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Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber).

Park TJ, Lu Y, Jüttner R, Smith ES, Hu J, Brand A, Wetzel C, Milenkovic N, Erdmann B, Heppenstall PA, Laurito CE, Wilson SP, Lewin GR - PLoS Biol. (2008)

Bottom Line: Nevertheless, the activation of capsaicin-sensitive sensory neurons in naked mole-rats does not produce pain-related behavior.However, the same nociceptors are also functionally connected to deep dorsal horn neurons, a connectivity that is rare in mice.The pain biology of the naked mole-rat is unique among mammals, thus the study of pain mechanisms in this unusual species can provide major insights into what constitutes "normal" mammalian nociception.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Integrative Neuroscience, Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America. tpark@uic.edu

ABSTRACT
In all mammals, tissue inflammation leads to pain and behavioral sensitization to thermal and mechanical stimuli called hyperalgesia. We studied pain mechanisms in the African naked mole-rat, an unusual rodent species that lacks pain-related neuropeptides (e.g., substance P) in cutaneous sensory fibers. Naked mole-rats show a unique and remarkable lack of pain-related behaviors to two potent algogens, acid and capsaicin. Furthermore, when exposed to inflammatory insults or known mediators, naked mole-rats do not display thermal hyperalgesia. In contrast, naked mole-rats do display nocifensive behaviors in the formalin test and show mechanical hyperalgesia after inflammation. Using electrophysiology, we showed that primary afferent nociceptors in naked mole-rats are insensitive to acid stimuli, consistent with the animal's lack of acid-induced behavior. Acid transduction by sensory neurons is observed in birds, amphibians, and fish, which suggests that this tranduction mechanism has been selectively disabled in the naked mole-rat in the course of its evolution. In contrast, nociceptors do respond vigorously to capsaicin, and we also show that sensory neurons express a transient receptor potential vanilloid channel-1 ion channel that is capsaicin sensitive. Nevertheless, the activation of capsaicin-sensitive sensory neurons in naked mole-rats does not produce pain-related behavior. We show that capsaicin-sensitive nociceptors in the naked mole-rat are functionally connected to superficial dorsal horn neurons as in mice. However, the same nociceptors are also functionally connected to deep dorsal horn neurons, a connectivity that is rare in mice. The pain biology of the naked mole-rat is unique among mammals, thus the study of pain mechanisms in this unusual species can provide major insights into what constitutes "normal" mammalian nociception.

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Comparison of Myelinated and Unmyelinated Axons in the Saphenous Nerve of Adult Laboratory Mice and 1-y-Old Naked Mole-Rats(A) Photograph showing the similar overall size of the animals as well as the similar size of the hind feet, which are innervated by the saphenous nerve.(B) Representative electron micrographs showing unmyelinated axons within Remak bundles (yellow arrows) and myelinated axons (red arrows) in saphenous nerves from the mouse and naked mole-rat (NMR). Scale bar = 2.0 μm.(C) At higher magnification, single unmyelinated fibers can be distinguished within the Remak bundles. Scale bar = 2.0 μm.(D) Quantification of myelinated and unmyelinated axon numbers in mouse (n = 6) and naked mole-rat (n = 4) saphenous nerves. Note that here and in subsequent figures, red bars denote data from mouse and gray bars indicate data from naked mole-rats.(E and F) Proportion of cultured sensory cells that label with IB4 in mice (E) and naked mole-rats (F). Distributions are based on soma area, and C-cells have soma areas less than 600 μm2.
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pbio-0060013-g001: Comparison of Myelinated and Unmyelinated Axons in the Saphenous Nerve of Adult Laboratory Mice and 1-y-Old Naked Mole-Rats(A) Photograph showing the similar overall size of the animals as well as the similar size of the hind feet, which are innervated by the saphenous nerve.(B) Representative electron micrographs showing unmyelinated axons within Remak bundles (yellow arrows) and myelinated axons (red arrows) in saphenous nerves from the mouse and naked mole-rat (NMR). Scale bar = 2.0 μm.(C) At higher magnification, single unmyelinated fibers can be distinguished within the Remak bundles. Scale bar = 2.0 μm.(D) Quantification of myelinated and unmyelinated axon numbers in mouse (n = 6) and naked mole-rat (n = 4) saphenous nerves. Note that here and in subsequent figures, red bars denote data from mouse and gray bars indicate data from naked mole-rats.(E and F) Proportion of cultured sensory cells that label with IB4 in mice (E) and naked mole-rats (F). Distributions are based on soma area, and C-cells have soma areas less than 600 μm2.

