Abstract | BACKGROUND AND PURPOSE: The α7 nicotinic ACh receptor subtype is abundantly expressed in the CNS and in the periphery. Recent evidence suggests that α7 nicotinic ACh receptor (nAChR) subtypes, which can be activated by an endogenous cholinergic tone comprising ACh and the α7 agonist choline, play an important role in chronic pain and inflammation. In this study, we evaluated whether type II α7 positive allosteric modulator PNU-120596 induces antinociception on its own and in combination with choline in the formalin pain model. EXPERIMENTAL APPROACH: We assessed the effects of PNU-120596 and choline and the nature of their interactions in the formalin test using an isobolographic analysis. In addition, we evaluated the interaction of PNU-120596 with PHA-54613, an exogenous selective α7 nAChR agonist, in the formalin test. Finally, we assessed the interaction between PNU-120596 and nicotine using acute thermal pain, locomotor activity, body temperature and convulsing activity tests in mice. KEY RESULTS: CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that type II α7 positive allosteric modulators produce antinociceptive effects in the formalin test through a synergistic interaction with the endogenous α7 agonist choline.
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Authors | K Freitas, S S Negus, F I Carroll, M I Damaj |
Journal | British journal of pharmacology
(Br J Pharmacol)
Vol. 169
Issue 3
Pg. 567-79
(Jun 2013)
ISSN: 1476-5381 [Electronic] England |
PMID | 23004024
(Publication Type: Comparative Study, Journal Article)
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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
- Analgesics
- Bridged Bicyclo Compounds, Heterocyclic
- Chrna7 protein, mouse
- Isoxazoles
- N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide
- Nicotinic Agonists
- Phenylurea Compounds
- Quinuclidines
- alpha7 Nicotinic Acetylcholine Receptor
- Nicotine
- Choline
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Topics |
- Acute Pain
(drug therapy)
- Allosteric Regulation
- Analgesics
(administration & dosage, adverse effects, therapeutic use)
- Animals
- Behavior, Animal
(drug effects)
- Body Temperature Regulation
(drug effects)
- Bridged Bicyclo Compounds, Heterocyclic
(adverse effects, therapeutic use)
- Choline
(administration & dosage, adverse effects, therapeutic use)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Drug Interactions
- Drug Therapy, Combination
- Isoxazoles
(administration & dosage, adverse effects, therapeutic use)
- Male
- Mice
- Mice, Inbred ICR
- Motor Activity
(drug effects)
- Nicotine
(adverse effects, therapeutic use)
- Nicotinic Agonists
(administration & dosage, adverse effects, therapeutic use)
- Nociceptive Pain
(drug therapy)
- Pain Measurement
- Phenylurea Compounds
(administration & dosage, adverse effects, therapeutic use)
- Quinuclidines
(adverse effects, therapeutic use)
- alpha7 Nicotinic Acetylcholine Receptor
(agonists, metabolism)
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