The effect of peripherally administered cdp-choline in an acute inflammatory pain model: the role of
7 nicotinic acetylcholine receptor

The Effect of Peripherally Administered CDP-Choline in an Acute Inflammatory Pain Model: The Role of 7 Nicotinic Acetylcholine Receptor
Mine Sibel Gurun, MD, PhD* Renee Parker, BS† James C. Eisenach, MD, PhD† Michelle Vincler, PhD†
BACKGROUND: CDP-choline (citicholine; cytidine-5 -diphosphate choline) is an endogenously produced nucleotide which, when injected intracerebroventricularly, exertsan antinociceptive effect in acute pain models mediated by central cholinergic mechanisms and 7 nicotinic acetylcholine receptors ( 7nAChR). Previous reports also suggest that the peripheral cholinergic system has an antiinflammatory role mediated by 7nAChRs on macrophages. METHODS: We used male Sprague-Dawley rats to assess the antihypersensitivity and antiinflammatory effect of CDP-choline afterintraplantar injection of carrageenan (100 L, 2%). Mechanical paw withdrawal thresholds and paw thickness were measured by Randall-Selitto testing and microcallipers, respectively. All drugs were administered intraplantarly in a volume 50 L. RESULTS: CDP-choline (1, 2.5, 5 mol; intraplantar) increased the mechanical paw withdrawal threshold and decreased paw edema in a dose- and time-dependentmanner in the carrageenan-injected hindpaw. CDP-choline administration to the noninflamed contralateral hindpaw did not alter ipsilateral inflammation. Methyllycaconitine (100 nmol), a selective 7nAChR antagonist, completely blocked the effects of CDP-choline when administered to the inflamed hindpaw. However, the administration of methyllycaconitine to the contralateral hindpaw did not block theeffects of CDP-choline in the ipsilateral paw. The administration of CDP-choline (5 mol) 10 min after carrageenan administration to the ipsilateral hindpaw did not reduce swelling and edema but did significantly reduce hypersensitivity. Treatment with CDP-choline decreased tumor necrosis factor- production in the rat paw tissue after carrageenan. CONCLUSIONS: The results of this study suggest thatintraplantar CDP-choline has antihypersensitivity and antiinflammatory effects mediated via 7nAChRs in the carrageenan-induced inflammatory pain model.
(Anesth Analg 2009;108:1680 –7)

ytidine-5-diphosphate choline (CDP-choline; citicoline), an endogenously synthesized nucleotide, exerts numerous cellular actions in different experimental models1 and has beneficial effects on the treatment ofsome neurodegenerative and neurovascular diseases.2,3 Orally, IV or intracerebroventricularly (i.c.v.) administered CDP-choline is rapidly metabolized to choline and cytidine/uridine, which leads to increased plasma and tissue concentrations of
From the *Department of Pharmacology and Clinical Pharmacology, Uludag University, Bursa, Turkey; and †Department of Anesthesiology, Wake Forest University,School of Medicine, Winston-Salem, North Carolina. Accepted for publication December 8, 2008. Supported by National Institutes of Health Grant NS048158 (to MV) and GM48085 (to JE) and Dr. Gurun was supported by Fulbright Commission Turkey. Address correspondence and reprint requests to Mine Sibel Gurun, MD, PhD, Department of Pharmacology and Clinical Pharmacology, Uludag University, 16059,Gorukle, Bursa, Turkey. ¨ ¨ Address e-mail to sgurun@uludag.edu.tr. Copyright © 2009 International Anesthesia Research Society
DOI: 10.1213/ane.0b013e31819dcd08

C

these metabolites.4,5 Choline is the main hydrolysis product of CDP-choline and also a precursor for the synthesis of the cholinergic neurotransmitter, acetylcholine (ACh).4,5 Treatments that increase plasma and tissue choline levelsincrease the synthesis6 and release of ACh7 and cholinergic neurotransmission.8 However, we recently demonstrated that the i.c.v. injection of CDP-choline produced dose- and timedependent antinociceptive effects mediated predominantly by the activation of 7 nicotinic ACh receptors ( 7nAChRs) central nicotinic receptors.9,10 Choline is a full agonist at 7nAChRs11 but also shows near equimolar...