The midbrain periaqueductal gray (PAG) is a crucial area involved in the descending pain inhibitory pathway. Using the whole cell patch clamp recording technique in the brain slices containing the PAG, we have proved the cellular mechanism of  mu-opioid-induced disinhibition in vlPAG neurons and the role of K_ATP channels in opioid-mediating antinociception. The PAG is one of dense distributed regions of a novel family member of opioid receptors, the nociceptin/orphanin FQ (N/OFQ) peptide  (NOP) receptor. Using PAG slice preparations, we have characterized the pharmacological profiles of tens of novel ligands of NOP receptors (6) and found there is functional heterogeneity of NOP receptors (3). We also explored the antinociceptive action of orexins (4), a novel hypothalamic neuropeptide family know for their roles in sleep, metabolic and reward regulations. Recently, we revealed a novel supraspinal antinociceptive mechanism mediated by orexin receptor-initiated endocannabinoid signaling in the PAG (1). Besides, we also found TRPV1 channel activation in the PAG can lead to analgesia via mGluR5 receptor-mediated endocannabinoid signaling (2). We are currently elucidating the role(s) of N/OFQ and orexins in the pathogenesis of several neurological and psychiatric disorders, including migraine, Tourette syndrome, schizophrenia, addiction, depression, parkinsonism, Alzheimer's diseases, and sleep disorders. In addition, using a postoperative pain model, we have revealed the role of the a2d subunit of calcium channels in the antinociceptive action of gabapentin (Neurontin) (7). My colleagues and I are also interested in the factors regulating hippocampal synaptic plasticity and learning and memory functions. We have found high-fat diet impairs hippocampal synaptic plasticity and learning in male but not female mice (5).

Publications:  

1] Activation of orexin 1 receptors in the periaqueductal gray of male rats leads to antinociception via retrograde endocannabinoid (2-arachidonoylglycerol)-induced disinhibition. J. Neurosci,31(41): 14600-14610. 2011  [Abstract]  [F1000 evaluated article]

2] Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition. Br. J. Pharmacol,163(2):330-345. 2011.  [Abstract]

3] Functional heterogeneity of nociceptin/orphanin FQ receptors revealed by (+)-5a Compound and Ro 64-6198 in rat periaqueductal gray slices. Int. J. Neuropsychopharmacol,14(7): 977-989. 2011.  [Abstract]

4] Orexins/Hypocretins: Pain regulation and cellular actions. Curr. Pharmaceut. Des,16(28): 3089-3100. 2010.  [Abstract]

5] Sex differences in high-fat diet-induced obesity, metabolic changes and learning and synaptic plasticity deficits in mice. Obesity,18(3): 463-469. 2010.  [Abstract]

6] Nociceptin/orphanin FQ peptide receptors: pharmacology and clinical implications. Curr. Drug Targets,8 (1): 117-135. 2007.  [Abstract]

7] Mechanisms of the antinociceptive action of gabapentin. J. Pharmacol. Sci. ,100: 471-486. 2006.  [Abstract]

1] Pharmacological characterization of novel NOP receptor ligands in rat PAG slices.

2] Heterogeneity of NOP receptors

3] Clinical implications of nociceptin and orexin A in neurological or psychiatric disorders

4] Antinociceptive mechanisms of orexins and capsaicin in the PAG

5] Interplays among nociceptin, orexins and endocannabinoids in stress-mediated effects

6] Synaptic plasticity changes induced by high-fat diets