutic use)
• Carrageenan (toxicity)
• Cytokines (genetics, metabolism)
• Diclofenac (therapeutic use)
• Freund's Adjuvant (toxicity)
• Gene Expression Regulation (drug effects)
• Hyperalgesia (drug therapy)
• Inflammation (chemically induced, complications, drug therapy)
• Isoxazoles (therapeutic use)
• Male
• Phenylurea Compounds (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptors, Nicotinic (metabolism)
• Thiophenes (therapeutic use)
• alpha7 Nicotinic Acetylcholine Receptor