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Leech Mechanosensation  

Brian D. Burrell

The medicinal leech (Hirudo verbana) is an annelid (segmented worm) and one of the classic model systems in neuroscience. It has been used in research for over 50 years and was one of the first animals in which intracellular recordings of mechanosensory neurons were carried out. Remarkably, the leech has three main classes of mechanosensory neurons that exhibit many of the same properties found in vertebrates. The most sensitive of these neurons are the touch cells, which are rapidly adapting neurons that detect low-intensity mechanical stimuli. Next are the pressure cells, which are slow-adapting sensory neurons that respond to higher intensity, sustained mechanostimulation. Finally, there are nociceptive neurons, which have the highest threshold and respond to potentially damaging mechanostimuli, such as a pinch. As observed in mammals, the leech has separate mechanosensitive and polymodal nociceptors, the latter responding to mechanical, thermal, and chemical stimuli. The cell bodies for all three types of mechanosensitive neurons are found in the central nervous system where they are arranged as bilateral pairs. Each neuron extends processes to the skin where they form discrete receptive fields. In the touch and pressure cells, these receptive fields are arranged along the dorsal-ventral axis. For the mechano-only and polymodal nociceptive neurons, the peripheral receptive fields overlap with the mechano-only nociceptor, which also innervates the gut. The leech also has a type of mechanosensitive cell located in the periphery that responds to vibrations in the water and is used, in part, to detect potential prey nearby. In the central nervous system, the touch, pressure, and nociceptive cells all form synaptic connections with a variety of motor neurons, interneurons, and even each other, using glutamate as the neurotransmitter. Synaptic transmission by these cells can be modulated by a variety of activity-dependent processes as well as the influence of neuromodulatory transmitters, such as serotonin. The output of these sensory neurons can also be modulated by conduction block, a process in which action potentials fail to propagate to all the synaptic release sites, decreasing synaptic output. Activity in these sensory neurons leads to the initiation of a number of different motor behaviors involved in locomotion, such as swimming and crawling, as well as behaviors designed to recoil from aversive/noxious stimuli, such as local bending and shortening. In the case of local bending, the leech is able to bend in the appropriate direction away from the offending stimuli. It does so through a combination of which mechanosensory cell receptive fields have been activated and the relative activation of multiple sensory cells decoded by a layer of downstream interneurons.


Pain and Its Modulation  

Asaf Keller

Sensory perceptions are inherently subjective, being influenced by factors such as expectation, attention, affect, and past experiences. Nowhere is this more commonly experienced than with the perception of pain, whose perceived intensity and emotional impact can fluctuate rapidly. The perception of pain in response to the same nociceptive signal can also vary substantially between individuals. Pain is not only a sensory experience. It also involves profound affective and cognitive dimensions, reflecting the activation of and interactions among multiple brain regions. The modulation of pain perception by such interactions has been most extensively characterized in the context of the “descending pain modulatory system.” This system includes a variety of pathways that directly or indirectly modulate the activity of neurons in the spinal dorsal horn, the second-order neurons that receive inputs directly from nociceptors. Less understood are the interactions among brain regions that modulate the affective and cognitive aspects of pain perception. Emerging data suggest that certain pain conditions result from dysfunction in pain modulation, suggesting that targeting these dysfunctions might have therapeutic value. Some therapies that are thought to target pain modulation pathways—such as cognitive behavior therapy, mindfulness-based stress reduction, and placebo analgesia—are safer and less expensive than pharmacologic or surgical approaches, further emphasizing the importance of understanding these modulatory mechanisms. Understanding the mechanisms through which pain modulation functions may also illuminate fundamental mechanisms of perception and consciousness.


Invertebrate Nociception  

Nathaniel J. Himmel, Atit A. Patel, and Daniel N. Cox

Nociception is a protective mechanism that mediates behavioral responses to a range of potentially damaging stimuli, including noxious temperature, chemicals, and mechanical stimulation. Nociceptive mechanisms are found throughout metazoans. Noxious stimuli are transduced by specialized, high-threshold peripheral nociceptors, which fire action potentials to elicit adaptive behavioral responses. Nociception is essential for survival and provides a mechanism for sensory perception of noxious stimuli, which alerts the organism to potential environmental dangers. When coupled with pain sensation and complex behavioral responses, this mechanism protects the organism from incipient damage. Moreover, acute and chronic pain may manifest as altered nociception in neuropathic pain states. Elucidating the neural bases of nociception is therefore important for identifying and implementing novel strategies for the treatment of neuropathic pain, as well as uncovering the mechanistic bases by which the nervous system integrates information to produce specific behaviors in response to a range of noxious stimuli. Invertebrate organisms, such as Drosophila melanogaster and Caenorhabditis elegans, have emerged as powerful, genetically tractable platforms for exploring these questions. Here, we concisely review the current state of knowledge regarding the cells, molecules, neural circuits, and behaviors associated with invertebrate nociception in the fruit fly and nematode worm.


Neuroinflammation and Neuroplasticity in Pain  

Jürgen Sandkühler

Much progress has been made in unraveling the mechanisms that underlie the transition from acute to chronic pain. Traditional beliefs are being replaced by novel, more powerful concepts that consider the mutual interplay of neuronal and non-neuronal cells in the nervous system during the pathogenesis of chronic pain. The new focus is on the role of neuroinflammation for neuroplasticity in nociceptive pathways and for the generation, amplification, and mislocation of pain. The latest insights are reviewed here and provide a basis for understanding the interdependence of chronic pain and its comorbidities. The new concepts will guide the search for future therapies to prevent and reverse chronic pain. Long-term changes in the properties and functions of nerve cells, including changes in synaptic strength, membrane excitability, and the effects of inhibitory neurotransmitters, can result from a wide variety of conditions. In the nociceptive system, painful stimuli, peripheral inflammation, nerve injuries, the use of or withdrawal from opioids—all can lead to enhanced pain sensitivity, to the generation of pain, and/or to the spread of pain to unaffected sites of the body. Non-neuronal cells, especially microglia and astrocytes, contribute to changes in nociceptive processing. Recent studies revealed not only that glial cells support neuroplasticity but also that their activation can trigger long-term changes in the nociceptive system.