Functional confirmation that the R1488* variant in SCN9A results in complete loss-of-function of Nav1.7.

BACKGROUND: Individuals with an extremely rare inherited condition, termed Congenital Insensitivity to Pain (CIP), do not feel pain in response to noxious stimuli. Variants in SCN9A, encoding the transmembrane voltage-gated sodium channel Nav1.7, have previously been reported in subjects with CIP accompanied by anosmia, which are typically transmitted in a recessive pattern. Functional characterisations of some of these SCN9A mutations show that they result in complete loss-of-function of Nav1.7. METHODS: In a consanguineous family we performed whole exome sequencing of three members who have a diagnosis of CIP and one unaffected family member. The functional effects of the segregating variant in SCN9A were determined using patch clamp electrophysiology in human embryonic kidney (HEK) 293 cells transfected with the variant. RESULTS: We found that each CIP subject was homozygous for a putatively nonsense variant, R1488*, in SCN9A. This variant was reported elsewhere in a subject with CIP, though the functional effect was not determined. Using electrophysiology, we confirm that this variant results in a complete loss-of-function of Nav1.7. CONCLUSIONS: We confirm through electrophysiological analysis that this R1488* variant in SCN9A results in complete loss-of-function of Nav1.7, which is consistent with reports on other variants in this gene in subjects with CIP.

Is pain the price of empathy? The perception of others' pain in patients with congenital insensitivity to pain.

Empathy is a complex form of psychological inference that enables us to understand the personal experience of another person through cognitive/evaluative and affective processes. Recent findings suggest that empathy for pain may involve a 'mirror-matching' simulation of the affective and sensory features of others' pain. Despite such evidence for a shared representation of self and other pain at the neural level, the possible influence of the observer's own sensitivity to pain upon his perception of others' pain has not been investigated yet. The aim of this study was to explore how patients with congenital insensitivity to pain (CIP), who are largely deprived of common stimulus-induced pain experiences, perceive the pain of others. Ratings of verbally presented imaginary painful situations showed that CIP patients' semantic knowledge regarding the pain of others did not differ from control subjects. Moreover, the propensity to infer pain from facial expressions was very similar between CIP patients and control subjects. On the other hand, when asked to rate pain-inducing events seen in video clips in the absence of visible or audible pain-related behaviour, CIP patients showed more variable and significantly lower pain ratings, as well as a reduction in aversive emotional responses, compared with control subjects. Interestingly, pain judgements, inferred either from facial pain expressions or from pain-inducing events, were strongly related to inter-individual differences in emotional empathy among CIP patients, while such correlation between pain judgement and empathy was not found in control subjects. The results suggest that a normal personal experience of pain is not necessarily required for perceiving and feeling empathy for others' pain. In the absence of functional somatic resonance mechanisms shaped by previous pain experiences, others' pain might be greatly underestimated, however, especially when emotional cues are lacking, unless the observer is endowed with sufficient empathic abilities to fully acknowledge the suffering experience of others in spite of his own insensitivity.

Activation of diffuse noxious inhibitory controls (DNIC) in rats with an experimental peripheral mononeuropathy.

Diffuse noxious inhibitory controls (DNIC), which involve supraspinal structures and modulate the transmission of nociceptive signals, were investigated in rats with chronic constriction injury of the sciatic nerve. Nerve-injured rats with increased sensitivity to mechanical and thermal stimulation on the operated side were anesthetized and recordings were made from trigeminal convergent neurons. Inhibitions of C-fiber-evoked neuronal responses during and after the application of nociceptive conditioning stimuli to the hindpaw, were measured to evaluate DNIC. The conditioning stimuli consisted of graded natural (pressure and heat) and electrical stimuli and were applied alternately to non-operated and operated hindpaws. Compared with the non-operated paw, inhibitions elicited by pressure on the operated hindpaw were increased significantly at all stimulus intensities. Albeit to a lesser extent, inhibitions elicited by thermal stimulation of the operated paw were also increased in the nerve-injured animals. Such exacerbation of DNIC-induced inhibitions produced by mechanical and thermal stimulation of the operated paw can be explained by an increase in the afferent input to the spinal cord. In contrast to the results obtained with natural stimulations, inhibitions evoked from the operated and non-operated paws were similar when graded electrical stimulation was used as the conditioning stimulus. This was true regardless of the intensity and frequency of stimulation and regardless of whether the stimuli were applied transcutaneously or directly to the sciatic nerve. The clear-cut difference between the results obtained with natural and electrical conditioning stimuli suggests that the nociceptive neurons involved in the triggering of DNIC may not be sensitized at the central level. Peripheral mechanisms such as the sensitization of nerve injured fibers and/or sprouting of nerve terminals may thus be the main causes of DNIC increase in this model of neuropathic pain.

