The hyperalgesic effects induced by the injection of angiotensin II into the caudal ventrolateral medulla are mediated by the pontine A5 noradrenergic cell group

Abstract

The caudal ventrolateral medulla (CVLM) is a key component of the supraspinal pain modulatory system. Pain modulation from the CVLM is partially relayed by spinally projecting noradrenergic neurons of the pontine A5 cell group, which leave collateral fibres at the CVLM. The injection of angiotensin II (Ang II) into the CVLM was recently shown to induce hyperalgesia mediated by angiotensin type 1 (AT1) receptors, expressed by CVLM neurons that do not project to the spinal cord. The present study evaluates the effects of lesioning the noradrenergic pontine A5 cell group by the retrograde transport of the selective toxin anti-dopamine β-hydroxylase-saporin (anti-DBH-SAP) from the CVLM in pain behavioural responses elicited by Ang II injection into the CVLM. The injection of anti-DBH-SAP induced neurodegeneration, identified by the marker Fluoro-Jade B, restricted to the A5 noradrenergic cell group. These results were confirmed by the decrease in the number of noradrenergic neurons only in the A5 group. Pain behavioural evaluation using the formalin test showed that Ang II injection into the CVLM induced hyperalgesia, which was partially prevented by lesion of the A5 noradrenergic cell group with anti-DBH-SAP. Immunostaining of AT1 receptors in CVLM neurons retrogradely labelled from the A5 noradrenergic cell group showed that CVLM neurons that project to the A5 express AT1 receptors, indicating that Ang II can modulate directly the CVLM-A5 connection. The results show that Ang II-induced hyperalgesia elicited from the CVLM is mediated by an indirect pathway relayed at the pontine noradrenergic A5 group.