Browse by Audience
Pruritus in atopic dermatitis has been studied extensively; however, evaluation of skin pain has been very limited. The aim of this study was to evaluate the presence, frequency and characteristics of skin pain in patients with atopic dermatitis. A survey was conducted of a representative sample of 5,000 18-80-year-old individuals selected from the French population according to sex, age, geographical area and socioprofessional status. Data on socio-demographic status and the presence of any skin disease were collected. Pain in the past month and health-related quality of life were evaluated. Average intensity of skin pain during the previous month was assessed with a horizontal visual analogue scale (0-10). Skin pain was reported by more than half of the patients with atopic dermatitis, at a pain intensity of almost 6/10. A neuropathic component was suggested by the Douleur Neuropathique – 4 questions (DN4) questionnaire (a tool for detection of neuropathic pain), as well as the presence of pain inside and outside of skin lesions. Severe alterations to health-related quality of life were assessed with the Dermatology Life Quality Index and Short Form 12 Health Survey (SF-12). Pain is reported frequently by patients with atopic dermatitis. Healthcare professionals should question patients about pain and provide effective treatments. Future clinical trials must take skin pain into account.
Learn More >Migraine is a complex disorder, involving peripheral and central brain structures, where mechanisms and site of attack initiation are an unresolved puzzle. While abnormal pontine neuronal activation during migraine attacks has been reported, exact implication of this finding is unknown. Evidence suggests an important role of glutamate in migraine, implying a possible association of pontine hyperactivity to increased glutamate levels. Migraine without aura patients were scanned during attacks after calcitonin gene-related peptide and sildenafil in a double-blind, randomized, double-dummy, cross-over design, on two separate study days, by proton magnetic resonance spectroscopy and pseudo-continuous arterial spin labeling at 3T. Headache characteristics were recorded until 24 h after drug administrations. Twenty-six patients were scanned during migraine, yielding a total of 41 attacks. Cerebral blood flow increased in dorsolateral pons, ipsilateral to pain side during attacks, compared to outside attacks (13.6%, p = 0.009). Glutamate levels in the same area remained unchanged during attacks (p = 0.873), while total creatine levels increased (3.5%, p = 0.041). In conclusion, dorsolateral pontine activation during migraine was not associated with higher glutamate levels. However, the concurrently increased total creatine levels may suggest an altered energy metabolism, which should be investigated in future studies to elucidate the role of pons in acute migraine.
Learn More >Neuroinflammation is a crucial mechanism in many neurological disorders. Injury to the peripheral sensory nerves leads to a neuroinflammatory response in the somatosensory pathway, from dorsal root ganglia (DRG) to the spinal cord, contributing to neuropathic pain. How the immune reaction is initiated peripherally and propagated to the spinal cord remains less clear. Here, we find that ciliary neurotrophic factor (CNTF), highly expressed in Schwann cells, mediates neuroinflammatory response through the activating signal transducer and activator of transcription 3 (STAT3) and inducing interleukin 6 (IL-6) in sensory neurons. Cntf deficiency attenuates neuroinflammation in DRG and the spinal cord with alleviated pain post-injury. Recombinant CNTF applied to the sensory nerves recapitulates neuroinflammation in the DRG and spinal cord, with consequent pain development. We delineate the CNTF-STAT3-IL-6 axis in mediating the onset and progression of the inflammatory cascade from the periphery to the spinal cord with therapeutic implications for neuropathic pain.
Learn More >Although the medical definition of itch has been in existence for 360 years, only in the last 20 years have we begun to understand the basic mechanisms that underlie this unique sensation. Therapeutics that specifically target chronic itch as a pathologic entity are currently still not available. Recent seminal advances in itch circuitry within the nervous system have intersected with discoveries in immunology in unexpected ways to rapidly inform emerging treatment strategies. The current review aims to introduce these basic concepts in itch biology and highlight how distinct immunologic pathways integrate with recently identified itch-sensory circuits in the nervous system to inform a major new paradigm of neuroimmunology and therapeutic development for chronic itch.
Learn More >Recent years have seen an increase in the adoption of cannabinoid medicines, which have demonstrated effectiveness for the treatment of chronic pain. However, the extent to which frequent cannabis use (CU) influences sensitivity to acute pain has not been systematically examined. Such a determination is clinically relevant in light of hypersensitivity to pain associated with prolonged use of other analgesics such as opioids, and reports of increased pain sensitivity to experimentally induced pain during acute cannabis intoxication. This study will explore differences on measures of pain intensity and tolerance. We hypothesize that individuals who report frequent CU will demonstrate greater experimental pain sensitivity.
