scholarly journals Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain

2021 ◽  
Author(s):  
Annemarie Dedek ◽  
Jian Xu ◽  
Louis-Étienne Lorenzo ◽  
Antoine G. Godin ◽  
Chaya M. Kandegedara ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sexual Dimorphism ◽  
Nmda Receptor ◽  
Ex Vivo ◽  
Female Rats ◽  
Pain Mechanisms ◽  
Human Organ ◽  
Neuronal Mechanism ◽  
Lamina I ◽  
Pathological Pain

The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn (SDH), direct investigations using rodent and human preclinical pain models have been lacking. Here, we discovered that in the Freund′s Adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and NMDA receptor potentiation within SDH neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator, BDNF, failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B, and pGluN2B) in female rats, resulting in no effect of ex vivo BDNF on synaptic NMDA receptor responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans. As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in SDH neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDA receptor potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.

scholarly journals An evolutionary medicine perspective on pain and its disorders

2019 ◽  
Vol 374 (1785) ◽  
pp. 20190288 ◽  
Author(s):  
Randolph M. Nesse ◽  
Jay Schulkin
Keyword(s):  
Chronic Pain ◽  
Tissue Damage ◽  
Mental States ◽  
Preliminary Evidence ◽  
Evolutionary Medicine ◽  
Smoke Detector ◽  
Pain Mechanisms ◽  
Trade Offs ◽  
Pathological Pain ◽  
The Cost

Enormous progress in understanding the mechanisms that mediate pain can be augmented by an evolutionary medicine perspective on how the capacity for pain gives selective advantages, the trade-offs that shaped the mechanisms, and evolutionary explanations for the system's vulnerability to excessive and chronic pain. Syndromes of deficient pain document tragically the utility of pain to motivate escape from and avoidance of situations causing tissue damage. Much apparently excessive pain is actually normal because the cost of more pain is often vastly less than the cost of too little pain (the smoke detector principle). Vulnerability to pathological pain may be explained in part because natural selection has shaped mechanisms that respond adaptively to repeated tissue damage by decreasing the pain threshold and increasing pain salience. The other half of an evolutionary approach describes the phylogeny of pain mechanisms; the apparent independence of different kinds of pain is of special interest. Painful mental states such as anxiety, guilt and low mood may have evolved from physical pain precursors. Preliminary evidence for this is found in anatomic and genetic data. Such insights from evolutionary medicine may help in understanding vulnerability to chronic pain. This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.

Dorsal Horn Pain Mechanisms

2019 ◽  
pp. 444-469 ◽  
Author(s):  
Hanns Ulrich Zeilhofer ◽  
Robert Ganley
Keyword(s):  
Dorsal Horn ◽  
Neuronal Excitability ◽  
Functional Organization ◽  
Synaptic Integration ◽  
Synaptic Efficacy ◽  
Pain Mechanisms ◽  
Pain Pathway ◽  
Pathological Pain ◽  
The Subject ◽  
Equivalent Structure

The spinal dorsal horn and its equivalent structure in the brainstem constitute the first sites of synaptic integration in the pain pathway. A huge body of literature exists on alterations in spinal nociceptive signal processing that contribute to the generation of exaggerated pain states and hence to what is generally known as “central sensitization.” Such mechanisms include changes in synaptic efficacy or neuronal excitability, which can be evoked by intense nociceptive stimulation or by inflammatory or neuropathic insults. Some of these changes cause alterations in the functional organization of dorsal horn sensory circuits, leading to abnormal pathological pain sensations. This article reviews the present state of this knowledge. It does not cover the contributions of astrocytes and microglia in detail as their functions are the subject of a separate chapter.

scholarly journals Adaptive mechanisms driving maladaptive pain: how chronic ongoing activity in primary nociceptors can enhance evolutionary fitness after severe injury

2019 ◽  
Vol 374 (1785) ◽  
pp. 20190277 ◽  
Author(s):  
Edgar T. Walters
Keyword(s):  
Chronic Pain ◽  
Motor Impairment ◽  
Low Frequency ◽  
Severe Injury ◽  
Ongoing Activity ◽  
Pain Mechanisms ◽  
Bodily Injury ◽  
Adaptive Mechanisms ◽  
Survival And Reproduction ◽  
Ongoing Pain

