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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 TRPV1 Staining in the Spinal Cord of the Mouse and Naked Mole-RatSections were stained with a primary anti-rat TRPV1 antibody that was detected with a secondary antibody conjugated to Cy3 (red), sections were co-stained with IB4 conjugated to Alexa-488 (green).(A–C) TRPV1 and IB4 staining is localized to the superficial laminae of the dorsal horn in the mouse.(D–F) Similar staining is observed in the naked mole-rat, although a thicker lamina II gives rise to increased IB4 staining.(G) Very little TRPV1 deep staining is observed in the mouse.(H) Deep TRPV1 staining is frequently observed in the naked mole-rat; white arrows highlight TRPV1 positive profiles in deeper laminae.(I) Quantification of TRPV1-positive profiles in deep dorsal horn of mouse and naked mole-rat. Scale bars for (A–H) are 100 μm.
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pbio-0060013-g006: Comparison of TRPV1 Staining in the Spinal Cord of the Mouse and Naked Mole-RatSections were stained with a primary anti-rat TRPV1 antibody that was detected with a secondary antibody conjugated to Cy3 (red), sections were co-stained with IB4 conjugated to Alexa-488 (green).(A–C) TRPV1 and IB4 staining is localized to the superficial laminae of the dorsal horn in the mouse.(D–F) Similar staining is observed in the naked mole-rat, although a thicker lamina II gives rise to increased IB4 staining.(G) Very little TRPV1 deep staining is observed in the mouse.(H) Deep TRPV1 staining is frequently observed in the naked mole-rat; white arrows highlight TRPV1 positive profiles in deeper laminae.(I) Quantification of TRPV1-positive profiles in deep dorsal horn of mouse and naked mole-rat. Scale bars for (A–H) are 100 μm.

Mentions: We went on to examine the distribution of TRPV1-positive fibers and varicosities in the spinal cord using immunocytochemistry. TRPV1-positive fibers in the mouse are predominantly found in the superficial dorsal horn [12]. We thus compared the distribution of TRPV1-positive fibers and varicosities in the naked mole-rat and the mouse (Figure 6). Double staining experiments revealed that in the mouse, TRPV1-positive profiles are more superficially located in laminas I and II outer, compared to IB4-positive fibers, which extend into lamina II inner (Figure 6A–6C). This distinction was less clear for the naked mole-rat, where many TRPV1 fibers were located deep in lamina II and overlapping with the IB4-positive fibers (Figure 6D–6F). In the deep dorsal horn, occasional TRPV1-positive fibers could be identified in the mouse cord (Figure 6G), but in the naked mole-rat deep dorsal horn, such TRPV1-positive profiles were more common (Figure 6H). A quantitative analysis of the incidence of deep TRPV1-positive profiles was carried out (30 sections from three mice compared with 33 sections from three naked mole-rats), and the mean incidence of such profiles was found to be more than twice as high in the naked mole-rat compared with in the mouse (Figure 6I).


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 TRPV1 Staining in the Spinal Cord of the Mouse and Naked Mole-RatSections were stained with a primary anti-rat TRPV1 antibody that was detected with a secondary antibody conjugated to Cy3 (red), sections were co-stained with IB4 conjugated to Alexa-488 (green).(A–C) TRPV1 and IB4 staining is localized to the superficial laminae of the dorsal horn in the mouse.(D–F) Similar staining is observed in the naked mole-rat, although a thicker lamina II gives rise to increased IB4 staining.(G) Very little TRPV1 deep staining is observed in the mouse.(H) Deep TRPV1 staining is frequently observed in the naked mole-rat; white arrows highlight TRPV1 positive profiles in deeper laminae.(I) Quantification of TRPV1-positive profiles in deep dorsal horn of mouse and naked mole-rat. Scale bars for (A–H) are 100 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2214810&req=5

pbio-0060013-g006: Comparison of TRPV1 Staining in the Spinal Cord of the Mouse and Naked Mole-RatSections were stained with a primary anti-rat TRPV1 antibody that was detected with a secondary antibody conjugated to Cy3 (red), sections were co-stained with IB4 conjugated to Alexa-488 (green).(A–C) TRPV1 and IB4 staining is localized to the superficial laminae of the dorsal horn in the mouse.(D–F) Similar staining is observed in the naked mole-rat, although a thicker lamina II gives rise to increased IB4 staining.(G) Very little TRPV1 deep staining is observed in the mouse.(H) Deep TRPV1 staining is frequently observed in the naked mole-rat; white arrows highlight TRPV1 positive profiles in deeper laminae.(I) Quantification of TRPV1-positive profiles in deep dorsal horn of mouse and naked mole-rat. Scale bars for (A–H) are 100 μm.
Mentions: We went on to examine the distribution of TRPV1-positive fibers and varicosities in the spinal cord using immunocytochemistry. TRPV1-positive fibers in the mouse are predominantly found in the superficial dorsal horn [12]. We thus compared the distribution of TRPV1-positive fibers and varicosities in the naked mole-rat and the mouse (Figure 6). Double staining experiments revealed that in the mouse, TRPV1-positive profiles are more superficially located in laminas I and II outer, compared to IB4-positive fibers, which extend into lamina II inner (Figure 6A–6C). This distinction was less clear for the naked mole-rat, where many TRPV1 fibers were located deep in lamina II and overlapping with the IB4-positive fibers (Figure 6D–6F). In the deep dorsal horn, occasional TRPV1-positive fibers could be identified in the mouse cord (Figure 6G), but in the naked mole-rat deep dorsal horn, such TRPV1-positive profiles were more common (Figure 6H). A quantitative analysis of the incidence of deep TRPV1-positive profiles was carried out (30 sections from three mice compared with 33 sections from three naked mole-rats), and the mean incidence of such profiles was found to be more than twice as high in the naked mole-rat compared with in the mouse (Figure 6I).

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