Abstract
Acute pain serves as a protective mechanism that alerts us to potential tissue damage and drives a behavioural response that removes us from danger. The neural circuitry critical for mounting this behavioural response is situated within the brainstem and is also crucial for producing analgesic and hyperalgesic responses. In particular, the periaqueductal grey, rostral ventromedial medulla, locus coeruleus and subnucleus reticularis dorsalis are important structures that directly or indirectly modulate nociceptive transmission at the primary nociceptive synapse. Substantial evidence from experimental animal studies suggests that plasticity within this system contributes to the initiation and/or maintenance of chronic neuropathic pain, and may even predispose individuals to developing chronic pain. Indeed, overwhelming evidence indicates that plasticity within this circuitry favours pro-nociception at the primary synapse in neuropathic pain conditions, a process that ultimately contributes to a hyperalgesic state. Although experimental animal investigations have been crucial in our understanding of the anatomy and function of the brainstem pain-modulation circuitry, it is vital to understand this system in acute and chronic pain states in humans so that more effective treatments can be developed. Recent functional MRI studies have identified a key role of this system during various analgesic and hyperalgesic responses including placebo analgesia, offset analgesia, attentional analgesia, conditioned pain modulation, central sensitisation and temporal summation. Moreover, recent MRI investigations have begun to explore brainstem pain-modulation circuitry plasticity in chronic neuropathic pain conditions and have identified altered grey matter volumes and functioning throughout the circuitry. Considering the findings from animal investigations, it is likely that these changes reflect a shift towards pro-nociception that ultimately contributes to the maintenance of neuropathic pain. The purpose of this review is to provide an overview of the human brain imaging investigations that have improved our understanding of the pain-modulation system in acute pain states and in neuropathic conditions. Our interpretation of the findings from these studies is often guided by the existing body of experimental animal literature, in addition to evidence from psychophysical investigations. Overall, understanding the plasticity of this system in human neuropathic pain conditions alongside the existing experimental animal literature will ultimately improve treatment options.
Highlights
Acute pain serves as a protective mechanism that leads to a behavioural response aimed at removing the individual from potential tissue damage
We found reduced connectivity between the locus coeruleus and periaqueductal grey matter (PAG) in patients, suggesting that altered resting interactions between the locus coeruleus and the PAG, subnucleus reticularis dorsalis (SRD), and rostral ventromedial medulla (RVM) may collectively contribute to the pro-nociceptive effects and reduced conditioned pain modulation (CPM) abilities that are often observed in patients with chronic neuropathic pain
There is growing evidence that the state of this brainstem system prior to injury is critical for the subsequent development of chronic pain, a situation that may reflect an individual’s ability to respond adequately to the cascade of events that occur at the dorsal horn (DH)/SpV following nerve injury
Summary
Acute pain serves as a protective mechanism that leads to a behavioural response aimed at removing the individual from potential tissue damage. Both preclinical and human post-mortem studies have reported chronic glial activation in the DH/SpV associated with chronic neuropathic pain [16,17,18,19] These changes are observed alongside a myriad of alterations in higher brain centres and are critical for the persistent activation of ascending pain pathways, contributing to the constant perception of pain. Advances in MRI scanner hardware and analysis techniques have recently allowed researchers to more directly examine small brainstem regions in humans [30,31,32] This has permitted the exploration of the function of this system in acute pain processing and during pain-modulation paradigms, and has allowed researchers to begin studying the structure and function of the endogenous pain-modulation circuitry in individuals with various chronic pain conditions, including chronic neuropathic pain. The review explores the results of these brain imaging investigations in the context of the existing experimental animal literature and clinical psychophysical studies
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