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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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Patch Clamp Recordings of Spinal Cells in Superficial and Deep Lamina of the Dorsal Horn with Bath Application of Capsaicin (10 μM)(A and B) Locations of cells in mouse (A) and naked mole-rat (B) spinal slices. White dots indicate cells that responded to capsaicin; black dots indicate cells that did not respond to capsaicin. Scale bar = 100 μm.(C) Mean number of mEPSCs recorded from all superficial mouse cells that responded to capsaicin. The histogram shows 100 s before and 100 s after bath application of capsaicin. The inset trace shows a typical recording from one mouse cell. Scale bars, 10 s, 10 pA.(D) Mean number of mEPSCs from four naked mole-rat cells that were located in superficial dorsal horn and responded to capsaicin.(E) Mean number of mEPSCs from six naked mole-rat cells that were located in deep dorsal horn and responded to capsaicin. Miniature EPSCs were recorded in the presence of strychnine (1 μM), picrotoxin (100 μM), and APV (100 μM) to block glycinergic and GABAergic input as well as NMDA receptor-mediated currents. TTX (1 μM) was used to block action-potential dependent neurotransmitter release. Bin size for (C–E), 5 s.
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pbio-0060013-g005: Patch Clamp Recordings of Spinal Cells in Superficial and Deep Lamina of the Dorsal Horn with Bath Application of Capsaicin (10 μM)(A and B) Locations of cells in mouse (A) and naked mole-rat (B) spinal slices. White dots indicate cells that responded to capsaicin; black dots indicate cells that did not respond to capsaicin. Scale bar = 100 μm.(C) Mean number of mEPSCs recorded from all superficial mouse cells that responded to capsaicin. The histogram shows 100 s before and 100 s after bath application of capsaicin. The inset trace shows a typical recording from one mouse cell. Scale bars, 10 s, 10 pA.(D) Mean number of mEPSCs from four naked mole-rat cells that were located in superficial dorsal horn and responded to capsaicin.(E) Mean number of mEPSCs from six naked mole-rat cells that were located in deep dorsal horn and responded to capsaicin. Miniature EPSCs were recorded in the presence of strychnine (1 μM), picrotoxin (100 μM), and APV (100 μM) to block glycinergic and GABAergic input as well as NMDA receptor-mediated currents. TTX (1 μM) was used to block action-potential dependent neurotransmitter release. Bin size for (C–E), 5 s.

Mentions: Our finding that naked mole-rats are behaviorally insensitive to capsaicin but have sensory neurons that respond normally to this irritant raised the following question: do capsaicin-sensitive C-fibers make functional connections in the spinal cord? We addressed this question by using whole-cell patch clamp recordings from dorsal horn neurons in transverse slices of spinal cord taken from juvenile mice (post-natal day 10–14 [p10–14]) and naked mole-rats. The slices were perfused with tetrodotoxin (TTX) to block action potential propagation and a cocktail of antagonists to isolate glutamatergic connections (see Materials and Methods). Once a whole-cell recording was achieved, miniature excitatory post-synaptic currents (mEPSCs) were recorded. The slice was superfused with 10 μM capsaicin and, if the recorded cell has direct monosynaptic connections with capsaicin-sensitive nociceptors, an increase in mEPSC frequency should be observed [45,46]. We found that 57% (16/28) of cells recorded in the mouse superficial dorsal horn responded with a substantial increase in mEPSC frequency after capsaicin application (Figure 5A and 5C). However, only two out of 30 cells recorded in deeper lamina in the mouse (6.6%) responded with increased mEPSC frequency to capsaicin superperfusion (Figure 5A). We made whole-cell recordings from superficially located neurons in slices from naked mole-rats, and the properties of the mEPSCs (amplitude, decay time, frequency) were essentially identical to those recorded in the mouse (Table S1). Also similar to the mouse, capsaicin in the naked mole-rat produced a substantial increase in mEPSC frequency in 50% (4/8) of the cells recorded in the superficial dorsal horn (Figure 5B and 5D). However, when we recorded cells located in the deep dorsal horn, we found that 46% (6/13) of the cells tested exhibited a pronounced increase in mEPSC frequency after superfusion with capsaicin (Figure 5B and 5E). The difference between the proportion of capsaicin-responding neurons in the mouse deep dorsal horn (6.6%) compared to the naked mole-rat (46%) was statistically significant (Chi squared test p < 0.01). Thus, TRPV1-responsive sensory fibers are synaptically connected to both superficial and deep dorsal horn neurons in the naked mole-rat. This direct connectivity between TRPV1-bearing fibers and deep dorsal horn neurons is much less frequent in the mouse than in the naked mole-rat spinal cord.


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)

Patch Clamp Recordings of Spinal Cells in Superficial and Deep Lamina of the Dorsal Horn with Bath Application of Capsaicin (10 μM)(A and B) Locations of cells in mouse (A) and naked mole-rat (B) spinal slices. White dots indicate cells that responded to capsaicin; black dots indicate cells that did not respond to capsaicin. Scale bar = 100 μm.(C) Mean number of mEPSCs recorded from all superficial mouse cells that responded to capsaicin. The histogram shows 100 s before and 100 s after bath application of capsaicin. The inset trace shows a typical recording from one mouse cell. Scale bars, 10 s, 10 pA.(D) Mean number of mEPSCs from four naked mole-rat cells that were located in superficial dorsal horn and responded to capsaicin.(E) Mean number of mEPSCs from six naked mole-rat cells that were located in deep dorsal horn and responded to capsaicin. Miniature EPSCs were recorded in the presence of strychnine (1 μM), picrotoxin (100 μM), and APV (100 μM) to block glycinergic and GABAergic input as well as NMDA receptor-mediated currents. TTX (1 μM) was used to block action-potential dependent neurotransmitter release. Bin size for (C–E), 5 s.
© Copyright Policy
Related In: Results  -  Collection

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

pbio-0060013-g005: Patch Clamp Recordings of Spinal Cells in Superficial and Deep Lamina of the Dorsal Horn with Bath Application of Capsaicin (10 μM)(A and B) Locations of cells in mouse (A) and naked mole-rat (B) spinal slices. White dots indicate cells that responded to capsaicin; black dots indicate cells that did not respond to capsaicin. Scale bar = 100 μm.(C) Mean number of mEPSCs recorded from all superficial mouse cells that responded to capsaicin. The histogram shows 100 s before and 100 s after bath application of capsaicin. The inset trace shows a typical recording from one mouse cell. Scale bars, 10 s, 10 pA.(D) Mean number of mEPSCs from four naked mole-rat cells that were located in superficial dorsal horn and responded to capsaicin.(E) Mean number of mEPSCs from six naked mole-rat cells that were located in deep dorsal horn and responded to capsaicin. Miniature EPSCs were recorded in the presence of strychnine (1 μM), picrotoxin (100 μM), and APV (100 μM) to block glycinergic and GABAergic input as well as NMDA receptor-mediated currents. TTX (1 μM) was used to block action-potential dependent neurotransmitter release. Bin size for (C–E), 5 s.
Mentions: Our finding that naked mole-rats are behaviorally insensitive to capsaicin but have sensory neurons that respond normally to this irritant raised the following question: do capsaicin-sensitive C-fibers make functional connections in the spinal cord? We addressed this question by using whole-cell patch clamp recordings from dorsal horn neurons in transverse slices of spinal cord taken from juvenile mice (post-natal day 10–14 [p10–14]) and naked mole-rats. The slices were perfused with tetrodotoxin (TTX) to block action potential propagation and a cocktail of antagonists to isolate glutamatergic connections (see Materials and Methods). Once a whole-cell recording was achieved, miniature excitatory post-synaptic currents (mEPSCs) were recorded. The slice was superfused with 10 μM capsaicin and, if the recorded cell has direct monosynaptic connections with capsaicin-sensitive nociceptors, an increase in mEPSC frequency should be observed [45,46]. We found that 57% (16/28) of cells recorded in the mouse superficial dorsal horn responded with a substantial increase in mEPSC frequency after capsaicin application (Figure 5A and 5C). However, only two out of 30 cells recorded in deeper lamina in the mouse (6.6%) responded with increased mEPSC frequency to capsaicin superperfusion (Figure 5A). We made whole-cell recordings from superficially located neurons in slices from naked mole-rats, and the properties of the mEPSCs (amplitude, decay time, frequency) were essentially identical to those recorded in the mouse (Table S1). Also similar to the mouse, capsaicin in the naked mole-rat produced a substantial increase in mEPSC frequency in 50% (4/8) of the cells recorded in the superficial dorsal horn (Figure 5B and 5D). However, when we recorded cells located in the deep dorsal horn, we found that 46% (6/13) of the cells tested exhibited a pronounced increase in mEPSC frequency after superfusion with capsaicin (Figure 5B and 5E). The difference between the proportion of capsaicin-responding neurons in the mouse deep dorsal horn (6.6%) compared to the naked mole-rat (46%) was statistically significant (Chi squared test p < 0.01). Thus, TRPV1-responsive sensory fibers are synaptically connected to both superficial and deep dorsal horn neurons in the naked mole-rat. This direct connectivity between TRPV1-bearing fibers and deep dorsal horn neurons is much less frequent in the mouse than in the naked mole-rat spinal cord.

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