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P.1.G.070 PHARMACOLOGICAL BLOCKADE of GPR55 in the ANTERIOR CINGULATE CORTEX REDUCES FORMALIN-EVOKED NOCICEPTIVE BEHAVIOUR in RATS Bright N

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P.1.G.070 PHARMACOLOGICAL BLOCKADE of GPR55 in the ANTERIOR CINGULATE CORTEX REDUCES FORMALIN-EVOKED NOCICEPTIVE BEHAVIOUR in RATS Bright N P.1.g.070 PHARMACOLOGICAL BLOCKADE OF GPR55 IN THE ANTERIOR CINGULATE CORTEX REDUCES FORMALIN-EVOKED NOCICEPTIVE BEHAVIOUR IN RATS Bright N. Okine 1, 3, Gemma McLaughlin 1 , Michelle Roche 2, 3 , David P. Finn 1, 3 1Pharmacology and Therapeutics, 2Physiology, School of Medicine, 3Galway Neuroscience Centre and Centre for Pain Research, NCBES, National University of Ireland Galway, University Road, Galway, Ireland Introduction Results Intra-ACC administration of the GPR55 antagonist Intra-ACC administration of the GPR55 •The G-protein coupled receptor 55 reduced second phase formalin-evoked antagonist reduced ERK (GPR55), is a putative novel cannabinoid nociceptive behaviour in rats phosphorylation in the ACC receptor expressed throughout the central nervous system (CNS), including key brain regions such as the anterior cingulate cortex (ACC)1 which is associated with the ERK 1 ERK 2 cognitive-affective components of pain2. 1.2 150 150 Vehicle •Pharmacological modulation of GPR55 in CID 100 100 the rat periaqueductal grey (PAG) affects 0.9 * nociceptive responding in rodents3. vehicle of 50 vehicle of 50 * expressed as a % a as expressed % a as expressed ERK 42 (phospho/total) 42 ERK (phospho/total) 44 ERK 0.6 0 0 •The PAG is a key component of the descending pain pathway, an endogenous pain modulatory system, and is subject to 0.3 Total ERK (1/2) modulation by higher brain centres including Vehicle CID the ACC. However, the role of. GPR55 150 p=0.06 Composite pain scorepain Composite 0.0 signalling in the ACC in pain processing is unknown. 0-5 100 6-10 11-1516-2021-2526-3031-3536-4041-4546-5051-5556-60 Vehicle 50 total 42+44 / total 42+44 •This study investigated the effects of direct Time bins (5 mins) / 44+42 Phospho administration of the selective GPR55 0 antagonist, CID16020046, into the ACC, on Figure 1. Effects of bilateral microinjections of the GPR55 formalin-evoked nociceptive behaviour in antagonist CID16020046 into the ACC on formalin-evoked Figure 3. Western blotting analysis of ERK 1/2 protein nociceptive behaviour in rats. CID16020046 reduced second phosphorylation in the ACC. Data are means ± SEM. * rats and the molecular and neuronal phase (21-35mins) formalin-evoked nociceptive behaviour. Data are p<0.05 veh vs CID16020046, Unpaired t-test. Vehicle n = 8 and mechanisms mediating these effects. means ± SEM. *p<0.05, vehicle vs CID16020046. Repeated CID16020046, n = 6 rats per group. ERK- extracellular signal measures ANOVA. Vehicle n = 8, CID16020046, n = 6 rats. regulated kinase. Methods Intra-ACC administration of the GPR55 Intra-ACC administration of the GPR55 antagonist did not alter pre-formalin antagonist prevented formalin–induced locomotor activity, grooming or rearing increases in c-FOS mRNA in the ipsilateral behaviour in rats dorsal horn of spinal cord Distance Grooming 2000 100 80 150 1500 contra 60 ipsi 1000 * 40 500 100 20 Duration (seconds) Duration Distance Moved (cm) Moved Distance 0 0 mRNA 50 Fos ipsi vehicle) ipsi c- Rearing (expressed as % as (expressed 150 Vehicle 0 CID 100 vehicle CID16020046 50 Figure 4. qRT-PCR measurement of c-Fos mRNA in the Duration (seconds) Duration spinal cord dorsal horn of vehicle-treated or CID16020046- 0 treated rats. Data are mean ± SEM, *p<0.05, Unpaired t-test. Figure 2 .Pre-formalin locomotor activity, grooming and rearing Vehicle, n = 8 and CID16020046, n = 6 rats per group, contra; behaviour in rats. Data are mean ± SEM, unpaired t-test ,Vehicle; n contra lateral, ipsi;ipsilateral. All procedures in animals were approved by the Animal Care and Research Ethics Committee, National University of Ireland, Galway, and carried out under licence from the Irish Department of Health and = 8, CID16020046; n = 6. Children, in line with the European Communities Council directive 86/609 guidelines on the use of animals in scientific research. References GPR55 protein expression in the Summary and Conclusions rat ACC • Selective GPR55 blockade in the rat ACC by 1. Henstridge, CM et al., (2011) Minireview: recent CID16020046 : developments in the physiology and pathology of the lysophosphatidylinositol-sensitive receptor GPR55. Mol •Reduced second phase of formalin-evoked nociceptive Endocrinol, 25, 1835-48 behaviour. 2. Shackman, AJ et al, (2011) The integration of negative •Reduced ERK phosphorylation in the ACC. affect, pain and cognitive control •Prevented formalin-induced increases in mRNA coding in the cingulate cortex Nature Reviews for Neuroscience 12, 154-167 3 Deliu, E., M. Sperow, et al. (2015). "The c-Fos in the ipsilateral dorsal horn of the spinal cord. Lysophosphatidylinositol Receptor GPR55 Modulates Pain Perception in the Periaqueduactal Grey." •These data suggest that endogenous activation of Mol Pharmacol. 2015 Aug;88(2):265-72 GPR55 signalling and ERK phosphorylation in the ACC may facilitate formalin-evoked nociceptive behaviour. Figure 5. Western blotting analysis of GPR55 Acknowledgements protein in the rat anterior cingulate cortex • The attenuation of formalin-evoked spinal c-Fos (ACC). Image is representative of n=3 samples / 3 expression by CID16020046 suggests modulatory effects rats. M-molecular weight marker of GPR55 signalling in the ACC on the descending pain Science foundation pathway. Ireland(10/IN.1/B2976) The authors have no conflicts of interest to declare.
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