Postnatal development shifts the balance of pain descending control

Abstract

The endogenous descending pain modulatory circuit consists of the midbrain periaqueductal grey (PAG), the rostral ventral medulla (RVM) and the spinal cord (Fig. 1) (Fields et al. 2006). The PAG integrates input from the limbic forebrain (including the amygdala) and the diencephalon with ascending input from the dorsal horn. Early studies have described the PAG–RVM system as a descending inhibitory control, playing a role in endogenous analgesia or in creating sufficient spinal gain for pain sensory signal detection. It is now clear that the descending control is bidirectional, including also facilitatory mechanisms. The final output of this system is determined by the dynamic balance between inhibition and facilitation, that can be altered in different behavioural, emotional and pathological states. Figure 1 Maturation of pain modulating pathways during postnatal development The RVM, which mainly consists of the midline nucleus raphe magnus and the adjacent gigantocellular reticular nucleus, is directly connected to dorsal horn neurons, particularly those located in laminae I, II and V. The spinal projections of RVM contain multiple transmitters, such as serotonin, GABA, glycine, somatostatin and enkephalin (Millan, 2002). The effects of RVM electrical stimulation on dorsal horn neuronal activity and on behavioural nocifensive responses (such as the nocifensive flexor reflex) are often bimodal: low stimulation intensities cause facilitation, while higher intensities generate inhibition (Zhuo & Gebhart, 1997). Two classes of pain modulatory neurons, on-cells and off-cells, could account for the biphasic control exerted by RVM. On-cells typically show a sudden increase of firing immediately before the onset of a nocifensive reflex, while off-cells exhibit a pause in activity before the nocifensive response. Selective activation of on-cells results in enhanced sensitivity to noxious stimulation (Neubert et al. 2004), while recruitment of off-cells produces behavioural antinociception (Heinricher & Tortorici, 1994). Several studies have proposed that a shift in the balance of the RVM circuitry, for example if on-cell activity predominates over that of off-cells, mediates the facilitatory role of the RVM in acute inflammation and after nerve injury (reviewed in Gebhart, 2004). Despite the critical role played by the PAG–RVM system in shaping the spinal response to noxious stimulation, very little is known about the control exerted by brain stem descending fibres during postnatal development. In the rat, the development of serotonin-containing descending fibres is quite prolonged, reaching the final maturation only after the third postnatal week. Similarly, the activation of PAG does not produce analgesia until P21, suggesting that descending inhibition could be less effective in the neonatal dorsal horn (Fitzgerald, 2005). The weakness of the descending inhibitory inputs during the first postnatal weeks could contribute to the exaggerated and diffuse cutaneous reflexes observed in neonates. Consistently, postnatal tuning of the nociceptive withdrawal reflex system is markedly disturbed in neonatally spinalized rats (Levinsson et al. 1999). The role of RVM projections in modulating the activity of dorsal horn neurons and the nocifensive withdrawal reflex during postnatal development has been investigated in the article by Hathway et al., published in this issue of The Journal of Physiology. In this study, electrical stimulation of RVM causes, in neonatal rats younger than P21, a facilitation of the nocifensive reflex at all stimulation intensities. Consistently, firing activity of deep dorsal neurons is mostly excited by RVM stimulation in young rats, while a net inhibition is observed in adult animals. This study provides, for the first time, evidence that the balance of excitatory and inhibitory influence of descending fibres changes during postnatal maturation, shifting from a facilitatory to a predominant inhibitory control over the spinal pain circuits. As previously hypothesized, the facilitatory influence of the RVM descending projections could contribute to the higher excitability of dorsal horn neurons in the immature spinal cord and participate to the postnatal development of nociceptive pathways (Fitzgerald, 2005). Further studies will be required to fully understand the synaptic circuits that participate in the descending control of pain, both in the immature and mature spinal cord. In particular, it is still not clear at which site (pre- vs. post-synaptic) the descending inhibitory and facilitatory fibres modulate dorsal horn neuron activity. Furthermore, the role of other neurotransmitters, beside serotonin, has not been fully characterized. A recent study has shown, by using in vivo patch-clamp recording from dorsal horn neurons, that RVM stimulation causes GABA and glycine release on lamina II neurons, evoking monosynaptic inhibitory responses (Kato et al. 2006). This experimental approach could be particularly useful to characterize the synaptic circuits and the modulatory mechanisms involved in brain stem descending control.