fMRI and Human Pain Perception

Almost 30 years ago, technology based on magnetic resonance imaging (MRI) made it possible to visualize the functional states of the human brain. This technology immediately spurred pain researchers to examine brain circuitry of human pain and relate brain activity patterns with verbal reports of subjective perception. There was a brief period prior to functional MRI (fMRI) when positron emission tomography (PET) and single-photon emission computed tomography (SPECT) technologies were used to identify brain states in humans reporting pain, but the noninvasiveness of fMRI and its higher spatial and temporal resolution quickly made the latter the preferred choice to study human brain physiology. Prior to the advent of such human brain imaging technologies, whether the neocortex was involved in pain perception was still an open question: In human brain injury studies, large cortical lesions seemed to have little effect on pain perception, and in animal electrophysiological studies (mostly done in anesthetized preparations) several years of single-unit electrophysiological explorations from large expanses of the cortex yielded a measly number of neurons responding to nociceptive stimuli and not a single neocortical column dedicated to nociception. What has been learned between the introduction of the technology and today? This chapter briefly reviews the subject, highlighting advances and novel insights and pointing to lingering gaps. It also outlines future directions from the viewpoint of understanding mechanisms for nociception, acute pain, and chronic pain. From a brain imaging viewpoint, the chapter tackles the last concepts regarding local neuronal representation and across neuronal integration of information.

Effect of Sleep Loss on Pain

With the advent of modern lifestyles, there has been a significant extension of daily activities, mostly at the cost of sleep. Lack of sleep affects many biological systems, including various cognitive functions, the immune system, metabolism, and pain. Both sleep and pain are complex neurological processes that encompass many dynamic components. As a result, defining the precise interactions between these two systems represents a challenge, especially for chronic paradigms. This chapter describes how sleep is measured and how it can be experimentally altered in humans and animal models, and, in turn, how sleep disturbances, either acute or chronic, can affect different aspects of pain. Possible mechanisms involved are discussed, including an increase in inflammatory processes, a loss of nociceptive inhibitory pathways, and a defect in the cognitive processing of noxious inputs.

Invertebrate Models of Nociception

Chronic pain is a significant public health problem, affecting 20–25% of the global population, and there is a clear need for more specific and effective therapeutics. To achieve this, a comprehensive understanding of the underlying mechanisms and molecular machinery driving pain-related diseases is required. The definition of pain as an “unpleasant sensory and emotional experience” associated with tissue injury is innately anthropomorphic, the emotional element being difficult to reconcile in nonhuman organisms. Even simple invertebrates are nevertheless capable of nociception, the neural processing of noxious stimuli. With the significant advantages of simpler nervous systems, experimental tractability, and a high level of conservation, they have a major role to play in advancing our understanding. This chapter reviews our current molecular- and circuit-level understanding of nociception in two of the most widely used invertebrate experimental models, the nematode Caenorhabditis elegans and the fly Drosophila melanogaster. In particular, it summarizes the molecules, cells, and circuits that contribute to nociception in response to diverse noxious stimuli in these model organisms and the behavioral paradigms that we can harness to study them. The chapter discusses how mechanistic insights gained from these experimental systems can improve our understanding of pain in humans.

The Neurobiology of Pain

The influence of development and sex on pain perception has long been recognized but only recently has it become clear that this is due to specific differences in underlying pain neurobiology. This chapter summarizes the evidence for mechanistic differences in male and female pain biology and for functional changes in pain pathways through infancy, adolescence, and adulthood. It describes how both developmental age and sex determine peripheral nociception, spinal and brainstem processing, brain networks, and neuroimmune pathways in pain. Finally, the chapter discusses emerging evidence for interactions between sex and development and the importance of sex in the short- and long-term effects of early life pain.

Potassium Channels and Pain

The K+ channel family is one of the most complex families of ion channels. The diversity of this channel family is a real challenge for the study of pain. Potassium channels form the largest family of ion channels in mammals, with more than 80 genes encoding α subunits in humans. Their differences in structures and functions divide them into four families, all of which are expressed in somatosensory neurons and supporting glial cells. The opening of K+ channels hyperpolarizes the plasma membrane, which opposes excitation of the neuron by all other depolarizing channels. K+ channels are very efficient regulators of the electrical activity of sensory neurons and of pain perception. Their potential for the development of antinociceptive pharmacology is immense.

