Animal Models of Peripheral Neuropathy: Modeling What We Feel, Understanding What They Feel

Abstract

A lmost everyone has experienced the severe discomfort associated with hitting the “funny bone,” the pushing of the humerus distal medial epicondyle against the ulnar nerve. There is nothing amusing, however, about neuropathic pains and paresthesias that occur chronically, as with peripheral neuropathy. This issue of the Journal details the science of peripheral neuropathy as discovered through animal models. This introduction highlights the clinical description of peripheral neuropathy in order to center on the challenges of constructing animal models. Peripheral neuropathy (PN) is a pervasive and complex condition affecting approximately 20 million people in the United States and more than 10% of persons aged 40 years or older (Gregg et al. 2004). PN encompasses a variety of etiologies and manifestations. The majority are acquired consequences of other conditions or processes. Table 1 summarizes some of the causes or contributors to PN. About one third of cases are considered to be idiopathic (Dyck et al. 1981). Many patients diagnosed with idiopathic PN have abnormal glucose tolerance tests or elevated fasting glucose levels and are considered to be prediabetic (Smith and Singleton 2013). Hypertriglyceridemia and obesity without diabetes also may be important etiologic or contributing factors in humans (Tesfaye et al. 2010) and rodents (Vincent et al. 2009). Diabetes mellitus is the most common identified cause of PN, and 60–70% of the current 26 million diabetics (Centers for Disease Control and Prevention 2011) have some degree of neuropathy. The increasing worldwide prevalence of metabolic syndrome and its associated conditions, including diabetes, suggest that PN will continue to be an important clinical subject. Mitochondrial abnormalities related to oxidative stress from hyperglycemia or hyperlipidemia are hypothesized to play an important role in diabetic PN (Picard and Turnball 2013; Sleigh et al. 2011). The use of pharmaceuticals (nucleoside/nucleotide reverse transcriptase inhibitors and cancer chemotherapy compounds) that target mitochondria is also associated with development or worsening of PN (Leung 2012; Xiao and Bennett 2012). Whether mitochondrial damage is a common mechanism in all PN remains to be determined. Without question, animal models will continue to be important in unraveling the pathobiology of PN. The most common type of PN is distal symmetrical sensorimotor polyneuropathy, which occurs in diabetes, with diminished thermal and vibratory sensation leading to sensory loss and eventually involving pain and autonomic fibers (Tesfaye et al. 2010). With PN, clinical symptoms depend on the predilection of causative conditions to target particular peripheral fiber types (sensory, motor, autonomic, or different permutations of these three) and the type of stimulus that activates each nociceptor (e.g., thermal or mechanical). Assorted regions and functions of the peripheral neuron are affected, whether by direct injury or genetic predisposition, including dorsal root ganglion cation channel signaling (Staaf et al. 2009), axon transport (Holzbauer and Scherer 2011), and myelin sheath formation (Robinson et al. 2008). Clinically, a continuum of symptoms can occur, ranging from muscle weakness, spasticity, hyporeflexia, burning-type or aching pain, hyperalgesias, hypoalgesias, allodynia, dysesthesias, paresthesias, anesthesia in the hands and feet, poor proprioception, and hypotension to cardiac conduction abnormalities. Sensorimotor and sensory neuropathies occur more frequently than autonomic neuropathy, which may affect bowel function, bladder emptying, heart rate variation, and blood pressure controls. Human peripheral nervous system (PNS) perturbations lead to sensations that are episodic, paroxysmal, or constant, as well as evoked or spontaneous sensations, a spectrum of situations that render preclinical modeling problematic. Joanna Brell, MD, is Program Director in the Division of Cancer Prevention, National Cancer Institute, at the National Institutes of Health in Bethesda, MD. Address correspondence and reprint requests to Dr. Joanna Brell at 9609 Medical Center Drive 5E436, Bethesda, MD 2892-9785 or email brelljm@ mail.nih.gov