Different strategies of modulation can be operative during hypnotic analgesia: a neurophysiological study.

Nociceptive electrical stimuli were applied to the sural nerve during hypnotically-suggested analgesia in the left lower limb of 18 highly susceptible subjects. During this procedure, the verbally reported pain threshold, the nociceptive flexion (RIII) reflex and late somatosensory evoked potentials were investigated in parallel with autonomic responses and the spontaneous electroencephalogram (EEG). The hypnotic suggestion of analgesia induced a significant increase in pain threshold in all the selected subjects. All the subjects showed large changes (i.e., by 20% or more) in the amplitudes of their RIII reflexes during hypnotic analgesia by comparison with control conditions. Although the extent of the increase in pain threshold was similar in all the subjects, two distinct patterns of modulation of the RIII reflex were observed during the hypnotic analgesia: in 11 subjects (subgroup 1), a strong inhibition of the reflex was observed whereas in the other seven subjects (subgroup 2) there was a strong facilitation of the reflex. All the subjects in both subgroups displayed similar decreases in the amplitude of late somatosensory evoked cerebral potentials during the hypnotic analgesia. No modification in the autonomic parameters or the EEG was observed. These data suggest that different strategies of modulation can be operative during effective hypnotic analgesia and that these are subject-dependent. Although all subjects may shift their attention away from the painful stimulus (which could explain the decrease of the late somatosensory evoked potentials), some of them inhibit their motor reaction to the stimulus at the spinal level, while in others, in contrast, this reaction is facilitated.

Can we share a pain we never felt? Neural correlates of empathy in patients with congenital insensitivity to pain.

Theories of empathy differ regarding the relative contributions of automatic resonance and perspective taking in understanding others' emotions. Patients with the rare syndrome of congenital insensitivity to pain cannot rely on "mirror matching" (i.e., resonance) mechanisms to understand the pain of others. Nevertheless, they showed normal fMRI responses to observed pain in anterior mid-cingulate cortex and anterior insula, two key regions of the so-called "shared circuits" for self and other pain. In these patients (but not in healthy controls), empathy trait predicted ventromedial prefrontal responses to somatosensory representations of others' pain and posterior cingulate responses to emotional representations of others' pain. These findings underline the major role of midline structures in emotional perspective taking and understanding someone else's feeling despite the lack of any previous personal experience of it--an empathic challenge frequently raised during human social interactions.

Comparison of the pain suppressive effects of clinical and experimental painful conditioning stimuli.

Studies in healthy volunteers suggested that the classical counterirritation phenomenon (i.e. pain inhibits pain effect) might depend on diffuse noxious inhibitory controls (DNIC), which modulate the spinal transmission of nociceptive signals. In the present study, we sought to determine whether similar mechanisms were at play in patients with different subtypes of neuropathic pain. Ten patients presenting with a traumatic peripheral nerve injury associated with dynamic mechano-allodynia (i.e. pain triggered by brushing) or static mechano-allodynia (i.e. pain triggered by light pressure stimuli) were included in this study. To investigate counterirritation mechanisms in these patients, we analysed the RIII nociceptive flexion reflex and concomitant painful sensation elicited by electrical stimulation of the sural nerve. We compared the effects of heterotopic 'clinical' conditioning stimuli (i.e. pain evoked by brushing or pressure within the allodynic area located in the upper limb or chest) to those of experimental heterotopic noxious stimuli (HNCS) consisting of a cold pressor test or tourniquet test applied to the normal upper limb. Static mechano-allodynia induced inhibitions of both the RIII reflex and the concomitant painful sensation. These effects were similar to those induced by HNCS and were probably due to an increased activation of DNIC. In contrast, in patients with dynamic allodynia, brushing within the allodynic area reduced the pain sensation at the foot, but did not inhibit the electrophysiological responses, suggesting that in this case the counterirritation effect may take place at the supraspinal level. Thus, the mechanisms of counterirritation are not univocal, but depend on the pathophysiological mechanisms of clinical pain.