Neurobiological Basis of Migraine

Migraine is the most common disabling primary headache globally. Attacks often present with unilateral throbbing headache and an array of associated symptoms, including, nausea, multisensory hypersensitivity, and marked fatigue. The diverse symptomatology highlights the complexity of migraine as a whole nervous system disorder involving somatosensory, autonomic, endocrine, and arousal networks. While attempts to describe the entirety of migraine are complex and daunting, this chapter focuses on recent advances in the understanding of its pathophysiology and treatment. The chapter focuses on the underlying neuroanatomical basis for migraine-related headache and associated symptomatology and discusses key clinical and preclinical findings that indicate that migraine likely results from dysfunctional homeostatic mechanisms. Whereby abnormal central nervous system responses to extrinsic and intrinsic cues may lead to increased attack susceptibility. Finally, the chapter considers the recent translational success of targeted calcitonin gene-related peptide and serotonin 1F receptor (5-HT1F) modulation for migraine.

Chemo- and Optogenetic Strategies for the Elucidation of Pain Pathways

Pain is not a simple phenomenon and, beyond its conscious perception, involves circuitry that allows the brain to provide an affective context for nociception, which can influence mood and memory. In the past decade, neurobiological techniques have been developed that allow investigators to elucidate the importance of particular groups of neurons in different aspects of the pain response, something that may have important translational implications for the development of novel therapies. Chemo- and optogenetics represent two of the most important technical advances of recent times for gaining understanding of physiological circuitry underlying complex behaviors. The use of these techniques for teasing out the role of neurons and glia in nociceptive pathways is a rapidly growing area of research. The major findings of studies focused on understanding circuitry involved in different aspects of nociception and pain are highlighted in this article. In addition, attention is drawn to the possibility of modification of chemo- and optogenetic techniques for use as potential therapies for treatment of chronic pain disorders in human patients.

Autoantibodies and Neuropathic Pain

A number of clinical studies indicated an association between autoantibodies and neuropathic pain. This is supported by the observation that immunotherapies that reduce antibody levels alleviate pain in patients and suggests that autoantibodies are not a byproduct of pathology but instead important drivers of neuropathic pain. These autoantibodies can target both neuronal and nonneuronal antigens within the sensory nervous system. Possible pathogenic mechanisms include nerve damage and inflammation as well as disruption of ion channel function. Whether autoantibodies are truly causal to neuropathic pain and exactly what their prevalence is in such pain conditions are important questions that are being addressed with the use of passive transfer in preclinical models and the screening of patient sera. Such studies support the idea that autoantibodies are a mechanism to cause neuropathic pain and provide insight into the molecular components regulating pain sensitivity in a pathological setting. Therefore, this work not only will be applicable to the treatment of patients with autoantibody-mediated pain, but also will facilitate the development of therapies to treat neuropathic pain in the more general context.

A History of Pain Research

Useful analgesic plant products have been known since antiquity. In recent times, the cell and molecular basis of damage detection and its complex relationship to pain perception have been explored in detail. A range of technical advances have given us considerable new knowledge about both the peripheral aspects of pain pathways and damage transduction as well as central mechanisms of pain modulation. Electrophysiology, imaging, genetic manipulation of animal models of pain, the role of the immune system, and genetic studies of human pain states have all provided new information. Remarkably, despite these advances, we are still uncertain about the locus of pain perception, while the development of new small-molecule analgesic drugs has had almost no success. This article summarizes the history of pain research and discusses present activities together with potential future routes to pain treatment.

Dorsal Horn Pain Mechanisms

The spinal dorsal horn and its equivalent structure in the brainstem constitute the first sites of synaptic integration in the pain pathway. A huge body of literature exists on alterations in spinal nociceptive signal processing that contribute to the generation of exaggerated pain states and hence to what is generally known as “central sensitization.” Such mechanisms include changes in synaptic efficacy or neuronal excitability, which can be evoked by intense nociceptive stimulation or by inflammatory or neuropathic insults. Some of these changes cause alterations in the functional organization of dorsal horn sensory circuits, leading to abnormal pathological pain sensations. This article reviews the present state of this knowledge. It does not cover the contributions of astrocytes and microglia in detail as their functions are the subject of a separate chapter.