Selective inflammatory pain insensitivity in the African naked mole-rat (Heterocephalus glaber).

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.

Interaural time difference processing in the mammalian medial superior olive: the role of glycinergic inhibition.

The dominant cue for localization of low-frequency sounds are microsecond differences in the time-of-arrival of sounds at the two ears [interaural time difference (ITD)]. In mammals, ITD sensitivity is established in the medial superior olive (MSO) by coincidence detection of excitatory inputs from both ears. Hence the relative delay of the binaural inputs is crucial for adjusting ITD sensitivity in MSO cells. How these delays are constructed is, however, still unknown. Specifically, the question of whether inhibitory inputs are involved in timing the net excitation in MSO cells, and if so how, is controversial. These inhibitory inputs derive from the nuclei of the trapezoid body, which have physiological and structural specializations for high-fidelity temporal transmission, raising the possibility that well timed inhibition is involved in tuning ITD sensitivity. Here, we present physiological and pharmacological data from in vivo extracellular MSO recordings in anesthetized gerbils. Reversible blockade of synaptic inhibition by iontophoretic application of the glycine antagonist strychnine increased firing rates and significantly shifted ITD sensitivity of MSO neurons. This indicates that glycinergic inhibition plays a major role in tuning the delays of binaural excitation. We also tonically applied glycine, which lowered firing rates but also shifted ITD sensitivity in a way analogous to strychnine. Hence tonic glycine application experimentally decoupled the effect of inhibition from the timing of its inputs. We conclude that, for proper ITD processing, not only is inhibition necessary, but it must also be precisely timed.

Extreme tolerance to ammonia fumes in African naked mole-rats: animals that naturally lack neuropeptides from trigeminal chemosensory nerve fibers.

Naked mole-rats (Heterocephalus glaber) naturally lack neuropeptides associated with the signaling of chemical irritants from C type trigeminal nerve fibers. The goal of the present study was to assess behavioral responses of these animals to stimulation of the trigeminal chemosensory system, and to determine if stimulation would increase post-synaptic activity in the trigeminal nucleus, as seen in laboratory mice and rats. The results show that naked mole-rats are behaviorally insensitive to capsaicin solution applied to the nostrils and to ammonia fumes in a behavioral avoidance test. Centrally, the number of c Fos labeled cells in the spinal trigeminal nucleus increased from exposure to ammonia although the magnitude of the increase was less than for rats. The increase observed in naked mole-rats likely reflects activity from glutamate release, which appears insufficient to drive pain and aversion behaviors. The results support the idea that neuropeptides in the C fibers of the trigeminal system may be required to signal the aversive quality of specific chemical irritants. The natural lack of neuropeptides in naked mole-rats may be an adaptation to living in a challenging subterranean environment with extremely high levels of ammonia and carbon dioxide, stimuli known to excite trigeminal chemosensory C fibers.

Dynamic changes in level influence spatial coding in the lateral superior olive.

It is well established that the responses of binaural auditory neurons can adapt and change dramatically depending on the nature of a preceding sound. Examples of how the effects of ensuing stimuli play a functional role in auditory processing include motion sensitivity and precedence-like effects. To date, these types of effects have been documented at the level of the midbrain and above. Little is known about sensitivity to ensuing stimuli below in the superior olivary nuclei where binaural response properties are first established. Here we report on single cell responses in the gerbil lateral superior olive, the initial site where sensitivity to interaural level differences is established. In contrast to our expectations we found a robust sensitivity to ensuing stimuli. The majority of the cells we tested (86%), showed substantial suppression and/or enhancement to a designated target stimulus, depending on the nature of a preceding stimulus. Hence, sensitivity to ensuing stimuli is already established at the first synaptic station of binaural processing.

Functional neurokinin and NMDA receptor activity in an animal naturally lacking substance P: the naked mole-rat.

