title: Impairment of adenylyl cyclase-mediated glutamatergic synaptic plasticity in the periaqueductal grey in a rat model of neuropathic pain.
abstract: CONCLUSIONS
  Long-lasting neuropathic pain has been attributed to elevated neuronal plasticity changes in spinal, peripheral and cortical levels. Here, we found that reduced neuronal plasticity in the ventrolateral periaqueductal grey (vlPAG), a midbrain region important for initiating descending pain inhibition, may also contribute to neuropathic pain. Forskolin- and isoproterenol (isoprenaline)-elicited EPSC potentiation was impaired in the vlPAG of a rat model of neuropathic pain induced by spinal nerve injury. Down-regulation of adenylyl cyclase-cAMP- PKA signalling, due to impaired adenylyl cyclase, but not phosphodiesterase, in glutamatergic terminals may contribute to the hypofunction of excitatory synaptic plasticity in the vlPAG of neuropathic rats and the subsequent descending pain inhibition, ultimately leading to long-lasting neuropathic pain. Our results suggest that drugs that activate adenylyl cyclase in the vlPAG have the potential for relieving neuropathic pain.
  Neuropathic pain has been attributed to nerve injury-induced elevation of peripheral neuronal discharges and spinal excitatory synaptic plasticity while little is known about the contribution of neuroplasticity changes in the brainstem. Here, we examined synaptic plasticity changes in the ventrolateral (vl) periaqueductal grey (PAG), a crucial midbrain region for initiating descending pain inhibition, in spinal nerve ligation (SNL)-induced neuropathic rats. In vlPAG slices of sham-operated rats, forskolin, an adenylyl cyclase (AC) activator, produced long-lasting enhancement of EPSCs. This is a presynaptic effect since forskolin decreased the paired-pulse ratio and failure rate of EPSCs, and increased the frequency, but not the amplitude, of miniature EPSCs. Forskolin-induced EPSC potentiation was mimicked by a β-adrenergic agonist (isoproterenol (isoprenaline)), and prevented by an AC inhibitor (SQ 22536) and a cAMP-dependent protein kinase (PKA) inhibitor (H89), but not by a phosphodiesterase (PDE) inhibitor (Ro 20-1724) or an A1 -adenosine antagonist (DPCPX). Both forskolin- and isoproterenol-induced EPSC potentiation was impaired in PAG slices of SNL rats. The SNL group had lower AC, but not PDE, activity in PAG synaptosomes than the sham group. Conversely, IPSCs in vlPAG slices were not different between SNL and sham groups. Intra-vlPAG microinjection of forskolin alleviated SNL-induced mechanical allodynia in rats. These results suggest that SNL leads to inadequate descending pain inhibition resulting from impaired glutamatergic synaptic plasticity mediated by the AC-cAMP-PKA signalling cascade, possibly due to AC down-regulation in the PAG, leading to long-term neuropathic pain.
authors: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.
authors: Yu-Cheng
authors: YC
authors: Ho
authors: Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan.|Department of Medicine, Mackay Medical College, New Taipei City, Taiwan.
authors: Jen-Kun
authors: JK
authors: Cheng
authors: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.|Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.|Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.|Neurobiology and Cognitive Science Centre, National Taiwan University, Taipei, 10051, Taiwan.
authors: Lih-Chu
authors: LC
authors: Chiou
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D009473:Neuronal Plasticity; D010487:Periaqueductal Gray / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D018698:Glutamic Acid; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases