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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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Hyperalgesia and Pain following Central Administration of SP(A) Paw withdrawal to radiant heat measured before and after administration of SP peptide to the lumbar spinal cord via an intrathecal cannula in lightly anesthetized animals (IT SP). Note that very low doses of SP lead to thermal hyperalgesia in mice (1 μM). Naked mole-rats also display hyperalgesia following intrathecal SP injection albeit only at higher doses (100 μM, n = 6 animals per dose).(B) Paw withdrawal to radiant heat was measured before and 1 wk after infection of one paw with transgenic herpes virus carrying the preprotachykinin gene (n = 4 naked mole-rats [NMR]). The virus treatment alone did not alter thermal thresholds (first three data points), but in contrast to naive animals, topical capsaicin leads to thermal hyperalgesia (shortened latencies) in the virus-treated paw.(C) Pain behavior following injection of capsaicin but not acid is observed following intrathecal administration of SP. Mice and naked mole-rats were lightly anesthetized via inhalation and given an intrathecal injection of 100 μM SP. After recovery from the anesthetic (∼5–10 min) the animals received a paw injection of capsaicin (n = 6 mice, 5 NMR) or acidic (pH 3.5) saline solution (n = 6 NMR) into one foot pad, and paw licking time was measured. Note that SP slightly increased licking behaviors in mice compared to capsaicin injection alone (Pre). Naked mole-rats showed significant licking behavior after intrathecal SP which was virtually absent in untreated animals. No change in the behavioral response to a pH 3.5 solution was observed.
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pbio-0060013-g007: Hyperalgesia and Pain following Central Administration of SP(A) Paw withdrawal to radiant heat measured before and after administration of SP peptide to the lumbar spinal cord via an intrathecal cannula in lightly anesthetized animals (IT SP). Note that very low doses of SP lead to thermal hyperalgesia in mice (1 μM). Naked mole-rats also display hyperalgesia following intrathecal SP injection albeit only at higher doses (100 μM, n = 6 animals per dose).(B) Paw withdrawal to radiant heat was measured before and 1 wk after infection of one paw with transgenic herpes virus carrying the preprotachykinin gene (n = 4 naked mole-rats [NMR]). The virus treatment alone did not alter thermal thresholds (first three data points), but in contrast to naive animals, topical capsaicin leads to thermal hyperalgesia (shortened latencies) in the virus-treated paw.(C) Pain behavior following injection of capsaicin but not acid is observed following intrathecal administration of SP. Mice and naked mole-rats were lightly anesthetized via inhalation and given an intrathecal injection of 100 μM SP. After recovery from the anesthetic (∼5–10 min) the animals received a paw injection of capsaicin (n = 6 mice, 5 NMR) or acidic (pH 3.5) saline solution (n = 6 NMR) into one foot pad, and paw licking time was measured. Note that SP slightly increased licking behaviors in mice compared to capsaicin injection alone (Pre). Naked mole-rats showed significant licking behavior after intrathecal SP which was virtually absent in untreated animals. No change in the behavioral response to a pH 3.5 solution was observed.

Mentions: In addition to displaying a highly unusual connectivity of nociceptive sensory neurons, the naked mole-rat also lacks the sensory neuropeptides SP and CGRP in the skin [18]. We asked whether reintroduction of SP into the naked mole-rat might be capable of “normalizing” pain behavior in this species. We measured noxious heat withdrawal latencies continuously before and after intrathecal infusion of SP (1–100 μM) in lightly anesthetized animals. Thermal hyperalgesia was observed within minutes after infusion of 1μM SP in mice. Naked mole-rats also displayed thermal hyperalgesia, but only at higher does (100 μM) (Figure 7A). In a second series of experiments, we used a neurotropic herpes virus engineered to express the preprotachykinin gene (PPT) to infect naked mole-rat DRG neurons innervating one paw. We tested the animals 1 wk after infection and found that thermal nociceptive latencies were unchanged (Figure 7B, first three data points). However, the naked mole-rats now displayed a robust thermal hyperalgesia when we applied topical capsaicin to the virus-treated paw at a concentration that produces reliable heat hyperalgesia in mice (1 mM).


