Nociceptive spinofugal pathways terminating at the caudal medulla oblongata target the dorsoreticular nucleus (DRt), the nucleus tractus solitarii (NTS) and the caudal ventrolateral reticular formation (VLM). While the spino-DRt pathway is involved in triggering pain-facilitating effects from the DRt, the spino-NTS and spino-VLM pathways have been implicated in nociceptive-cardiovascular integration. Spinal dorsal horn neurones involved are distributed through laminae I and IV-V. Curiously, the medullary projections of the two neuronal populations are in all cases segregated, pointing to differences in the role played by each of them. In the DRt, lamina I targets the ipsilateral dorsal-most portion, immediately beneath the cuneate nucleus, and laminae IV-V the remaining ventral two-thirds, bilaterally. In the NTS, lamina I targets the medial commissural subnucleus, bilaterally, and laminae IV-V the lateral subnucleus, ipsilaterally. In the VLM, lamina I targets the reticular formation (VLMlat) located between the lateral reticular nucleus (LRt) and the spinal trigeminal nucleus, pars caudalis, and laminae IV-V the lateral portion of the LRt. Furthermore, the structural types of lamina I neurones participating in the spino-NTS and spino-VLM pathways are the same (fusiform, pyramidal and flattened), while those projecting to the DRt differ, belonging mainly in the multipolar type followed by the pyramidal and flattened types. Both the NTS and VLM exert anti-nociceptive effects as revealed by the depression of nociceptive reflexes and inhibition of nociceptive responses of spinal neurones upon local stimulation. Direct pathways connect the NTS commissural subnucleus and the VLMlat with both superficial and deep spinal dorsal horn laminae. The VLMlat is also connected with the spinal cord through a disynaptic pathway relaying in the pontine A5 noradrenergic group, which is thought to convey the spinal a2-adrenoreceptor-mediated anti-nociception elicited from the VLM.
The well-known role of the NTS commissural subnucleus and the VLM in cardiovascular control, together with the demonstration that they are sites of termination of nociceptive spinal afferents, has been taken as a strong indication of the involvement of both areas in nociceptive and cardiovascular integration, namely in the genesis of autonomic reactions to pain. Taking into account their role in pain control, it is also possible that both areas can modulate spinal nociceptive transmission in response to changes in cardiovascular parameters. Hypertensive subjects, either humans or experimental animals, were shown to have higher pain thresholds than normotensive subjects. In spite of the large amount of data supporting those hypotheses, experimental studies aimed at their evaluation are lacking. We have recently addressed this issue by investigating the role of the VLM in hypertension-induced hypoalgesia. In rats in which hypertension was produced by either pharmacological (L-NAME) or surgical (renal artery constriction) means, spinal c-fos induction following noxious mechanical stimulation of the skin was reduced compared with normotensive animals. Lesioning the VLM in hypertensive animals prior to noxious stimulation prevented the decrease in spinal c-fos expression. Since the hypertension-induced hypoalgesia is mediated by spinal a2-adrenoreceptors, and the noradrenergic anti-nociceptive effects of the VLM are conveyed by the VLMlat-A5-spinal circuit, the observed VLM-dependent decrease of spinal c-fos expression in response to rises in blood presure is most likely accounted for by the VLMlat. On the other hand, the VLMlat by itself is capable of exerting the vasodepressor effects normally attributed to the VLM, as revealed by decrease in blood pressure and heart rate upon local stimulation and the opposite effect after lesioning. The VLMlat thus seems to be not only the VLM site in charge of pain control through both direct or indirect spinopetal pathways, but also an important centre for nociceptive and cardiovascular integration.