Many psychoactive substances are used with the aim of altering experience, e.g. as analgesics, antidepressants or antipsychotics. These drugs act on specific receptor systems in the brain, including the opioid, serotonergic and dopaminergic systems. In this talk, I will summarise human drug studies targeting opioid receptors and their role for human experience, with focus on the experience of pain, stress, mood, and social connection. Opioids are only indicated for analgesia, due to their potential to cause addiction. When these regulations occurred, other known effects were relegated to side effects. This may be the cause of the prevalent myth that opioids are the most potent painkillers, despite evidence from head-to-head trials, Cochrane reviews and network meta-analyses that opioids are not superior to non-opioid analgesics in the treatment of acute or chronic non-cancer pain. However, due to the variability and diversity of opioid effects across contexts and experiences, some people under some circumstances may indeed benefit from prolonged treatment. I will present data on individual differences in opioid effects due to participant sex and stress induction. Understanding the effects of these commonly used medications on other aspects of the human experience is important to ensure correct use and to prevent unnecessary pain and addiction risk.

We provide protocols for the social transfer of pain and analgesia in mice. We describe the steps to induce pain or analgesia (pain relief) in bystander mice with a 1-h social interaction with a partner injected with CFA (complete Freund’s adjuvant) or CFA and morphine, respectively. We detail behavioral tests to assess pain or analgesia in the untreated bystander mice. This protocol has been validated in mice and rats and can be used for investigating mechanisms of empathy. Highlights • A protocol for the rapid social transfer of pain in rodents • Detailed requirements for handling and housing conditions • Procedures for habituation, social interaction, and pain induction and assessment • Adaptable for social transfer of analgesia and may be used to study empathy in rodents https://doi.org/10.1016/j.xpro.2022.101756

How the brain creates a painful experience remains a mystery. Solving this mystery is crucial to understanding the fundamental biological processes that underlie the perception of body integrity, and to creating better, non-addictive pain treatments. My laboratory’s goal is to resolve the neural basis of pain. We aim to understand the mechanisms by which our nervous system produces and assembles the sensory-discriminative, affective-motivational, and cognitive-evaluative dimensions of pain to create this unique and critically important experience. To capture every component of the pain experience, we examine the entirety of the pain circuitry, from sensory and spinal ascending pathways to cortical/subcortical circuits and brainstem descending pain modulation systems, at the molecular, cellular, circuit and whole-animal levels. For these studies, we have invented novel behavioral paradigms to interrogate the affective and cognitive dimensions of pain in mice while simultaneously imaging and manipulating nociceptive circuits. My laboratory also investigates how opioids suppress pain. Remarkably, despite their medical and societal significance, how opium poppy alkaloids such as morphine produce profound analgesia remains largely unexplained. By identifying where and how opioids act in neural circuits, we not only establish the mechanisms of action of one of the oldest drugs known to humans, but also reveal the critical elements of the pain circuitry for developing of novel analgesics and bringing an end to the opioid epidemic.

Empathy plays a critical role in social interactions, and many species, including rodents, display evolutionarily conserved behavioral antecedents of empathy. In both humans and rodents, the anterior cingulate cortex (ACC) encodes information about the affective state of others. However, little is known about which downstream targets of the ACC contribute to empathy behaviors. We optimized a protocol for the social transfer of pain behavior in mice and compared the ACC-dependent neural circuitry responsible for this behavior with the neural circuitry required for the social transfer of two related states: analgesia and fear. We found that a 1-hour social interaction between a bystander mouse and a cagemate experiencing inflammatory pain led to congruent mechanical hyperalgesia in the bystander. This social transfer led to activation of neurons in the ACC and several downstream targets, including the nucleus accumbens (NAc), which was revealed by monosynaptic rabies virus tracing to be directly connected to the ACC. Bidirectional manipulation of activity in ACC-to-NAc inputs influenced the acquisition of socially transferred pain. Further, the social transfer of analgesia also depended upon ACC-NAc inputs. By contrast, the social transfer of fear instead required activity in ACC projections to the basolateral amygdala. This shows that mice rapidly adopt the sensory-affective state of a social partner, regardless of the valance of the information (pain, fear, or pain relief). We find that the ACC generates specific and appropriate empathic behavioral responses through distinct downstream targets. More sophisticated understanding of evolutionarily conserved brain mechanisms of empathy will also expedite the development of new therapies for the empathy-related deficits associated with a broad range of neuropsychiatric disorders.

The ability to experience pain is old in evolutionary terms. It is an experience shared across species. Acute pain is the body’s alarm system, and as such it is a good thing. Pain that persists beyond normal tissue healing time (3-4 months) is defined as chronic – it is the system gone wrong and it is not a good thing. Chronic pain has recently been classified as both a symptom and disease in its own right. It is one of the largest medical health problems worldwide with one in five adults diagnosed with the condition. The brain is key to the experience of pain and pain relief. This is the place where pain emerges as a perception. So, relating specific brain measures using advanced neuroimaging to the change patients describe in their pain perception induced by peripheral or central sensitization (i.e. amplification), psychological or pharmacological mechanisms has tremendous value. Identifying where amplification or attenuation processes occur along the journey from injury to the brain (i.e. peripheral nerves, spinal cord, brainstem and brain) for an individual and relating these neural mechanisms to specific pain experiences, measures of pain relief, persistence of pain states, degree of injury and the subject's underlying genetics, has neuroscientific and potential diagnostic relevance. This is what neuroimaging has afforded – a better understanding and explanation of why someone’s pain is the way it is. We can go ‘behind the scenes’ of the subjective report to find out what key changes and mechanisms make up an individual’s particular pain experience. A key area of development has been pharmacological imaging where objective evidence of drugs reaching the target and working can be obtained. We even now understand the mechanisms of placebo analgesia – a powerful phenomenon known about for millennia. More recently, researchers have been investigating through brain imaging whether there is a pre-disposing vulnerability in brain networks towards developing chronic pain. So, advanced neuroimaging studies can powerfully aid explanation of a subject’s multidimensional pain experience, pain relief (analgesia) and even what makes them vulnerable to developing chronic pain. The application of this goes beyond the clinic and has relevance in courts of law, and other areas of society, such as in veterinary care. Relatively far less work has been directed at understanding what changes in the brain occur during altered states of consciousness induced either endogenously (e.g. sleep) or exogenously (e.g. anaesthesia). However, that situation is changing rapidly. Our recent multimodal neuroimaging work explores how anaesthetic agents produce altered states of consciousness such that perceptual experiences of pain and awareness are degraded. This is bringing us fascinating insights into the complex phenomenon of anaesthesia, consciousness and even the concept of self-hood. These topics will be discussed in my talk alongside my ‘side-story’ of life as a scientist combining academic leadership roles with doing science and raising a family.