Welcome by chair
Evolutionary adaptations of nociceptors in mammals
Dr Ewan St John Smith, University of Cambridge, UK
Utilising comparative biology, single-cell transcriptome analysis, human tissue and the study of variation in human nociception, the Smith lab and collaborators have identified a variety of evolutionary adaptations in mammalian nociceptors. Unusually among animals, it was found that naked mole-rats lacked a behavioural response to capsaicin or acid, even though receptors for detecting both substances are expressed by naked mole-rat nociceptors. However, an absence of nociceptor neuropeptides alongside altered spinal cord connectivity underpins the capsaicin insensitivity, whereas acid-insensitivity largely results from an amino acid variation in the voltage-gated sodium channel 1.7 such that acid switches it off. It was further demonstrated that naked mole-rats lack nerve-growth factor (NGF) induced hyperalgesia due to hypofunctionality of the NGF receptor TrkA. Using transcriptomic analysis of identified sensory neurones in mice, the Smith lab have recently discovered sensory neurone subsets that have likely evolved for specific functional purposes, ie subsets subserving pain and subsets mediating mechanosensation, using human tissue to validate findings. In further studies, altered pain phenotypes have been identified in humans and tracked back to changes in ion channel function, demonstrating a shared sensory pathway in mice. Overall, this research highlights a variety of evolutionary adaptations in mammalian nociceptors across species.
Primitive and recently evolved mechanisms driving persistent pain in mammals
Dr Theodore Price, University of Texas, USA
Damaging stimuli change the excitability of nociceptors in species where experiments have been conducted to examine such changes. In many cases this plasticity, which leads to a lowering of action potential threshold and increased excitability upon depolarization, is long-lasting, outliving the duration of the plasticity-inducing stimulus. This plasticity also sometimes leads to the development of spontaneous activity in nociceptors, which is believed to be a key driver of chronic pain. Dr Price will argue that this form of intrinsic neuronal plasticity is ancient, perhaps the first form of neuronal plasticity, and is critically dependent on changes in gene expression within the sensitized neuron. Interestingly, this plasticity is not dependent on transcription but is reliant on translation and the existing evidence strongly supports the conclusion that the signaling mechanism is conserved across evolution. In Aplysia, mice, rats, and humans, persistent nociceptor plasticity requires activation of the mechanistic target of rapamycin (mTOR) and mitogen activated protein kinase (MAPK) pathways. Emerging evidence suggests that this translational event may be mediated by a single phosphorylation event at a site on a protein that binds the 5’ cap structure of mRNAs called eukaryotic translation initiation factor 4E (eIF4E) in vertebrates and invertebrates. Despite the striking conservation of this signaling event, translational events that occur downstream of eIF4E are likely divergent across species and point to the importance of degeneracy in signaling in nociceptor plasticity. This degeneracy is likely to be a key challenge in developing chronic pain medicines that can target this form of sensitization.
Epigenetics and mechanisms of chronic pain
Dr Sandrine Géranton, University College London, UK
Two factors influence animal behaviors: the genes we inherit and environmental experiences. For example, in both rats and humans, stressful early life events such as being reared by an inattentive mother can leave a lasting trace and affect stress response in adult life. This is due to a chemical trace left on the chromatin, the combination of DNA and proteins that make up chromosomes. This trace has been attributed to so called epigenetic mechanisms and can have long-term consequences of the functioning of our genes. In other words, epigenetic processes provide a bridge between the genes and the environment by imprinting experiences such as social interactions onto the genome, thereby allowing individuals to adapt to their environment within their lifetime.
This talk will focus on the role of the stress axis in the development of persistent pain and will describe how past experience, such as injury, can be imprinted onto our chromatin by epigenetic mechanisms and could therefore be a major determinant not only of the pain experience but also, perhaps, of the susceptibility to chronic pain. Dr Géranton will also discuss the likelihood that these epigenetic mechanisms are evolutionarily conserved across phyla, like other sensization mechanisms that drive long-lasting pain states. Finally, the possibility that epigenetic effects of stress can be transmitted across generations and therefore might modulate the pain experience across generations will be debated with the audience.
Emotional and cognitive processes related to chronic pain in mammals revealed by brain imaging
Dr Catherine Bushnell, National Institutes of Health, USA
Chronic pain in humans can lead to many co-morbidities, including anxiety, depression and cognitive deficits. On the reverse side, emotional and cognitive factors, including attention and mood state, alter pain perception. Studies in rats, rhesus monkeys and humans show a preservation of the relationship between pain, emotions and cognitions across mammalian species. Almost half of people who experience chronic pain have associated anxiety, depression and/or cognitive changes. We have examined the development of similar co-morbidities in rats and mice and found that after a neuropathic injury causing long-term pain behaviours, the rodents develop memory deficits, anxiety-like behaviour and anhedonia, a cardinal sign of depression. In both rodents and humans, structural changes in brain areas, including in pain-modulatory brain circuitry, develop along with the pain co-morbidities. In humans, descending pain-modulatory circuitry involved in attentional and emotional modulation of pain has been identified using brain imaging methodology. In rhesus monkeys, we have examined the activity of single neurons in afferent pain pathways and shown that nociceptive activity is reduced when the monkey’s attention is diverted away from the noxious stimulus, similar to what is shown in humans using functional MRI. Finally, in both humans and rodents, there is evidence that chronic pain leads to reductions in the availability of opioid receptors within pain-modulatory brain regions. Together, these findings suggest that the brain circuitry underlying pain perception and modulation by psychological factors is preserved across mammalian species.
Mice are people too: social modulation of and by pain in mice and undergraduates
Dr Jeffrey Mogil, McGill University, Canada
Many believe social phenomena such as empathy and helping behaviours to be the sole province of humans. However, evidence of these abilities are starting to be demonstrated in non-human animals, and even in rodents. The speaker will discuss recent experiments in my lab and others' showing the effect of social communication on pain behaviour, and the effect of pain on social interactions. The group have found that mice are capable of empathy (emotional contagion) and apparent helping behaviour, that pain status is communicated by facial expression, and that intriguing mouse-mouse and mouse-human interactions can importantly affect laboratory studies of pain. Many of these phenomena can be translated to human beings in a surprisingly direct manner. The ease of such translation has direct implications for evolutionary theories of pain communication.