Pain. 2016 Aug 16. [Epub ahead of print]
N-palmitoylethanolamide in the anterior cingulate cortex attenuates inflammatory pain behaviour indirectly via a CB1 receptor-mediated mechanism.
Okine BN1, Madasu MK, McGowan F, Prendergast C, Gaspar JC, Harhen B, Roche M, Finn DP.
1aPharmacology and Therapeutics, National University of Ireland, Galway, IrelandbGalway Neuroscience Centre and Centre for Pain Research, National University of Ireland, University Road, Galway, IrelandcPhysiology, School of Medicine, National University of Ireland, Galway, Ireland.
The neural substrates and mechanisms mediating the antinociceptive effects of the endogenous bioactive lipid, N-palmitoylethanolamide (PEA), require further investigation. We investigated the effects of exogenous PEA administration into the anterior cingulate cortex (ACC), an important brain region linked with cognitive and affective modulation of pain, on formalin-evoked nociceptive behaviour in rats. Potential involvement of peroxisome proliferator-activated receptor isoforms (PPAR) a and ? or endocannabinoid-mediated entourage effects at cannabinoid1 (CB1) receptors or transient receptor potential subfamily V member 1 (TRPV1) in mediating the effects of PEA was also investigated. Intra-ACC administration of PEA significantly attenuated the first and early second phases of formalin-evoked nociceptive behaviour. This effect was attenuated by the CB1 receptor antagonist AM251, but not by the PPARa antagonist GW6471, the PPAR? antagonist GW9662, or the TRPV1 antagonist 5'-iodo resiniferatoxin. All antagonists, administered alone, significantly reduced formalin-evoked nociceptive behaviour, suggesting facilitatory/permissive roles for these receptors in the ACC in inflammatory pain. Post-mortem tissue analysis revealed a strong trend for increased levels of the endocannabinoid anandamide in the ACC of rats that received intra-ACC PEA. Expression of c-Fos, a marker of neuronal activity, was significantly reduced in the basolateral nucleus of the amygdala, but not in the central nucleus of the amygdala, the rostral ventromedial medulla or the dorsal horn of the spinal cord. In conclusion, these data indicate that PEA in the ACC can reduce inflammatory pain-related behaviour, possibly via AEA-induced activation of CB1 receptors and associated modulation of neuronal activity in the basolateral amygdala.
Sci Rep. 2016 Sep 19;6:33302. doi: 10.1038/srep33302.
Human CB1 Receptor Isoforms, present in Hepatocytes and ß-cells, are Involved in Regulating Metabolism.
González-Mariscal I1, Krzysik-Walker SM1, Doyle ME2, Liu QR1, Cimbro R2, Santa-Cruz Calvo S1, Ghosh S1, Ciesla L1, Moaddel R1, Carlson OD1, Witek RP3, O'Connell JF1, Egan JM1.
1Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
2Department of Medicine, Johns Hopkins Medical Institutes, Baltimore, MD 21224, USA.
3Thermo Fisher Scientific, 7300 Governor's Way, Frederick, MD 21704 USA.
Therapeutics aimed at blocking the cannabinoid 1 (CB1) receptor for treatment of obesity resulted in significant improvements in liver function, glucose uptake and pancreatic ß-cell function independent of weight loss or CB1 receptor blockade in the brain, suggesting that peripherally-acting only CB1 receptor blockers may be useful therapeutic agents. Neuropsychiatric side effects and lack of tissue specificity precluded clinical use of first-generation, centrally acting CB1 receptor blockers. In this study we specifically analyzed the potential relevance to diabetes of human CB1 receptor isoforms in extraneural tissues involved in glucose metabolism. We identified an isoform of the human CB1 receptor (CB1b) that is highly expressed in ß-cells and hepatocytes but not in the brain. Importantly, CB1b shows stronger affinity for the inverse agonist JD-5037 than for rimonabant compared to CB1 full length. Most relevant to the field, CB1b is a potent regulator of adenylyl cyclase activity in peripheral metabolic tissues. CB1b blockade by JD-5037 results in stronger adenylyl cyclase activation compared to rimonabant and it is a better enhancer of insulin secretion in ß-cells. We propose this isoform as a principal pharmacological target for the treatment of metabolic disorders involving glucose metabolism. |
