BRAIN NOCICEPTIVE IMAGING IN RATS USING 18 F- FLUORODEOXYGLUCOSE SMALL-ANIMAL POSITRON EMISSION TOMOGRAPHY Y.-Y. I. SHIH, a Y.-C. CHIANG, a,b1 J.-C. CHEN, c,d C.-H. HUANG, a,b Y.-Y. CHEN, e R.-S. LIU, f C. CHANG a * AND F.-S. JAW b * a Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China b Institute of Biomedical Engineering, National Taiwan University, Tai- pei, Taiwan, Republic of China c Department of Biomedical Imaging and Radiological Sciences, Na- tional Yang-Ming University, Taipei, Taiwan, Republic of China d Department of Education and Research, Taipei City Hospital, Taipei, Taiwan, Republic of China e Department of Electrical and Control Engineering, National Chiao- Tung University, Hsinchu, Taiwan, Republic of China f School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China Abstract—Preclinical exploration of pain processing in the brain as well as evaluating pain-relief drugs in small ani- mals embodies the potential biophysical effects in hu- mans. However, it is difficult to measure nociception-re- lated cerebral metabolic changes in vivo, especially in unanesthetized animals. The present study used 18 F-flu- orodeoxyglucose small-animal positron emission tomog- raphy to produce cerebral metabolic maps associated with formalin-induced nociception. Anesthesia was not applied during the uptake period so as to reduce possible con- founding effects on pain processing in the brain. The for- malin stimulation at the hind paw of rats resulted in signif- icant metabolic increases in the bilateral cingulate cortex, motor cortex, primary somatosensory cortex, secondary somatosensory cortex, insular cortex, visual cortex, cau- date putamen, hippocampus, periaqueductal gray, amyg- dala, thalamus, and hypothalamus. Among the measured areas, clear lateralization was only evident in the primary somatosensory cortex and hypothalamus. In addition, pre- treatment with lidocaine (4 mg/kg, i.v.) and morphine (10 mg/kg, i.v.) significantly suppressed formalin-induced cerebral metabolic increases in these areas. The present protocol allowed identification of the brain areas involved in pain processing, and should be useful in further evalu- ations of the effects of new drugs and preclinical therapies for pain. © 2008 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: PET, pain, morphine, lidocaine, rat. Novel pain-relief drugs and therapeutic techniques have been developed in recent years to alleviate human suffer- ing from pain. However, the mechanisms and circuits un- derlying pain processing are extremely complex, involving not only sensory responses to noxious stimuli, but also cognitive and emotional factors (McMahon and Koltzen- burg, 2005). This makes it difficult to conclusively identify the brain areas that specifically process nociceptive stim- uli. Imaging approaches such as positron emission tomog- raphy (PET) and functional magnetic resonance imaging (fMRI) allow functional mapping of the intact brain and measurement of the responses in multiple areas simulta- neously, thus bringing the study of pain into a deep level (Phelps et al., 1979; Ogawa et al., 1990a,b; Phelps, 2000). Preclinical verification for evaluating the efficacy of pain-alleviation strategies is usually essential. Of the nu- merous pain-testing models in animals, formalin test is one of the most commonly used techniques for generating nociception since it evokes inflammatory pain responses without influencing other sensory modalities; furthermore, the associated behavioral responses have been well in- vestigated (Tjolsen et al., 1992). Our recent animal fMRI studies have shown that formalin stimulation of the rat hind paw significantly activates the cingulate cortex (Cg), motor cortex (M), primary somatosensory cortex (S1), secondary somatosensory cortex (S2), insular cortex (IC), visual cor- tex (VC), caudate putamen (CPu), hippocampus (HIP), periaqueductal gray (PAG), thalamus (Th), and hypothal- amus (HT) (Shih et al., in press, 2008b). However, it is usually essential to apply anesthesia during fMRI experi- ments in order to sedate the animal and reduce motion artifacts. This tackles a very difficult technical obstacle when imaging the representation of pain in anesthetized animals. Small-animal positron emission tomography (mi- croPET) might be more suitable for imaging brain activa- tion in the conscious animals (Schiffer et al., 2007; Ohashi et al., 2008). An animal can react to stimuli outside the scanner without stresses during the uptake of radionuclide, and then be lightly anesthetized for imaging the accumu- lated responses, thus minimizing possible confounding variables that could influence central nociceptive process- ing. 1 Equal contribution with first author. *Corresponding author. Tel: +886-2-2789-9027; fax: +886-2-2788- 7641 (C. Chang); Tel: +886-2-3366-5266; fax: +886-2-2394-0049 (F.-S. Jaw). E-mail address: bmcchen@ibms.sinica.edu.tw (C. Chang), jaw@ntu. edu.tw (F.-S. Jaw). Abbreviations: Amyg, amygdala; Cg, cingulate cortex; CPu, caudate putamen; fMRI, functional magnetic resonance imaging; HIP, hip- pocampus; HT, hypothalamus; IC, insular cortex; M, motor cortex; MAP, maximum a posteriori; microPET, small-animal positron emis- sion tomography; PAG, periaqueductal gray; PET, positron emission tomography; S1, primary somatosensory cortex; S2, secondary so- matosensory cortex; Th, thalamus; VC, visual cortex; 18 F-FDG, 18 F- fluorodeoxyglucose; %ID/g, percentage injected dose per gram. Neuroscience 155 (2008) 1221–1226 0306-4522/08 © 2008 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2008.07.013 1221