Mentions: We studied the saphenous nerve, which innervates the skin of the medial hind limb and paw, because primary afferents in this nerve have been well characterized anatomically and physiologically in many species [23–25]. We made an electron microscopic analysis of the saphenous nerve in the naked mole-rat to determine the number and morphology of myelinated A-fiber axons and unmyelinated C-fiber axons. We used laboratory mice as a comparison species, because their feet, as well as overall body, are of comparable size (Figure 1A). The ultrastructure of both C-fiber axons in Remak bundles and myelinated fibers in the naked mole-rat is qualitatively similar to that in the mouse (Figure 1B and 1C). We counted the number of A- and C-fiber axons and found that the saphenous nerve of naked mole-rats contains about 30% fewer myelinated axons than that of the mouse. The myelinated axons had a smaller diameter in the naked mole-rat compared to the mouse (Figure S1), and this was reflected in slower conduction velocities (Table 1). It has often been observed that cutaneous nerves of rodents, primates, and humans contain many more unmyelinated fibers than they do myelinated fibers. For example, in rats, mice, and humans, cutaneous nerves contain four times as many C-fiber than A-fiber axons [25–27]. We found that in the naked mole-rat, saphenous nerve unmyelinated C-fibers were scarce compared with other species. The mean ratio of C-fiber axons to A-fiber axons in this species is 1.1 compared to 3.8 in the mouse (Figure 1D).


Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber).

Park TJ, Lu Y, Jüttner R, Smith ES, Hu J, Brand A, Wetzel C, Milenkovic N, Erdmann B, Heppenstall PA, Laurito CE, Wilson SP, Lewin GR - PLoS Biol. (2008)

Comparison of Myelinated and Unmyelinated Axons in the Saphenous Nerve of Adult Laboratory Mice and 1-y-Old Naked Mole-Rats(A) Photograph showing the similar overall size of the animals as well as the similar size of the hind feet, which are innervated by the saphenous nerve.(B) Representative electron micrographs showing unmyelinated axons within Remak bundles (yellow arrows) and myelinated axons (red arrows) in saphenous nerves from the mouse and naked mole-rat (NMR). Scale bar = 2.0 μm.(C) At higher magnification, single unmyelinated fibers can be distinguished within the Remak bundles. Scale bar = 2.0 μm.(D) Quantification of myelinated and unmyelinated axon numbers in mouse (n = 6) and naked mole-rat (n = 4) saphenous nerves. Note that here and in subsequent figures, red bars denote data from mouse and gray bars indicate data from naked mole-rats.(E and F) Proportion of cultured sensory cells that label with IB4 in mice (E) and naked mole-rats (F). Distributions are based on soma area, and C-cells have soma areas less than 600 μm2.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2214810&req=5

