Chronic, destructive inflammation is at the core of a wide variety of diseases and conditions.
Inflammation, whether acute or chronic, is very often associated with pain. Similar to inflammation, pain can be physiological (an adaptive means of protecting tissues from real or perceived danger) or pathological (chronic, and often debilitating despite resolution of the original stimulus). Chronic pain can be caused by a variety of situations including inflammatory diseases such as osteo‐ and rheumatoid arthritis (inflammatory pain), tumor formation (cancer pain), and nerve injury (neuropathic pain).
While the process of physiological nociception and pain perception is very complex, depending on the quality, intensity, and locality of the stimulus and the species, developmental age, and psychological state of the subjects (i.e., stress level, anticipation, emotional state, etc.), the general pathway for transmitting pain information to the brain is well documented. Nociceptors are pseudounipolar neurons with unencapsulated peripheral terminals the skin, muscles, joints, or viscera; cell bodies residing in the dorsal root ganglion (DRG); and central terminals in the dorsal horn of the spinal cord. There are generally two types of nociceptors – A‐fibers are fast‐conducting with myelinated axons and have small receptive fields for stimulus localization while C‐fibers are slower with unmyelinated axons that are bundled into fascicles wrapped by Schwann cells and have broad receptive fields. Nociceptors normally are electrically silent and have a high threshold compared to somatosensory neurons involved in, for example, vision or hearing. Once stimulated, nociceptors produce all or nothing action potentials releasing glutamate as their primary neurotransmitter and having excitatory effects on postsynaptic cells in the dorsal horn. In the dorsal horn, primary afferent neurons either synapse directly with projection neurons or, more commonly, first with a variety of excitatory and inhibitory interneurons for signal modification. Ascending projection neurons extend, mostly contralaterally, to supraspinal targets including the caudal ventrolateral medulla, the nucleus of the solitary tract, the lateral parabrachial area, the periaqueductal grey matter, and the thalamus. Descending pathways projecting from the nucleus raphe magnus and the locus coeruleus release serotonin and norepenephrin, respectively, via volume transmission in the DRG to further modify pain processing. All along the pain processing pathway, from the primary afferent nociceptors, to the dorsal horn of the spinal cord, to the supraspinal processing centers and including descending projections that further modify processing, there is a delicate balance of excitation and inhibition that is important for properly representing the pain stimulus. Miss‐communication at any of these locations can result in chronic pain.
Selecting Relevant Preclinical Models
Pain therapies can provide relief either through targeting sensitizing agents or by inhibiting the activity of neurons involved in the pain processing directly. Choosing the appropriate pain model should be based off the primary mechanism, site of action, drug class, and required behavioral readouts. Additionally, pain models themselves can be highly customized once the appropriate model has been selected based on the mode of delivery and target. MD Biosciences has extensive experience working with a wide range of drug classes as well as customized applications for route of delivery. We can help choose the appropriate model and approach for your pain therapeutics program. Read a case study covering customized approaches in pain therapies and contact us if you would like to discuss your program.