The role of PKA and PKCε pathways in prostaglandin E2-mediated hypernociception

Background and purpose:

Protein kinase (PK) A and the ε isoform of PKC (PKCε) are involved in the development of hypernociception (increased sensitivity to noxious or innocuous stimuli) in several animal models of acute and persistent inflammatory pain. The present study evaluated the contribution of PKA and PKCε to the development of prostaglandin E₂ (PGE₂)-induced mechanical hypernociception.

Experimental approach:

Prostaglandin E₂-induced mechanical hypernociception was assessed by constant pressure rat paw test. The activation of PKA or PKCε was evaluated by radioactive enzymic assay in the dorsal root ganglia (DRG) of sensory neurons from the hind paws.

Key results:

Hypernociception induced by PGE₂ (100 ng) by intraplantar (i.pl.) injection, was reduced by i.pl. treatment with inhibitors of PKA [A-kinase-anchoring protein St-Ht31 inhibitor peptide (AKAPI)], PKCε (PKCεI) or adenylyl cyclase. PKA activity was essential in the early phase of the induction of hypernociception, whereas PKC activity was involved in the maintenance of the later phase of hypernociception. In the DRG (L4-L5), activity of PKA increased at 30 min after injection of PGE₂ but PKC activity increased only after 180 min. Moreover, i.pl. injection of the catalytic subunit of PKA induced hypernociception which was markedly reduced by pretreatment with an inhibitor of PKCε, while the hypernociception induced by paw injection of PKCε agonist was not affected by an inhibitor of PKA (AKAPI).

Conclusions and implications:

Taken together, these findings are consistent with the suggestion that PKA activates PKCε, which is a novel mechanism of interaction between these kinases during the development of PGE₂-induced mechanical hypernociception.     

Multi-center transferability of a breath-hold T2 technique for myocardial iron assessment

Background

Cardiac iron overload is the leading cause of death in thalassemia major and is usually assessed using myocardial T2* measurements. Recently a cardiovascular magnetic resonance (CMR) breath-hold T2 sequence has been developed as a possible alternative. This cardiac T2 technique has good interstudy reproducibility, but its transferability to different centres has not yet been investigated.

Methods and Results

The breath-hold black blood spin echo T2 sequence was installed and validated on 1.5T Siemens MR scanners at 4 different centres across the world. Using this sequence, 5–10 thalassemia patients from each centre were scanned twice locally within a week for local interstudy reproducibility (n = 34) and all were rescanned within one month at the standardization centre in London (intersite reproducibility). The local interstudy reproducibility (coefficient of variance) and mean difference were 4.4% and -0.06 ms. The intersite reproducibility and mean difference between scanners were 5.2% and -0.07 ms.

Conclusion

The breath-hold myocardial T2 technique is transferable between Siemens scanners with good intersite and local interstudy reproducibility. This technique may have value in the diagnosis and management of patients with iron overload conditions such as thalassemia.