Neuropeptides and neurotrophin receptor mRNAs primary sensory neurons of aged rats

Abstract

Neuropeptides and neurotrophin receptors are regulated in primary sensory neurons in response to axonal injury, and axonal lesions are characteristic stigmata of aging primary sensory neurons. We have therefore examined the expression of neuropeptides and neurotrophin receptor mRNAs in 30-month-old (median survival age) Sprague-Dawley rats to see if similar adaptive mechanisms operate in senescence. The content of neuropeptides was examined with immunohistochemistry (IHC) and in situ hybridization (ISH), and the cellular mRNA expression of neurotrophin receptors was studied with ISH. All of the aged rats had symptoms of hind limb incapacity (posterior paralysis), but fore limbs did not seem affected. The size-distribution of neuronal profiles in cervical and lumbar dorsal root ganglia (DRGs) was similar in aged and young adult (2-3 months old) rats. In aged rats, the DRG neurons showed an increase in both immunolabelling and mRNA content of neuropeptide tyrosine (NPY), as well as an increased cellular expression of galanin mRNA. In the same animals, there were decreased cellular levels of calcitonin gene-related peptide (CGRP; IHC and ISH) and substance P (SP; IHC and ISH), while the difference in neuronal somatostatin (IHC and ISH) was small. The distribution of neuropeptide immunoreactivities in the dorsal horn of the corresponding spinal cord segments revealed a decreased labelling for CGRP-, SP-, and somatostatin-like immunoreactivities (LI) in the aged rats at both cervical and lumbar levels. NPY- and galanin-LI had a similar distribution in aged and young adult rats. NPY-immunoreactive fibers were also encountered in the dorsal column of aged but not young adult rats. ISH revealed that most of the primary sensory neurons express mRNA for the p75 low-affinity neurotrophin receptor (p75-LANR) and that there was no discernible difference between young adult and aged rats. The labelling intensity for mRNA encoding high-affinity tyrosine kinase receptors (TrkA, TrkB, and TrkC) was decreased in aged rat DRG neurons, while the percentage of neuronal profiles expressing mRNA for TrkA/B/C was similar in young adult and aged rats. The changed pattern of neuropeptide expression in primary sensory neurons of aged rats resembled that seen in young adult rats subjected to axonal injury of peripheral sensory nerves and may, thus, indicate aging-related lesions of sensory fibers. Since NPY is primarily present in large and galanin in small DRG neurons, the stronger effect on NPY as compared to galanin expression may indicate that aging preferentially affects neurons associated with mechanoreception (A alpha and A beta fibers) as compared to nociceptive units (A delta and C fibers). Furthermore, the observed changes in neuropeptide expression were most pronounced in lumbar DRGs, that harbors the sensory neurons supplying the affected hindlimbs of the rats.

Primary afferent nociceptor mechanisms mediating NGF‐induced mechanical hyperalgesia

“…This supports the suggestion that NGF acts on the nociceptive afferent to induce mechanical hyperalgesia and that TrkA is the NGF receptor on primary afferent nociceptors at which NGF acts to produce mechanical hyperalgesia. Our studies do not rule out a role for the p75 neurotrophin receptor, which is also found in primary afferent nociceptors (Bergman et al, 1996). Indeed, in our preliminary behavioural experiments, we found that while there was a detectable inhibition of NGF-induced hyperalgesia in the presence of antisense oligodeoxynucleotide against p75, such inhibition was much smaller in magnitude than the inhibition we observed using antisense targeting TrkA (unpublished observations).…”

Peripheral and spinal mechanisms of nociception in a rat reserpine-induced pain model

“…This pattern of altered mechanical sensitivity combined with a reduced number of mechanoresponsive unmyelinated C-fibers is also observed in aging 28,29,51,53 and diabetic neuropathy, 18,36 and may also correspond with reports of small-fiber polyneuropathy in some patients diagnosed with fibromyalgia 32 and restless legs syndrome. 38 These changes seem to be related with decreased neurotrophic factors in primary sensory neurons, 3,18 however, in a reserpine-induced pain model, no apparent histological changes were detected in the sciatic nerve bundle and DRG by light microscopy, 27 which suggests that this paradoxical change in mechanical sensitivity likely results from reserpine-mediated functional alterations in the peripheral nervous system.…”

Augmented mechanical response of muscular thin‐fiber receptors in aged rats recorded in vitro

“…Changes in the peripheral nociceptive pathways with age have also been studied: decrease in the number of thin-fiber afferents (Nakayama et al, 1998;Azcoitia et al, 2003), conduction velocity (Sato et al, 1985), and sensory neurons containing neuropeptides (Bergman et al, 1996).…”