Learn More >Diminished synaptic inhibition in the superficial spinal dorsal horn contributes to exaggerated pain responses that accompany peripheral inflammation and neuropathy. α2GABA receptors (α2GABAR) constitute the most abundant GABAR subtype at this site and are the targets of recently identified antihyperalgesic compounds. Surprisingly, hoxb8-α2 mice that lack α2GABAR from the spinal cord and peripheral sensory neurons exhibit unaltered sensitivity to acute painful stimuli and develop normal inflammatory and neuropathic hyperalgesia. Here, we provide a comprehensive analysis of GABAergic neurotransmission, of behavioral phenotypes and of possible compensatory mechanisms in hoxb8-α2 mice. Our results confirm that hoxb8-α2 mice show significantly diminished GABAergic inhibitory postsynaptic currents (IPSCs) in the superficial dorsal horn but no hyperalgesic phenotype. We also confirm that the potentiation of dorsal horn GABAergic IPSCs by the α2-preferring GABAR modulator HZ-166 is reduced in hoxb8-α2 mice and that hoxb8-α2 mice are resistant to the analgesic effects of HZ-166. Tonic GABAergic currents, glycinergic IPSCs, and sensory afferent-evoked EPSCs did show significant changes in hoxb8-α2 mice rendering a compensatory up-regulation of other GABAR subtypes or of glycine receptors unlikely. Although expression of serotonin and of the serotonin producing enzyme tryptophan hydroxylase (TPH2) was significantly increased in the dorsal horn of hoxb8-α2 mice, ablation of serotonergic terminals from the lumbar spinal cord failed to unmask a nociceptive phenotype. Our results are consistent with an important contribution of α2GABAR to spinal nociceptive control but their ablation early in development appears to activate yet-to-be identified compensatory mechanisms that protect hoxb8-α2 mice from hyperalgesia.
Learn More >General anesthesia (GA) can produce analgesia (loss of pain) independent of inducing loss of consciousness, but the underlying mechanisms remain unclear. We hypothesized that GA suppresses pain in part by activating supraspinal analgesic circuits. We discovered a distinct population of GABAergic neurons activated by GA in the mouse central amygdala (CeA neurons). In vivo calcium imaging revealed that different GA drugs activate a shared ensemble of CeA neurons. CeA neurons also possess basal activity that mostly reflects animals' internal state rather than external stimuli. Optogenetic activation of CeA potently suppressed both pain-elicited reflexive and self-recuperating behaviors across sensory modalities and abolished neuropathic pain-induced mechanical (hyper-)sensitivity. Conversely, inhibition of CeA activity exacerbated pain, produced strong aversion and canceled the analgesic effect of low-dose ketamine. CeA neurons have widespread inhibitory projections to many affective pain-processing centers. Our study points to CeA as a potential powerful therapeutic target for alleviating chronic pain.
Learn More >The Sigma-1 receptor (σR) is highly expressed in the primary sensory neurons (PSNs) that are the critical site of initiation and maintenance of pain following peripheral nerve injury. By immunoblot and immunohistochemistry, we observed increased expression of both σR and σR-binding immunoglobulin protein (BiP) in the lumbar (L) dorsal root ganglia (DRG) ipsilateral to painful neuropathy induced by spared nerve injury (SNI). To evaluate the therapeutic potential of PSN-targeted σR inhibition at a selected segmental level, we designed a recombinant adeno-associated viral (AAV) vector expressing a small hairpin RNA (shRNA) against rat σR. Injection of this vector into the L4/L5 DRGs induced downregulation of σR in DRG neurons of all size groups, while expression of BiP was not affected. This was accompanied by attenuation of SNI-induced cutaneous mechanical and thermal hypersensitivity. Whole-cell current-clamp recordings of dissociated neurons showed that knockdown of σR suppressed neuronal excitability, suggesting that σR silencing attenuates pain by reversal of injury-induced neuronal hyperexcitability. These findings support a critical role of σR in modulating PSN nociceptive functions, and that the nerve injury-induced elevated σR activity in the PSNs can be a significant driver of neuropathic pain. Further understanding the role of PSN-σR in pain pathology may open routes to exploit this system for DRG-targeted pain therapy.
Learn More >Prospective trials of enhanced recovery after spine surgery are lacking. We tested the hypothesis that an enhanced recovery pathway improves quality of recovery after one- to two-level lumbar fusion.
Learn More >