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Differential aging-related changes in neurophysiology and gene expression in IB4-positive and IB4-negative nociceptive neurons.

ABSTRACT: Despite pain prevalence altering with age, the effects of aging on the properties of nociceptors are not well understood. Nociceptors, whose somas are located in dorsal root ganglia, are frequently divided into two groups based on their ability to bind isolectin B4 (IB4). Here, using cultured neurons from 1-, 3-, 5-, 8-, 12-, and 18-month-old mice, we investigate age-dependent changes in IB4-positive and IB4-negative neurons. Current-clamp experiments at physiological temperature revealed nonlinear changes in firing frequency of IB4-positive, but not IB4-negative neurons, with a peak at 8 months. This was likely due to the presence of proexcitatory conductances activated at depolarized membrane potentials and significantly higher input resistances found in IB4-positive neurons from 8-month-old mice. Repetitive firing in nociceptors is driven primarily by the TTX-resistant sodium current, and indeed, IB4-positive neurons from 8-month-old mice were found to receive larger contributions from the TTX-resistant window current around the resting membrane potential. To further address the mechanisms behind these differences, we performed RNA-seq experiments on IB4-positive and IB4-negative neurons from 1-, 8-, and 18-month-old mice. We found a larger number of genes significantly affected by age within the IB4-positive than IB4-negative neurons from 8-month-old mice, including known determinants of nociceptor excitability. The above pronounced age-dependent changes at the cellular and molecular levels in IB4-positive neurons point to potential mechanisms behind the reported increase in pain sensitivity in middle-aged rodents and humans, and highlight the possibility of targeting a particular group of neurons in the development of age-tailored pain treatments.

SUBMITTER: Mis MA

PROVIDER: S-EPMC6052481 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Differential aging-related changes in neurophysiology and gene expression in IB4-positive and IB4-negative nociceptive neurons.

Mis Malgorzata A MA Rogers Mark F MF Jeffries Aaron R AR Wilbrey Anna L AL Chen Lubin L Yang Yang Y Dib-Hajj Sulayman S Waxman Stephen G SG Stevens Edward B EB Randall Andrew D AD

Aging cell 20180625 4

Despite pain prevalence altering with age, the effects of aging on the properties of nociceptors are not well understood. Nociceptors, whose somas are located in dorsal root ganglia, are frequently divided into two groups based on their ability to bind isolectin B4 (IB4). Here, using cultured neurons from 1-, 3-, 5-, 8-, 12-, and 18-month-old mice, we investigate age-dependent changes in IB4-positive and IB4-negative neurons. Current-clamp experiments at physiological temperature revealed nonlin ...[more]

PMID: 29943484

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Project description:BackgroundAlthough a number of clinical and preclinical studies have demonstrated analgesic effects of cannabinoid treatments, there are also instances when cannabinoids have had no effect or even exacerbated pain. The observed pro-nociceptive effects appear to be due to cannabinoid-induced disinhibition of afferent synaptic input to nociceptive circuits. To better understand how cannabinoid-mediated plasticity can have both pro- and anti-nociceptive effects, we examined the possibility that cannabinoids differentially modulate nociceptive vs. non-nociceptive synapses onto a shared postsynaptic target. These experiments were carried out in the central nervous system (CNS) of the medicinal leech, in which it is possible to intracellularly record from presynaptic nociceptive (N-cell) or pressure-sensitive (P-cell) neurons and their shared postsynaptic targets.ResultsThe endocannabinoid 2-arachidonoyl glycerol (2AG) elicited significant long-lasting depression in nociceptive (N-cell) synapses. However, non-nociceptive (P-cell) synapses were potentiated following 2AG treatment. 2AG-induced potentiation of non-nociceptive synapses was blocked by the TRPV antagonist SB366791, suggesting involvement of the same TRPV-like receptor that has already been shown to mediate endocannabinoid-dependent depression in nociceptive inputs. Treatment with the GABA receptor antagonist bicuculline also blocked 2AG-induced potentiation, consistent with the idea that increased synaptic signaling was the result of endocannabinoid-mediated disinhibition. Interestingly, while bicuculline by itself increased non-nociceptive synaptic transmission, nociceptive synapses were depressed by this GABA receptor antagonist indicating that nociceptive synapses were actually excited by GABAergic input. Consistent with these observations, GABA application depolarized the nociceptive afferent and hyperpolarized the non-nociceptive afferent.ConclusionsThese findings show that endocannabinoids can differentially modulate nociceptive vs. non-nociceptive synapses and that GABAergic regulation of these synapses plays an important role in determining whether endocannabinoids have a potentiating or depressing effect.

Project description:Proinflammatory cytokines are major mediators in the pathogenesis of diseases of joints such as rheumatoid arthritis and osteoarthritis. This review emphasizes that proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6 and interleukin-17 are also mediators of pain by directly acting on the nociceptive system. Proportions of nociceptive sensory neurons express receptors for these cytokines, and the application of cytokines rapidly changes the excitability, ion currents and second messenger systems of these neurons. By inducing persistent sensitization of nociceptive sensory neurons (C- and a proportion of Aδ-fibers) for mechanical stimuli in the joint (a process called peripheral sensitization), these cytokines significantly contribute to the persistent hyperalgesia typical for many disease states of the joint. In addition, the disease-associated release of cytokines in the spinal cord supports the generation of central sensitization. The therapeutic neutralization of proinflammatory cytokines thus not only reduces the process of inflammation but may directly reduce hyperalgesia and pain by reversing the neuronal effects of cytokines. It is emerging that different cytokines have different actions on neurons. The neutralization of tumor necrosis factor-alpha reduces both mechanical and thermal hyperalgesia of the joint. The neutralization of interleukin-1 beta attenuates thermal hyperalgesia whereas the neutralization of interleukin-6 and interleukin-17 mainly reduces mechanical hyperalgesia. These different effects are partly explained by influencing different target molecules in sensory neurons. For example, in cultured sensory neurons tumor necrosis factor-alpha and interleukin-1 beta upregulate the TRPV1 ion channel, which is involved in the transduction of heat stimuli, consistent with an effect of these cytokines in thermal hyperalgesia. By contrast, interleukin-17 upregulates the TRPV4 ion channel, which has a role in the transduction of mechanical stimuli. Thus, the analgesic potential of neutralizing cytokines seems to depend on which cytokine is mainly involved in the particular pain state.

Dataset Information

Differential aging-related changes in neurophysiology and gene expression in IB4-positive and IB4-negative nociceptive neurons.

Publications

Differential aging-related changes in neurophysiology and gene expression in IB4-positive and IB4-negative nociceptive neurons.

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