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)

Hyperalgesia and Pain following Central Administration of SP(A) Paw withdrawal to radiant heat measured before and after administration of SP peptide to the lumbar spinal cord via an intrathecal cannula in lightly anesthetized animals (IT SP). Note that very low doses of SP lead to thermal hyperalgesia in mice (1 μM). Naked mole-rats also display hyperalgesia following intrathecal SP injection albeit only at higher doses (100 μM, n = 6 animals per dose).(B) Paw withdrawal to radiant heat was measured before and 1 wk after infection of one paw with transgenic herpes virus carrying the preprotachykinin gene (n = 4 naked mole-rats [NMR]). The virus treatment alone did not alter thermal thresholds (first three data points), but in contrast to naive animals, topical capsaicin leads to thermal hyperalgesia (shortened latencies) in the virus-treated paw.(C) Pain behavior following injection of capsaicin but not acid is observed following intrathecal administration of SP. Mice and naked mole-rats were lightly anesthetized via inhalation and given an intrathecal injection of 100 μM SP. After recovery from the anesthetic (∼5–10 min) the animals received a paw injection of capsaicin (n = 6 mice, 5 NMR) or acidic (pH 3.5) saline solution (n = 6 NMR) into one foot pad, and paw licking time was measured. Note that SP slightly increased licking behaviors in mice compared to capsaicin injection alone (Pre). Naked mole-rats showed significant licking behavior after intrathecal SP which was virtually absent in untreated animals. No change in the behavioral response to a pH 3.5 solution was observed.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2214810&req=5

pbio-0060013-g007: Hyperalgesia and Pain following Central Administration of SP(A) Paw withdrawal to radiant heat measured before and after administration of SP peptide to the lumbar spinal cord via an intrathecal cannula in lightly anesthetized animals (IT SP). Note that very low doses of SP lead to thermal hyperalgesia in mice (1 μM). Naked mole-rats also display hyperalgesia following intrathecal SP injection albeit only at higher doses (100 μM, n = 6 animals per dose).(B) Paw withdrawal to radiant heat was measured before and 1 wk after infection of one paw with transgenic herpes virus carrying the preprotachykinin gene (n = 4 naked mole-rats [NMR]). The virus treatment alone did not alter thermal thresholds (first three data points), but in contrast to naive animals, topical capsaicin leads to thermal hyperalgesia (shortened latencies) in the virus-treated paw.(C) Pain behavior following injection of capsaicin but not acid is observed following intrathecal administration of SP. Mice and naked mole-rats were lightly anesthetized via inhalation and given an intrathecal injection of 100 μM SP. After recovery from the anesthetic (∼5–10 min) the animals received a paw injection of capsaicin (n = 6 mice, 5 NMR) or acidic (pH 3.5) saline solution (n = 6 NMR) into one foot pad, and paw licking time was measured. Note that SP slightly increased licking behaviors in mice compared to capsaicin injection alone (Pre). Naked mole-rats showed significant licking behavior after intrathecal SP which was virtually absent in untreated animals. No change in the behavioral response to a pH 3.5 solution was observed.
Mentions: In addition to displaying a highly unusual connectivity of nociceptive sensory neurons, the naked mole-rat also lacks the sensory neuropeptides SP and CGRP in the skin [18]. We asked whether reintroduction of SP into the naked mole-rat might be capable of “normalizing” pain behavior in this species. We measured noxious heat withdrawal latencies continuously before and after intrathecal infusion of SP (1–100 μM) in lightly anesthetized animals. Thermal hyperalgesia was observed within minutes after infusion of 1μM SP in mice. Naked mole-rats also displayed thermal hyperalgesia, but only at higher does (100 μM) (Figure 7A). In a second series of experiments, we used a neurotropic herpes virus engineered to express the preprotachykinin gene (PPT) to infect naked mole-rat DRG neurons innervating one paw. We tested the animals 1 wk after infection and found that thermal nociceptive latencies were unchanged (Figure 7B, first three data points). However, the naked mole-rats now displayed a robust thermal hyperalgesia when we applied topical capsaicin to the virus-treated paw at a concentration that produces reliable heat hyperalgesia in mice (1 mM).

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