Aging impairs collateral sprouting of nociceptive axons in the rat
Introduction
A variety of age-related functional, structural and biochemical changes have been implicated in peripheral nerve disorders as well as in the reduced neuronal plasticity after peripheral nerve injury in old age (Cowen and Gavazzi, 1998, Gavazzi and Cowen, 1996, Ulfhake et al., 2000, Verdú et al., 2000). Functional recovery after peripheral nerve injury highly depends on adequate reinnervation of target organs provided either by regeneration of injured axons or by collateral sprouting of adjacent uninjured axons. The capability of intact motor (Jacob and Robbins, 1990, Pestronk et al., 1980) and sympathetic axons (Kuchel, 1993, Navarro and Kennedy, 1988) for collateral sprouting is reduced with aging. The influence of aging on collateral sprouting of sensory axons is not well established.
Among sensory axons, only high-threshold myelinated, and to a lesser extent unmyelinated axons were shown unambiguously to sprout collaterally in adult mammals (Diamond et al., 1987, Doucette and Diamond, 1987). Collateral sprouting of cutaneous high-threshold afferents in rats depends upon the nerve growth factor (NGF) (Diamond et al., 1987, Doubleday and Robinson, 1992). Accordingly, the levels of mRNA for both types of NGF receptors (TrkA and p75) increased in the sprouting sensory neurons in the dorsal root ganglion (DRG) (Mearow et al., 1994). A decline of NGF receptor expression in the DRG of aged rats (Parhad et al., 1995) suggests a reduced response of aged sensory neurons to target derived NGF. On the other hand, in vitro studies demonstrated that non-soluble extracellular matrix (ECM) components, such as laminin, also enhanced the axonal outgrowth of sensory neurons (Millaruelo et al., 1988, Tucker et al., 2006) and the sprouting of aged sympathetic neurons (Cowen et al., 1997). In addition, an intact peripherin intermediate filament (IF) network is required for collateral sprouting of nociceptive axons (Belecky-Adams et al., 2003). Axonal atrophy in aging is associated with reduced expression of another member of IF proteins, neurofilament (Parhad et al., 1995). However, it is not known if the level of peripherin, which is involved in axonal growth (Oblinger et al., 1989, Troy et al., 1990), is also reduced in aged sensory neurons.
The aim of this study was to examine the hypothesis that the collateral sprouting of nociceptive axons in the rat is reduced with aging, and if so, then to establish the cause of possible age-related differences in neuronal plasticity after peripheral nerve injury, i.e. whether it is due to intrinsic changes in the aged neurons and/or due to alterations of the components of axonal pathways (Cowen and Gavazzi, 1998, Crutcher, 2002, Goldberg, 2003, Ide, 1996, Ulfhake et al., 2000).
Section snippets
Experimental animals and anesthesia
Young adult (4–5 months), middle aged (14–16 months) and aged (24–26 months) male albino rats (Wistar, Medical Experimental Center, Faculty of Medicine, University of Ljubljana, Slovenia), weighing 200–250, 300–400, and 350–450 g at the beginning of the study, respectively, were used. The rats were delivered by a local breeder at an age of 2–3 months and thereafter kept under standardized barrier conditions at our department, on a 12-h day:12-h night cycle and ad libitum access to water and
Recovery of nociception due to collateral sprouting of sural nerve axons in the skin—Experiment A
Immediately after transection of all the nerves in the hind limb with the exception of the sural nerve, only about 20% of the skin on the dorsum of the hind foot remained sensitive to pain produced by the pinch test. This skin area corresponds to the maximal nociceptive innervation area of the uninjured sural nerve (see Supplementary Fig. S1). A slow recovery of nociceptive sensitivity in adjacent insensitive skin took place during the next weeks. The spatial pattern of the recovery of
Discussion
In young adult rats, sprouting-related expansion of the cutaneous nociceptive territory of the uninjured sural nerve into the adjacent denervated skin, as detected by the pinch test, was faster than in aged rats, and the absolute reinnervated area at the end of experiment was about 50% larger in young adult than in aged rats. This is in agreement with a previous coincidental finding that collateral sensory reinnervation in the skin was more rapid in very young than in older rabbits (Weddell et
Conclusion
Collateral sprouting of primary nociceptive afferents is less extensive in aged than in young adult rats. This is mostly due to the age-induced alterations in the peripheral neural pathways, and not due to the limited sprouting capacity of sensory neurons or their reduced responsiveness to trophic factors. Age-related alterations in the ECM components of neural pathways, like laminin, might be important in this respect. Understanding relative contributions of neurons and their peripheral
Disclosure statement
Authors state that they have no actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within 3 years of beginning the work submitted that could inappropriately influence (bias) their work.
The experiments were approved by the Veterinary Administration of the Ministry for Agriculture, Forestry and Food of the Republic of Slovenia, permit No. 323-349/2003-3, verifying that appropriate approval and procedures were used
Acknowledgements
The authors thank Mrs. T. Šprajcar and Dr. M. Erdani Kreft for help with histological analysis. The work was supported by grants P0-0518-0381 and Z3-3348-0381-02 from the Agency for Research and Development of the Republic of Slovenia to Dr. Sketelj and Dr. Bajrović, respectively.
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