Abstract
The rostroventral medial medulla (RVM) is part of a rapidly acting spino-bulbo-spinal loop that is activated by ascending nociceptive inputs and drives descending feedback modulation of spinal nociception. In the adult rat, the RVM can facilitate or inhibit dorsal horn neuron inputs but in young animals descending facilitation dominates. It is not known whether this early life facilitation is part of a feedback loop. We hypothesized that the newborn RVM functions independently of sensory input, before the maturation of feedback control. We show here that noxious hind paw pinch evokes no fos activation in the RVM or the periaqueductal gray at postnatal day (P) 4 or P8, indicating a lack of nociceptive input at these ages. Significant fos activation was evident at P12, P21, and in adults. Furthermore, direct excitation of RVM neurons with microinjection of DL-homocysteic acid did not alter the net activity of dorsal horn neurons at P10, suggesting an absence of glutamatergic drive, whereas the same injections caused significant facilitation at P21. In contrast, silencing RVM neurons at P8 with microinjection of lidocaine inhibited dorsal horn neuron activity, indicating a tonic descending spinal facilitation from the RVM at this age. The results support the hypothesis that early life descending facilitation of spinal nociception is independent of sensory input. Since it is not altered by RVM glutamatergic receptor activation, it is likely generated by spontaneous brainstem activity. Only later in postnatal life can this descending activity be modulated by ascending nociceptive inputs in a functional spinal-bulbo-spinal loop.
Highlights
To test the age at which ascending functional nociceptive connections are formed in the brainstem, and the afferent limb of the spinal-bulbo-spinal loop is established, noxious-evoked fos activity was mapped in 3 brainstem regions: the PB nucleus, ventrolateral PAG (vlPAG), and the rostroventral medulla (RVM) (Figs. 1A–I)
There was no fos increase in the vlPAG and the RVM after hind paw, noxious pinch stimulation at P4 or P8 but a significant increase in the number of Fos-ir cells compared with control at P12, P21, and in adults (2-way analysis of variance (ANOVA) with Bonferroni post hoc analysis, control vs pinch, P, 0.05-0.001 at different ages, Figs. 1K and L)
In this early postnatal period, RVM descending control on dorsal horn neurons is independent of noxious sensory input to the RVM
Summary
Spinal dorsal horn sensory inputs and nociceptive reflexes are modulated by descending brainstem controls[45] that underlie the control of pain by stress, fear, reward, and expectation.[6,13,25,44] The rostroventral medulla (RVM) plays a key role in this process as it contains neurons that project down to the spinal dorsal horn[27,30] and receive inputs from higher centers such as the insular cortex,[47] the periaqueductal gray (PAG), and parabrachial (PB) nucleus.[8,39,55] Nociceptive dorsal horn pathways terminate in the PB nucleus and PAG (the afferent limb), which in turn activate RVM neurons projecting back to the dorsal horn (the efferent limb) forming a spinal-bulbospinal loop. Descending RVM modulation in adult animals is biphasic and can facilitate or inhibit acute spinal nociception[16,17,60] in an injury and context-specific manner.[10,38,51,60]
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