Chronic pain is considered maladaptive by clinicians because it provides no apparent protective or recuperative benefits. Similarly, evolutionary speculations have assumed that chronic pain represents maladaptive or evolutionarily neutral dysregulation of acute pain mechanisms. By contrast, the present hypothesis proposes that chronic pain can be driven by mechanisms that evolved to reduce increased vulnerability to attack from predators and aggressive conspecifics, which often target prey showing physical impairment after severe injury. Ongoing pain and anxiety persisting long after severe injury continue to enhance vigilance and behavioural caution, decreasing the heightened vulnerability to attack that results from motor impairment and disfigurement, thereby increasing survival and reproduction (fitness). This hypothesis is supported by evidence of animals surviving and reproducing after traumatic amputations, and by complex specializations that enable primary nociceptors to detect local and systemic signs of injury and inflammation, and to maintain low-frequency discharge that can promote ongoing pain indefinitely. Ongoing activity in nociceptors involves intricate electrophysiological and anatomical specializations, including inducible alterations in the expression of ion channels and receptors that produce persistent hyperexcitability and hypersensitivity to chemical signals of injury. Clinically maladaptive chronic pain may sometimes result from the recruitment of this powerful evolutionary adaptation to severe bodily injury. This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.

scholarly journals Vitamin D Deficiency Induces Chronic Pain and Microglial Phenotypic Changes in Mice

2021 ◽  
Vol 22 (7) ◽  
pp. 3604
Author(s):  
Nicola Alessio ◽  
Carmela Belardo ◽  
Maria Consiglia Trotta ◽  
Salvatore Paino ◽  
Serena Boccella ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Vitamin D ◽  
Chronic Pain ◽  
Vitamin D Deficiency ◽  
Morphological Analysis ◽  
Pain Perception ◽  
Ex Vivo ◽  
Ros Generation ◽  
Peroxisome Proliferator ◽  
Neuroprotective Effects

The bioactive form of vitamin .D, 1,25-dihydroxyvitamin D (1,25D3), exerts immunomodulatory actions resulting in neuroprotective effects potentially useful against neurodegenerative and autoimmune diseases. In fact, vitamin D deficiency status has been correlated with painful manifestations associated with different pathological conditions. In this study, we have investigated the effects of vitamin D deficiency on microglia cells, as they represent the main immune cells responsible for early defense at central nervous system (CNS), including chronic pain states. For this purpose, we have employed a model of low vitamin D intake during gestation to evaluate possible changes in primary microglia cells obtained from postnatal day(P)2-3 pups. Afterwards, pain measurement and microglia morphological analysis in the spinal cord level and in brain regions involved in the integration of pain perception were performed in the parents subjected to vitamin D restriction. In cultured microglia, we detected a reactive—activated and proliferative—phenotype associated with intracellular reactive oxygen species (ROS) generation. Oxidative stress was closely correlated with the extent of DNA damage and increased β-galactosidase (B-gal) activity. Interestingly, the incubation with 25D3 or 1,25D3 or palmitoylethanolamide, an endogenous ligand of peroxisome proliferator-activated-receptor-alpha (PPAR-α), reduced most of these effects. Morphological analysis of ex-vivo microglia obtained from vitamin-D-deficient adult mice revealed an increased number of activated microglia in the spinal cord, while in the brain microglia appeared in a dystrophic phenotype. Remarkably, activated (spinal) or dystrophic (brain) microglia were detected in a prominent manner in females. Our data indicate that vitamin D deficiency produces profound modifications in microglia, suggesting a possible role of these cells in the sensorial dysfunctions associated with hypovitaminosis D.

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

2016 ◽  
Vol 473 (18) ◽  
pp. 2717-2736 ◽  
Author(s):  
Christoforos Tsantoulas ◽  
Elizabeth R. Mooney ◽  
Peter A. McNaughton
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Ion Channels ◽  
Warning Signal ◽  
Sensory Nerves ◽  
Nociceptive Neurons ◽  
Pain Syndromes ◽  
Medical Need ◽  
Pathological Pain ◽  
Genetic Deletion

Nociception — the ability to detect painful stimuli — is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a ‘pacemaker for pain’, in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

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