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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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Model Showing the Patterns of C-fiber Innervation in the Spinal Cord of Mouse and Naked Mole-Rat(A) Both mouse and naked mole-rat have populations of capsaicin-insensitive and capsaicin-sensitive C-fiber nociceptors. Symbols (hammer, match, chilli pepper) indicate the type of stimuli (mechanical, thermal, chemical irritant) that can generate spiking activity in each population. In both species, capsaicin-insensitive and capsaicin-sensitive fibers terminate in the superficial lamina of the dorsal horn (above the dashed line in the spinal cord schematic). A major difference between species is that in the naked mole-rat, a substantial number of capsaicin-sensitive fibers also provide synaptic input to deep lamina. Another major difference is that C-fibers in naked mole-rats lack the neuropeptides SP and CGRP (yellow dots represent neuropeptides, blue dots represent glutamate).(B) Capsaicin test: Injection of capsaicin into the skin of the paw induces pain behaviors (licking) in mice but not naked mole-rats, except in naked mole-rats that have received an intrathecal infusion of SP.(C) Topical capsaicin + heat: Topical application of capsaicin induced thermal hyperalgesia in mice but not naked mole-rats, except in naked mole-rats that have received gene therapy with the PPT gene.
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pbio-0060013-g008: Model Showing the Patterns of C-fiber Innervation in the Spinal Cord of Mouse and Naked Mole-Rat(A) Both mouse and naked mole-rat have populations of capsaicin-insensitive and capsaicin-sensitive C-fiber nociceptors. Symbols (hammer, match, chilli pepper) indicate the type of stimuli (mechanical, thermal, chemical irritant) that can generate spiking activity in each population. In both species, capsaicin-insensitive and capsaicin-sensitive fibers terminate in the superficial lamina of the dorsal horn (above the dashed line in the spinal cord schematic). A major difference between species is that in the naked mole-rat, a substantial number of capsaicin-sensitive fibers also provide synaptic input to deep lamina. Another major difference is that C-fibers in naked mole-rats lack the neuropeptides SP and CGRP (yellow dots represent neuropeptides, blue dots represent glutamate).(B) Capsaicin test: Injection of capsaicin into the skin of the paw induces pain behaviors (licking) in mice but not naked mole-rats, except in naked mole-rats that have received an intrathecal infusion of SP.(C) Topical capsaicin + heat: Topical application of capsaicin induced thermal hyperalgesia in mice but not naked mole-rats, except in naked mole-rats that have received gene therapy with the PPT gene.

Mentions: We showed that naked mole-rats are behaviorally insensitive to capsaicin. Birds and amphibians are also insensitive to capsaicin [10,56], and the avian TRPV1 gene encodes a proton- and heat-sensitive channel that is not activated by capsaicin, which explains behavioral insensitivity in this species [10]. It thus appears that the capsaicin sensitivity of TRPV1 is an attribute gained in higher vertebrates during the course of evolution. In contrast, the naked mole-rat is behaviorally capsaicin-insensitive but has TRPV1 ion channels and nociceptors that are potently activated by capsaicin (Figure 4). We identified two populations of C-fiber nociceptors in the naked mole-rat: one is capsaicin sensitive and one is capsaicin insensitive (Figure 4 and Figure 8A). Noxious mechanical and thermal stimuli clearly lead to paw withdrawal, and chemical stimuli can produce paw licking and guarding behavior in the naked mole-rat (Figure 3). The question arises why activation of nociceptors with TRPV1 ion channels in these animals does not normally drive pain and hyperalgesia? To address this question, we measured the functional connectivity of capsaicin-sensitive nociceptors in the spinal cord dorsal horn. Whole-cell patch clamp recordings from spinal cord slices before and after capsaicin application indicated that capsaicin-sensitive C-fibers can robustly excite superficially located dorsal horn neurons both in the mouse and naked mole-rat (Figure 5). However, in the naked mole-rat, ∼50% of the deep dorsal horn neurons also receive direct synaptic input from capsaicin-sensitive fibers; this connectivity was much less pronounced in mouse slices (Figure 5). We also found that TRPV1-positive profiles in the deep dorsal horn were more prominent and numerous in the naked mole-rat compared to in the mouse (Figure 6). This finding provides an anatomical basis for the unusual functional connectivity that we observed in the naked mole-rat cord. It is well established that deep dorsal horn neurons, in general, usually receive multimodal sensory input with predominant direct input from mechanoreceptors, which signal innocuous stimulation [57]. Sensory information conveyed by C-fibers can, however, reach deep dorsal horn neurons, and some of this input may be direct monosynaptic input to the dendrites of deep dorsal horn neurons that extend into lamina II [58,59]. Interestingly, deep dorsal horn neurons that receive dendritic input from C-fibers express neurokinin-1 receptors, the receptor for SP that is absent from naked mole-rat nociceptors [18]. However, the number of deep dorsal horn neurons in the mouse that receive direct input via superficially located dendrites is likely to be low (Figure 5). Thus compared with mice, the naked mole-rat has an expanded functional connectivity between capsaicin-sensitive C-fibers and deep dorsal horn neurons. Noxious mechanical and heat stimuli activate C-fibers and lead to pain behaviors in the naked mole-rat (Figure 3A and 3B). However, exclusive excitation of capsaicin-sensitive C-fibers with thermal or mechanical stimuli probably do not lead to pain-related behavior. It appears that the novel connectivity of capsaicin-sensitive fibers fails to sufficiently activate circuits involved in the generation of pain behavior. We postulate that capsaicin-sensitive C-fibers connect to a neuronal network in the naked mole-rat spinal cord, the integrated output of which is insufficient to generate pain-related behavior. Capsaicin-insensitive fibers in the naked mole-rat do activate circuits involved in the generation of pain (Figure 3A and 3B), and our data suggest that these are the only C-fibers that normally mediate acute nociception and mechanical hyperalgesia in this species.


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)

Model Showing the Patterns of C-fiber Innervation in the Spinal Cord of Mouse and Naked Mole-Rat(A) Both mouse and naked mole-rat have populations of capsaicin-insensitive and capsaicin-sensitive C-fiber nociceptors. Symbols (hammer, match, chilli pepper) indicate the type of stimuli (mechanical, thermal, chemical irritant) that can generate spiking activity in each population. In both species, capsaicin-insensitive and capsaicin-sensitive fibers terminate in the superficial lamina of the dorsal horn (above the dashed line in the spinal cord schematic). A major difference between species is that in the naked mole-rat, a substantial number of capsaicin-sensitive fibers also provide synaptic input to deep lamina. Another major difference is that C-fibers in naked mole-rats lack the neuropeptides SP and CGRP (yellow dots represent neuropeptides, blue dots represent glutamate).(B) Capsaicin test: Injection of capsaicin into the skin of the paw induces pain behaviors (licking) in mice but not naked mole-rats, except in naked mole-rats that have received an intrathecal infusion of SP.(C) Topical capsaicin + heat: Topical application of capsaicin induced thermal hyperalgesia in mice but not naked mole-rats, except in naked mole-rats that have received gene therapy with the PPT gene.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-0060013-g008: Model Showing the Patterns of C-fiber Innervation in the Spinal Cord of Mouse and Naked Mole-Rat(A) Both mouse and naked mole-rat have populations of capsaicin-insensitive and capsaicin-sensitive C-fiber nociceptors. Symbols (hammer, match, chilli pepper) indicate the type of stimuli (mechanical, thermal, chemical irritant) that can generate spiking activity in each population. In both species, capsaicin-insensitive and capsaicin-sensitive fibers terminate in the superficial lamina of the dorsal horn (above the dashed line in the spinal cord schematic). A major difference between species is that in the naked mole-rat, a substantial number of capsaicin-sensitive fibers also provide synaptic input to deep lamina. Another major difference is that C-fibers in naked mole-rats lack the neuropeptides SP and CGRP (yellow dots represent neuropeptides, blue dots represent glutamate).(B) Capsaicin test: Injection of capsaicin into the skin of the paw induces pain behaviors (licking) in mice but not naked mole-rats, except in naked mole-rats that have received an intrathecal infusion of SP.(C) Topical capsaicin + heat: Topical application of capsaicin induced thermal hyperalgesia in mice but not naked mole-rats, except in naked mole-rats that have received gene therapy with the PPT gene.