pbio-0060013-g001: Comparison of Myelinated and Unmyelinated Axons in the Saphenous Nerve of Adult Laboratory Mice and 1-y-Old Naked Mole-Rats(A) Photograph showing the similar overall size of the animals as well as the similar size of the hind feet, which are innervated by the saphenous nerve.(B) Representative electron micrographs showing unmyelinated axons within Remak bundles (yellow arrows) and myelinated axons (red arrows) in saphenous nerves from the mouse and naked mole-rat (NMR). Scale bar = 2.0 μm.(C) At higher magnification, single unmyelinated fibers can be distinguished within the Remak bundles. Scale bar = 2.0 μm.(D) Quantification of myelinated and unmyelinated axon numbers in mouse (n = 6) and naked mole-rat (n = 4) saphenous nerves. Note that here and in subsequent figures, red bars denote data from mouse and gray bars indicate data from naked mole-rats.(E and F) Proportion of cultured sensory cells that label with IB4 in mice (E) and naked mole-rats (F). Distributions are based on soma area, and C-cells have soma areas less than 600 μm2.
Mentions: We studied the saphenous nerve, which innervates the skin of the medial hind limb and paw, because primary afferents in this nerve have been well characterized anatomically and physiologically in many species [23–25]. We made an electron microscopic analysis of the saphenous nerve in the naked mole-rat to determine the number and morphology of myelinated A-fiber axons and unmyelinated C-fiber axons. We used laboratory mice as a comparison species, because their feet, as well as overall body, are of comparable size (Figure 1A). The ultrastructure of both C-fiber axons in Remak bundles and myelinated fibers in the naked mole-rat is qualitatively similar to that in the mouse (Figure 1B and 1C). We counted the number of A- and C-fiber axons and found that the saphenous nerve of naked mole-rats contains about 30% fewer myelinated axons than that of the mouse. The myelinated axons had a smaller diameter in the naked mole-rat compared to the mouse (Figure S1), and this was reflected in slower conduction velocities (Table 1). It has often been observed that cutaneous nerves of rodents, primates, and humans contain many more unmyelinated fibers than they do myelinated fibers. For example, in rats, mice, and humans, cutaneous nerves contain four times as many C-fiber than A-fiber axons [25–27]. We found that in the naked mole-rat, saphenous nerve unmyelinated C-fibers were scarce compared with other species. The mean ratio of C-fiber axons to A-fiber axons in this species is 1.1 compared to 3.8 in the mouse (Figure 1D).

Bottom Line: Nevertheless, the activation of capsaicin-sensitive sensory neurons in naked mole-rats does not produce pain-related behavior.However, the same nociceptors are also functionally connected to deep dorsal horn neurons, a connectivity that is rare in mice.The pain biology of the naked mole-rat is unique among mammals, thus the study of pain mechanisms in this unusual species can provide major insights into what constitutes "normal" mammalian nociception.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Integrative Neuroscience, Department of Biological Sciences, University of Illinois at Chicago, Chicago, Illinois, United States of America. tpark@uic.edu

ABSTRACT
In all mammals, tissue inflammation leads to pain and behavioral sensitization to thermal and mechanical stimuli called hyperalgesia. We studied pain mechanisms in the African naked mole-rat, an unusual rodent species that lacks pain-related neuropeptides (e.g., substance P) in cutaneous sensory fibers. Naked mole-rats show a unique and remarkable lack of pain-related behaviors to two potent algogens, acid and capsaicin. Furthermore, when exposed to inflammatory insults or known mediators, naked mole-rats do not display thermal hyperalgesia. In contrast, naked mole-rats do display nocifensive behaviors in the formalin test and show mechanical hyperalgesia after inflammation. Using electrophysiology, we showed that primary afferent nociceptors in naked mole-rats are insensitive to acid stimuli, consistent with the animal's lack of acid-induced behavior. Acid transduction by sensory neurons is observed in birds, amphibians, and fish, which suggests that this tranduction mechanism has been selectively disabled in the naked mole-rat in the course of its evolution. In contrast, nociceptors do respond vigorously to capsaicin, and we also show that sensory neurons express a transient receptor potential vanilloid channel-1 ion channel that is capsaicin sensitive. Nevertheless, the activation of capsaicin-sensitive sensory neurons in naked mole-rats does not produce pain-related behavior. We show that capsaicin-sensitive nociceptors in the naked mole-rat are functionally connected to superficial dorsal horn neurons as in mice. However, the same nociceptors are also functionally connected to deep dorsal horn neurons, a connectivity that is rare in mice. The pain biology of the naked mole-rat is unique among mammals, thus the study of pain mechanisms in this unusual species can provide major insights into what constitutes "normal" mammalian nociception.

Show MeSH
Related in: MedlinePlus