Top‐down control of pain

The symposium on the ‘Top‐down control of pain’, held at Physiology 2016 in Dublin, highlighted recent advances in our understanding of the profound effects of the brain on spinal pain transmission. Often, when considering neuronal processing of nociceptive information, our focus is primarily on ascending pathways sub‐serving localisation and perception, and the complex behaviours and affective responses evoked by that pain are very often overlooked. Pain evokes multiple effects on the body resulting in, for example, movement away from the cause of the pain, and autonomic responses affecting cardiovascular and respiratory systems (Bandler et al. 2000). Under some circumstances, endogenous systems can both inhibit and enhance pain, depending on conditions (Vanegas & Schaible, 2004). When thought about carefully, it is obvious that the brain can exert potent effects on our perception of pain. For example mindfulness meditation is being used as an adjunct method of pain management to enable coping, and to reduce the impact of pain on the individual (Grant, 2014), and there is some evidence that mindfulness meditation practice can target and activate/change specific brain regions associated with pain (Tang et al. 2015).

The periaqueductal grey matter (PAG) together with the rostroventral medulla (RVM) and the dorsal horn of the spinal cord (in descending order) represents a descending control system than can modulate spinal processing through both inhibitory and facilitatory mechanisms (Behbehani, 1995; Lei et al. 2014). This symposium brought together overviews on the different ways in which the central nervous system, with a focus on the PAG–RVM–spinal cord pathway, can modulate sensory and motor systems, ranging from exercise, to specific neurotransmitter pathways, and from facilitation to inhibition. The symposium also covered important advances in the understanding of how these mechanisms change throughout development.

The symposium was opened by Kathleen Sluka (University of Iowa, USA), who in the first review covers the conundrum of how exercise can produce both analgesia and pain (Lima et al. 2017). Exercise is commonly recommended for various painful musculoskeletal conditions, including osteoarthritis and fibromyalgia, and has been shown to be effective in many trials. Patients with pain, in whom exercise can initially exacerbate that pain, may find this counter‐intuitive; the exacerbation of pain can also result in patients finding treatment very challenging. The analgesic effects of exercise can be reduced by naloxone suggesting that opioidergic descending inhibitory pathways are involved. There is also evidence that exercise reduces central excitability, in addition to engaging inhibitory pathways, as temporal summation, interpreted as a measure of central excitability, is enhanced in both healthy subjects and people with arthritis. In animal models, short periods of exercise produce analgesia in healthy animals and in neuropathic pain and other pain models, that results from an engagement and enhancement of descending endogenous opioidergic, serotonergic and cannabinoid inhibitory systems, while activity in brainstem excitatory glutamatergic systems is reduced (DeSantana et al. 2009; Radhakrishnan & Sluka, 2009; Da Silva et al. 2010). In contrast to these findings, more prolonged fatigue‐inducing exercise in animal models, such as two hours of wheel running, enhances pain in both male and female mice, but to a greater degree in females, attributable to the effects of oestrogen. The pain resulting from this fatiguing exercise combined with a low grade localised inflammation in muscle results in widespread pain in the animals. These effects can be attributed to activation and phosphorylation of NR1 subunits of NMDA receptors in the RVM, specifically in the nucleus raphe obscurus and nucleus raphe pallidus.

The second speaker Stella Koutsikou (University of Bristol, UK) introduced the midbrain PAG, an integrative control area that controls RVM activity, providing an overview of the control exerted by the PAG on the integration of sensorimotor systems (Koutsikou et al. 2017). Stella extended the theme of descending control, to encompass controls over both sensory and motor systems. Her review succinctly summarises very recent findings on how the PAG integrates both proprioceptive and nociceptive information in order to inform cerebellar responses (Watson et al. 2013; Koutsikou et al. 2015). Additionally, the PAG controls motor outputs; it has been known for some time that stimulation of different areas of the PAG can produce either passive (e.g. freezing), or active (e.g. flight or fight) behaviours (Carrive, 1993; Bandler & Shipley, 1994; Behbehani, 1995; Bandler et al. 2000; Keay & Bandler, 2002), ensuring appropriate motor responses to external and internal challenges. Koutsikou and colleagues show how different motor responses are produced by descending facilitatory controls on spinal α‐motoneurons. This work shows that the PAG is an important interface for the control and integration of both sensory and motor functions (Koutsikou et al. 2015), receiving inputs from higher centres such as the amygdala, hypothalamus and cortex, and relaying modulatory responses to brainstem, cerebellum and spinal cord to effect appropriate behavioural responses that enhance survival.

Kirsty Bannister (University College London, UK) discussed diffuse noxious inhibitory controls (DNIC), the neurochemicals that control the spinal cord processing of nociceptive inputs, and the balance between noradrenaline (inhibitory) and serotonin (facilitatory) actions in this system and alterations in neuropathic pain (Bannister & Dickenson, 2017). DNIC, first described by Le Bars and colleagues, is a descending control system that mediates the inhibition of one pain by another noxious input (Villanueva & Le Bars, 1995). This system involves multiple brainstem regions, including RVM, PAG, locus coeruleus, parabrachial nucleus and nucleus subreticularis dorsalis, with controls from higher centres such as the cingulate cortex and limbic areas. Kirsty gave an overview of comprehensive evidence showing the change in balance between inhibitory noradrenergic and facilitatory serotonergic influences in spinal neuronal processing following nerve injury, with a loss of descending inhibitory controls, and enhanced facilitation through de novo activation of spinal cord 5‐HT7 receptors (Bannister et al. 2015, 2017). Importantly from a translational perspective, these mechanisms also apply to conditioned pain modulation (CPM), the human correlate of DNIC (Bannister et al. 2009; Yarnitsky, 2010).

The symposium concluded with the final speaker Gareth Hathway (University of Nottingham, UK), who extended the discussions further by considering the development of these descending control systems, from infancy to adulthood. Very little is known about descending control systems in early development and the effect of pain experience in these systems. Work from Gareth and others shows that not only is there refinement of descending control systems such as opioidergic pathways during postnatal maturation, there is also postnatal refinement in ascending pathways through thalamus and cortex (Devonshire et al. 2015). Recent evidence also shows that early life exposure to noxious events can alter the development of descending control systems from the RVM (Walker et al. 2015). In addition to covering the emerging evidence in postnatal development alterations in nociceptive processing, Gareth gave a comprehensive overview of very recent evidence on neurochemical pathways involved. Developmental changes in descending opioidergic pathways are known to occur (Hathway et al. 2009, 2012; Kwok et al. 2014); in this presentation Gareth covered new evidence suggesting there are also functional developmental changes in the endocannabinoid system from the neonate to the adult.

Top‐down control of pain is a major determinant of sensory, cognitive, affective and behavioural aspects of the pain experience. The topics included in this workshop emphasise the diverse nature and importance of such top‐down controls to the performance of vital functions that support normal activity and survival throughout life.

Additional information

Competing interests

None declared.