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Postoperative pain has a major influence on older adults' rehabilitation. There is a lack of knowledge regarding how older adults return to daily living after discharge.
Learn More >Periostin, an extracellular matrix and matricellular protein, binds to several types of integrins that transduce its signals. Its function in allergic inflammation is the establishment of sustained chronic inflammation through an amplification of T helper type 2‒immune responses. In addition, recent studies have shown a significant role of periostin in itch sensation through direct integrin-mediated stimulation of nerve fibers and interaction with immune and nonimmune cells (e.g., macrophages, eosinophils, basophils, and keratinocytes). The objective of this review is to describe the role of periostin in itch induction in human and animal models and its expression in human pruritic conditions.
Learn More >In rheumatology, chronic pain most often sets in after a musculoskeletal injury. Its persistence is not always due to the progression of the initial injury, but in some cases to the onset of central sensitization. Much scientific data suggests that this central sensitization is caused by multiple complex interactions between the nervous system and immune system. Afferent nerve fibers carrying pain information are responsible for peripheral sensitization partly linked to inflammation molecules. These afferent fibers release neurotransmitters in the dorsal root ganglion and dorsal horn of the spinal cord, capable of activating microglia, which are the local immune cells. The activated microglia will produce pro-inflammatory cytokines, chemokines and neuropeptides capable of interacting with the second-order neuron, but also segmental and descending inhibitory neurons. This is referred to as neuroinflammation, which will amplify the hypersensitivity of second-order neurons, otherwise called central sensitization. This neuroinflammation will be able to reach the higher brain structures, which are involved in pain modulation and the emotional and cognitive aspects of pain. The aim of this update is to describe the pathophysiology of chronic pain, incorporating the latest scientific data on neuroplasticity and neuroinflammation.
Learn More >Pain is a prevalent issue for elderly individuals. Unfortunately, it remains unclear how acute and chronic pain differs as a function of age, and surprisingly, there is even disagreement on how the sensory and affective dimensions of pain change with age. Therefore, the current investigation evaluated such age differences with behavioral methodology using a preclinical model of arthritis. The primary factors of interest were age and chronicity of pain using behavioral assessments designed to measure sensory and affective dimensions of pain processing. Mechanical and thermal paw withdrawal thresholds demonstrated unique outcomes associated with sensory processing across age. The processing of pain affect measured by the Place Escape/Avoidance Paradigm (PEAP testing) also demonstrated age related effects. Overall, younger animals appeared more sensitive to nociceptive stimuli than older animals. However, the results from the current study suggest that chronicity of pain can be impactful for how older animals process pain related affect and avoidance. The finding of unique patterns of pain across age and duration of pain highlights the clinical literature. Future research should aim to elucidate mechanisms for affective processing of chronic pain in older subjects.
Learn More >Opioid-based drugs are frequently used for pain management in both males and females despite the known risk of prefrontal cortex dysfunction and cognitive impairments. Although poorly understood, loss of cognitive control following chronic drug use has been linked to decreased activation of frontal cortex regions. Here, we show that self-administration of the potent opioid, remifentanil, causes a long-lasting hypoactive basal state evidenced by a decrease in ex vivo excitability that is paralleled by an increase in firing capacity of layer 5/6 pyramidal neurons in the prelimbic, but not infralimbic region of the medial prefrontal cortex. This phenomenon was observed in females after as few as 5 days and up to 25-30 days of self-administration. In contrast, pyramidal neurons in males showed increased excitability following 10-16 days of self-administration, with hypoactive states arising only following 25-30 days of self-administration. The emergence of a hypoactive, but not hyperactive basal state following remifentanil self-administration aligned with deficits in cognitive flexibility as assessed using an operant-based attentional set-shifting task. In females, the hypoactive basal state is driven by a reduction in excitatory synaptic transmission mediated by AMPA-type glutamate receptors. Alternatively, hyper- and hypoactive states in males align selectively with decreased and increased GABA signaling, respectively. Chemogenetic compensation for this hypoactive state prior to testing restored cognitive flexibility, basal hypoactive state, and remifentanil-induced plasticity. These data define cellular and synaptic mechanisms by which opioids impair prefrontal function and cognitive control; indicating that interventions aimed at targeting opioid-induced adaptations should be tailored based on biological sex.
Learn More >Humans with loss-of-function mutations in the Na1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Na1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Na1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Na1.7 target modulation in vivo. The potent and selective Na1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Na1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Na1.7 loss-of-function patients. These data demonstrate that it is possible to measure Na1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.
Learn More >To test whether contralateral sensory abnormalities in the clinically unaffected area of patients with unilateral neuropathic pain are due to the neuropathy or pain mechanisms.
Learn More >RFamide-related peptide-3 (RFRP-3) and neuropeptide FF (NPFF) target two different receptor subtypes called neuropeptide FF1 (NPFF1R) and neuropeptide FF2 (NPFF2R) that modulate several functions. However, the study of their respective role is severely limited by the absence of selective blockers. We describe here the design of a highly selective NPFF1R antagonist called RF3286, which potently blocks RFRP-3-induced hyperalgesia in mice and luteinizing hormone release in hamsters. We then showed that the pharmacological blockade of NPFF1R in mice prevents the development of fentanyl-induced hyperalgesia while preserving its analgesic effect. Altogether, our data indicate that RF3286 represents a useful pharmacological tool to study the involvement of the NPFF1R/RFRP-3 system in different functions and different species. Thanks to this compound, we showed that this system is critically involved in the development of opioid-induced hyperalgesia, suggesting that NPFF1R antagonists might represent promising therapeutic tools to improve the use of opioids in the treatment of chronic pain.
Learn More >α-Conotoxins are small disulfide-rich peptides found in the venom of marine cone snails and are potent antagonists of nicotinic acetylcholine receptors (nAChRs). They are valuable pharmacological tools and have potential therapeutic applications for the treatment of chronic pain or neurological diseases and disorders. In the present study, we synthesized and functionally characterized a novel α-conotoxin Bt1.8, which was cloned from Conus betulinus. Bt1.8 selectively inhibited ACh-evoked currents in Xenopus oocytes expressing rat(r) α6/α3β2β3 and rα3β2 nAChRs with an IC of 2.1 nM and 9.4 nM, respectively, and similar potency for human (h) α6/α3β2β3 and hα3β2 nAChRs Additionally, Bt1.8 had higher binding affinity with a slower dissociation rate for the rα6/α3β2β3 subtype compared to rα3β2. The amino acid sequence of Bt1.8 is significantly different from other reported α-conotoxins targeting the two nAChR subtypes. Further Alanine scanning analyses demonstrated that residues Ile9, Leu10, Asn11, Asn12 and Asn14 are critical for its inhibitory activity at the α6/α3β2β3 and α3β2 subtypes. Moreover, the NMR structure of Bt1.8 indicated the presence of a relatively larger hydrophobic zone than other α4/7-conotoxins which may explain its potent inhibition of α6/α3β2β3 nAChRs.
Learn More >Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.
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