Reticular Formation and Pain: The Past and the Future

Abstract

The involvement of the reticular formation (RF) in the transmission and modulation of nociceptive information has been extensively studied. The brainstem RF contains several areas which are targeted by spinal cord afferents conveying nociceptive input. The arrival of nociceptive input to the RF may trigger alert reactions which generate a protective/defense reaction to pain. RF neurons located at the medulla oblongata and targeted by ascending nociceptive information are also involved in the control of vital functions that can be affected by pain, namely cardiovascular control. The RF contains centers that belong to the pain modulatory system, namely areas involved in bidirectional balance (decrease or enhancement) of pain responses. It is currently accepted that the imbalance of pain modulation towards pain facilitation accounts for chronic pain. The medullary RF has the peculiarity of harboring areas involved in bidirectional pain control namely by the existence of specific neuronal populations involved in antinociceptive or pronociceptive behavioral responses, namely at the rostroventromedial medulla (RVM) and the caudal ventrolateral medulla (VLM). Furthermore the dorsal reticular nucleus (also known as subnucleus reticularis dorsalis; DRt) may enhance nociceptive responses, through a reverberative circuit established with spinal lamina I neurons and inhibit wide-dynamic range (WDR) neurons of the deep dorsal horn. The components of the triad RVM-VLM-DRt are reciprocally connected and represent a key gateway for top-down pain modulation. The RVM-VLM-DRt triad also represents the neurobiological substrate for the emotional and cognitive modulation of pain, through pathways that involve the periaqueductal gray (PAG)-RVM connection. Collectively, we propose that the RVM-VLM-DRt triad represents a key component of the “dynamic pain connectome” with special features to provide integrated and rapid responses in situations which are life-threatening and involve pain. The new available techniques in neurobiological studies both in animal and human studies are producing new and fascinating data which allow to understand the complex role of the RF in pain modulation and its integration with several body functions and also how the RF accounts for chronic pain.

Pain Processing in Older Adults and Its Association with Prefrontal Characteristics

“…In this study, we aimed to investigate whether experimental pain responses in older individuals correlate with FA of the white matter tracts between the prefrontal cortex and the periaqueductal gray (PAG), located in the brainstem. The PAG has direct anatomical connections with the prefrontal cortex [38] and sends neuronal input to key components of the descending pain modulatory system, including the rostroventromedial medulla, caudal ventrolateral medulla, and dorsal reticular nucleus [39]. Stein et al (2012) have demonstrated that FA of the white matter tracts connecting the prefrontal cortex with the PAG correlates with placebo analgesia [40].…”

Serotoninergic pain modulation from the rostral ventromedial medulla (RVM) in chemotherapy‐induced neuropathy: The role of spinal 5‐HT3 receptors

“…The PAG is proposed to function as the gateway for pain control from higher brain centres to the spinal cord (Close, Cetas, Heinricher, & Selden, ; Martins & Tavares, ; Silva, Costa‐Pereira, Martins, & Tavares, ). The PAG does not project directly to the spinal cord but uses a relay located at the rostral ventromedial medulla (RVM).…”

A Review on Chronic Pain in Rheumatoid Arthritis: A Focus on Activation of NR2B Subunit of N-Methyl-D-Aspartate Receptors

“…In another study, using CFA-induced chronic inflammatory pain model, Hu et al (27) found a strong activity of the NR2B subunit of NMDAR that was selectively upregulated in the PAG. RVM is an intermediate in PAG to modulate pain as this region is a crucial integrated relay in the descending modulation of pain (27,68,69). The activation of ON cells in RVM results in the facilitation of nociceptive transmission while the stimulation of OFF cells mediates the inhibition of nociceptive processing (69).…”