Neuropathic Pain: Basic Mechanisms (Animal)

Chronic pain represents one of the most significant health problems globally and is the most common reason for seeking medical attention. According to the World Health Organization (WHO), 22% of primary care patients have chronic pain lasting more than 6 months. The socioeconomic cost of chronic pain in the US alone is estimated to be $90 billion due to lost productivity, sick time, and direct medical costs. One chronic pain condition that is difficult to manage medically is neuropathic pain. Neuropathic pain may result from traumatic injury to nerves, infection that involves the nerve (e.g., varicella), progressive diseases such as diabetes or may be pharmacologically induced by, for example, chemotherapeutic agents. Individuals with neuropathic pain often present with spontaneous burning pain, recurrent paroxysmal pain, and allodynia, defined as intense pain in response to a stimulus that is normally not perceived as being painful, or as an exaggerated response or perception of intensity of a noxious stimulus. Although the mechanisms that drive such pain are not fully understood, substantial experimental evidence has uncovered neuronal pathways and mediators through which neuropathic pain may be initiated and/or maintained. Considerable evidence suggests that enhanced sensitivity and/or abnormal enhanced excitability of peripheral nerves promote enhanced pain perception. Peripheral sensitization may be result as a consequence of the release of proinflammatory mediators and growth factors. Processes of nociceptor sensitization can involve both rapid adaptations of molecular sensors as well as time-dependent adaptations, which can include transcriptional regulation and changes in trafficking of these molecules. Wallerian degeneration of injured peripheral nerves is associated with increased expression of trophic factors, such as nerve growth factor (NGF), which may elicit increased sensitivity of peripheral nociceptive fibers through increased expression of ion channels in injured or adjacent uninjured nerves, thus lowering their response thresholds to external stimuli. The enhanced activity of peripheral afferent fibers entering the spinal cord can lead to increased sensitivity (spinal sensitization) of second-order neurons that project to pain processing sites in the brain. Prolonged afferent input can also elicit other postsynaptic adaptations including increased expression of excitatory neurotransmitters in the spinal dorsal horn, which can result in long-term sensitization of spinal cord neurons. These changes result in increased sensitivity of projection neurons to peripheral stimulation, upregulation of NK1 receptors, N-methyl-d-aspartic acid (NMDA) receptors, increased PGE2 release, and elevated levels of spinal dynorphin. Finally, it has been found that sustained increased afferent inputs lead to neuroplastic changes in supraspinal sites critical to descending modulation of nociception. In experimental models of chronic pain conditions, the rostralventromedial medulla (RVM) shows evidence of increased activity of descending pain facilitatory pathways to the spinal cord. These projections from the RVM enhance the sensitivity of dorsal horn neurons to afferent input and also promote the release of excitatory neurotransmitters from primary afferent terminals. Evidence suggests that experimental neuropathic pain may be maintained by a spinal–supraspinal–spinal loop that provides a feedback to constantly maintain abnormal pain. These processes and how they relate to neuropathic pain will be discussed.