Naked mole-rats are extremely unusual among mammals in that their cutaneous C-fibers lack the neuropeptide Substance P (SP). In other mammals, SP plays an important role in nociception: it is released from C-fibers onto spinal neurons where it facilitates NMDA receptor activity and causes sensitization that can last for minutes, hours or days. In the present study, we tested the effects of intrathecal application of: 1) SP, 2) an SP antagonist (GR-82334), and 3) an NMDA antagonist (APV) on heat-evoked foot withdrawal. In the naked mole-rat, at a high enough concentration, application of SP caused a large, immediate, and long-lasting sensitization of foot withdrawal latency that was transiently reversed by application of either antagonist. However, neither SP nor NMDA antagonists had an effect when administered alone to naïve animals. In contrast, both antagonists induced an increase in basal withdrawal latency in mice. These results indicate that spinal neurons in naked mole-rats have functional SP and NMDA receptors, but that these receptors do not participate in heat-evoked foot withdrawal unless SP is experimentally introduced. We propose that the natural lack of SP in naked mole-rat C-fibers may have resulted during adaptation to living in a chronically high carbon dioxide, high ammonia environment that, in other mammals, would stimulate C-fibers and evoke nocifensive behavior.

Auditory response properties in the superior paraolivary nucleus of the gerbil.

The ascending auditory pathway is characterized by parallel processing. At the brain stem level, several structures are involved that are known to serve different well-defined functions. However, the function of one prominent brain stem nucleus, the rodent superior paraolivary nucleus (SPN) and its putative homologue in other mammals, the dorsomedial periolivary nucleus, is unknown. Based on extracellular recordings from anesthetized gerbils, we tested the role of the SPN in sound localization and temporal processing. First, the existence of binaural inputs indicates that the SPN might be involved in sound localization. Although almost half of the neurons exhibited binaural interactions (most of them excited from both sides), effects of interaural time and intensity differences (ITD; IID) were weak and ambiguous. Thus a straightforward function of SPN in sound localization appears to be implausible. Second, inputs from octopus and multipolar/stellate cells of the cochlear nucleus and from principal cells of the medial nucleus of the trapezoid body could relate to precise temporal processing in the SPN. Based on discharge types, two subpopulations of SPN cells were observed: about 60% of the neurons responded to pure tones with sustained discharges, with irregular spike patterns and no phase-locking. Only four neurons showed a regular spike pattern ("chopping"). About 40% of the neurons responded with phasic ON or OFF discharges. Average first spike latency observed in neurons with sustained discharges was significantly shorter than that of ON responders, but had a considerably higher trial-to-trial variation ("jitter"). A subpopulation of ON responders showed a jitter of less than +/-0.1 ms. Most neurons (66%) responded to sinusoidally amplitude-modulated sounds (SAM) with an ongoing response, phase-locked to the stimulus envelope. Again, ON responders showed a significantly higher temporal precision in the phase-locked discharge compared with the sustained responders. High variability was observed among spike-rate-based modulation transfer functions. Histologically, a massive concentration of cytochemical markers for glycinergic input to SPN cells was demonstrated. Application of glycine or its blockade revealed profound effects of glycinergic inhibition on the auditory responses of SPN neurons. The existence of at least two subpopulations of neurons is in line with different subsets of SPN cells that can be distinguished morphologically. One temporally less precise population might modulate the processing of its target structures by providing a rather diffuse inhibition. In contrast, precise ON responders might provide a short, initial inhibitory pulse to its targets.

Precise inhibition is essential for microsecond interaural time difference coding.

Microsecond differences in the arrival time of a sound at the two ears (interaural time differences, ITDs) are the main cue for localizing low-frequency sounds in space. Traditionally, ITDs are thought to be encoded by an array of coincidence-detector neurons, receiving excitatory inputs from the two ears via axons of variable length ('delay lines'), to create a topographic map of azimuthal auditory space. Compelling evidence for the existence of such a map in the mammalian lTD detector, the medial superior olive (MSO), however, is lacking. Equally puzzling is the role of a--temporally very precise glycine--mediated inhibitory input to MSO neurons. Using in vivo recordings from the MSO of the Mongolian gerbil, we found the responses of ITD-sensitive neurons to be inconsistent with the idea of a topographic map of auditory space. Moreover, local application of glycine and its antagonist strychnine by iontophoresis (through glass pipette electrodes, by means of an electric current) revealed that precisely timed glycine-controlled inhibition is a critical part of the mechanism by which the physiologically relevant range of ITDs is encoded in the MSO. A computer model, simulating the response of a coincidence-detector neuron with bilateral excitatory inputs and a temporally precise contralateral inhibitory input, supports this conclusion.