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.
Highlights
The neurobiology of pain is of fundamental interest
We describe a member of the rodent family, the African naked mole-rat (Heterocephalus glaber), that is behaviorally completely oblivious to capsaicin and acid
No other mammal has so far been described that is selectively insensitive to chemical pain or that lacks thermal hyperalgesia
Summary
The neurobiology of pain is of fundamental interest. Pain is usually experienced in two main contexts. The second, more clinically relevant, context for pain is that following tissue injury or inflammation. Long lasting inflammation is often associated with ongoing pain and enhanced sensitivity to stimuli that are normally only mildly unpleasant, so-called hyperalgesia. Inflammatory pain following tissue damage usually lasts for many hours or even days. The development of inflammatory pain is a complex process involving events at the site of injury, in primary sensory neurons and the central nervous system (CNS) [1,2,3]. Tissue injury triggers the release of inflammatory mediators that can stimulate and sensitize specialized sensory neurons, called nociceptors, that detect stimuli harmful to the organism [1,4]. It is widely accepted that this nociceptor-driven plasticity can produce a central sensitization state required for the maintenance of hyperalgesia [2,3]
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