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.
Chemicals such as capsaicin and acid are considered noxious because they cause irritation and pain when applied to the skin. Acid is, for example, a very noxious stimulus and can cause intense pain. Indeed, acid is both noxious and painful to all animals including amphibians and fish. Here we describe a member of the rodent family, the African naked mole-rat (Heterocephalus glaber), that is behaviorally completely oblivious to capsaicin and acid. Tissue injury and inflammation increase sensitivity to normally non painful stimuli, a phenomenon called hyperalgesia. Here we show that the naked mole-rat does not experience hyperalgesia to painful thermal stimuli after inflammation. To our knowledge, no other mammal has so far been described that is selectively insensitive to chemical pain or that lacks thermal hyperalgesia. Naked mole-rats live in very large subterranean social groups and are remarkably tolerant to low-oxygen and high–carbon dioxide conditions. We hypothesize that naked mole-rats are selectively pain insensitive partly because of selection pressure arising from the extremity of their normal habitat.
Naked but far from vulnerable, the African naked mole-rat is an unusual mammal that is unique because it is impervious to painful chemicals that cause severe pain in all other species studied.