Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes

Abstract

Diabetic neuropathy (DN) is a common severe complication of type 2 diabetes. The symptoms of chronic pain, tingling, and numbness are generally attributed to small fiber dysfunction. However, little is known about the pathology among innervation to distal extremities, where symptoms start earliest and are most severe, and where the innervation density is the highest and includes a wide variety of large fiber sensory endings. Our study assessed the immunochemistry, morphology, and density of the nonvascular innervation in glabrous skin from the hands of aged nondiabetic rhesus monkeys and from age-matched monkeys that had different durations of spontaneously occurring type 2 diabetes. Age-related reductions occurred among all types of innervation, with epidermal C-fiber endings preferentially diminishing earlier than presumptive Adelta-fiber endings. In diabetic monkeys epidermal innervation density diminished faster, became more unevenly distributed, and lost immunodetectable expression of calcitonin gene-related peptide and capsaicin receptors, TrpV1. Pacinian corpuscles also deteriorated. However, during the first few years of hyperglycemia, a surprising hypertrophy occurred among terminal arbors of remaining epidermal endings. Hypertrophy also occurred among Meissner corpuscles and Merkel endings supplied by Abeta fibers. After longer-term hyperglycemia, Meissner corpuscle hypertrophy declined but the number of corpuscles remained higher than in age-matched nondiabetics. However, the diabetic Meissner corpuscles had an abnormal structure and immunochemistry. In contrast, the expanded Merkel innervation was reduced to age-matched nondiabetic levels. These results indicate that transient phases of substantial innervation remodeling occur during the progression of diabetes, with differential increases and decreases occurring among the varieties of innervation.

H3 Receptors and Pain Modulation: Peripheral, Spinal, and Brain Interactions

“…It should also be noted that studies of human skin of patients with complex regional pain syndrome type 1 and postherpetic neuralgia and studies of rhesus monkeys with type 2 diabetes have revealed significant structural and chemical pathologies among the various components of the skin that normally express H 3 Rs in rats and mice. These include not only perivascular A␦ fibers, but also epidermal keratinocytes, A␤ fiber Meissner's corpuscle endings, and lanceolate endings (Petersen et al, 2002;Albrecht et al, 2006;Cannon et al, 2007a;Paré et al, 2007;Zhao et al, 2008).…”

Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy

“…These can be at multiple sites along the axons, including distal terminals. Evidence from earlier studies has implicated multiple sites in the generation of ectopic activity, including peripheral nerve terminals (Albrecht et al, 2006;Kauppila et al, 2002;Pare et al, 2007), at the site of nerve injury (Bird et al, 2007;Coward et al, 2000;Devor et al, 1993;Novakovic et al, 1998;Omana-Zapata et al, 1997a,b;Tal and Eliav, 1996), along the nerve (Amir et al, 2005;Gold et al, 2003;Pertin et al, 2005), adjacent nerves (Sotgiu et al, 2006), and in the dorsal root ganglia (Amir et al, 1999;Chaplan et al, 2003;Craner et al, 2002;Liu et al, 2000bLiu et al, , 2002Michaelis et al, 2000;Na et al, 2000;Novakovic et al, 1998;Omana-Zapata et al, 1997a,b;Study and Kral, 1996;Xie et al, 1995).…”

Epidermal nerve fiber quantification in the assessment of diabetic neuropathy

“…The literature describing cutaneous innervation in non-human primates with diabetes is currently limited to a single paper assessing innervation of glabrous skin from monkeys with naturally occurring type 2 diabetes (Pare et al, 2007). Biopsies from monkeys with short-term hyperglycemia showed a hypertrophy of epidermal nerve fibers.…”