Mentions: We showed that naked mole-rats are behaviorally insensitive to capsaicin. Birds and amphibians are also insensitive to capsaicin [10,56], and the avian TRPV1 gene encodes a proton- and heat-sensitive channel that is not activated by capsaicin, which explains behavioral insensitivity in this species [10]. It thus appears that the capsaicin sensitivity of TRPV1 is an attribute gained in higher vertebrates during the course of evolution. In contrast, the naked mole-rat is behaviorally capsaicin-insensitive but has TRPV1 ion channels and nociceptors that are potently activated by capsaicin (Figure 4). We identified two populations of C-fiber nociceptors in the naked mole-rat: one is capsaicin sensitive and one is capsaicin insensitive (Figure 4 and Figure 8A). Noxious mechanical and thermal stimuli clearly lead to paw withdrawal, and chemical stimuli can produce paw licking and guarding behavior in the naked mole-rat (Figure 3). The question arises why activation of nociceptors with TRPV1 ion channels in these animals does not normally drive pain and hyperalgesia? To address this question, we measured the functional connectivity of capsaicin-sensitive nociceptors in the spinal cord dorsal horn. Whole-cell patch clamp recordings from spinal cord slices before and after capsaicin application indicated that capsaicin-sensitive C-fibers can robustly excite superficially located dorsal horn neurons both in the mouse and naked mole-rat (Figure 5). However, in the naked mole-rat, ∼50% of the deep dorsal horn neurons also receive direct synaptic input from capsaicin-sensitive fibers; this connectivity was much less pronounced in mouse slices (Figure 5). We also found that TRPV1-positive profiles in the deep dorsal horn were more prominent and numerous in the naked mole-rat compared to in the mouse (Figure 6). This finding provides an anatomical basis for the unusual functional connectivity that we observed in the naked mole-rat cord. It is well established that deep dorsal horn neurons, in general, usually receive multimodal sensory input with predominant direct input from mechanoreceptors, which signal innocuous stimulation [57]. Sensory information conveyed by C-fibers can, however, reach deep dorsal horn neurons, and some of this input may be direct monosynaptic input to the dendrites of deep dorsal horn neurons that extend into lamina II [58,59]. Interestingly, deep dorsal horn neurons that receive dendritic input from C-fibers express neurokinin-1 receptors, the receptor for SP that is absent from naked mole-rat nociceptors [18]. However, the number of deep dorsal horn neurons in the mouse that receive direct input via superficially located dendrites is likely to be low (Figure 5). Thus compared with mice, the naked mole-rat has an expanded functional connectivity between capsaicin-sensitive C-fibers and deep dorsal horn neurons. Noxious mechanical and heat stimuli activate C-fibers and lead to pain behaviors in the naked mole-rat (Figure 3A and 3B). However, exclusive excitation of capsaicin-sensitive C-fibers with thermal or mechanical stimuli probably do not lead to pain-related behavior. It appears that the novel connectivity of capsaicin-sensitive fibers fails to sufficiently activate circuits involved in the generation of pain behavior. We postulate that capsaicin-sensitive C-fibers connect to a neuronal network in the naked mole-rat spinal cord, the integrated output of which is insufficient to generate pain-related behavior. Capsaicin-insensitive fibers in the naked mole-rat do activate circuits involved in the generation of pain (Figure 3A and 3B), and our data suggest that these are the only C-fibers that normally mediate acute nociception and mechanical hyperalgesia in this species.

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