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Oxytocin (OT), a nonapeptide, has a variety of functions. Despite extensive studies on OT over past decades, our understanding of its neural functions and their regulation remains incomplete. OT is mainly produced in OT neurons in the supraoptic nucleus (SON), paraventricular nucleus (PVN) and accessory nuclei between the SON and PVN. OT exerts neuromodulatory effects in the brain and spinal cord. While magnocellular OT neurons in the SON and PVN mainly innervate the pituitary and forebrain regions, and parvocellular OT neurons in the PVN innervate brainstem and spinal cord, the two sets of OT neurons have close interactions histologically and functionally. OT expression occurs at early life to promote mental and physical development, while its subsequent decrease in expression in later life stage accompanies aging and diseases. Adaptive changes in this OT system, however, take place under different conditions and upon the maturation of OT release machinery. OT can modulate social recognition and behaviors, learning and memory, emotion, reward, and other higher brain functions. OT also regulates eating and drinking, sleep and wakefulness, nociception and analgesia, sexual behavior, parturition, lactation and other instinctive behaviors. OT regulates the autonomic nervous system, and somatic and specialized senses. Notably, OT can have different modulatory effects on the same function under different conditions. Such divergence may derive from different neural connections, OT receptor gene dimorphism and methylation, and complex interactions with other hormones. In this review, brain functions of OT and their underlying neural mechanisms as well as the perspectives of their clinical usage are presented.
Learn More >Complex regional pain syndrome (CRPS) is a rare but debilitating chronic pain condition of the extremities, which often develops after an injury. Its multifactorial pathophysiology includes the immune and nervous systems and, potentially, autoimmune, genetic, and psychological factors. Psychiatric illnesses can be comorbid with CRPS, including mood disorders, anxiety disorders, insomnia, substance use disorder, personality disorders, and somatic symptom disorder. This article discusses these psychiatric symptoms and offers treatment guidance.
Learn More >More patients are turning to medical marijuana as an alternative treatment, yet there are apparent knowledge gaps on the risk benefit of medical marijuana for a variety of indications. This study aimed to determine the priorities for medical marijuana research from the perspective of multiple stakeholders including patients, clinicians, and industry representatives.
Learn More >Orofacial pain disorders are predominately experienced by women. Progesterone, a major ovarian hormone, is neuroprotective and antinociceptive. We recently reported that progesterone attenuates estrogen-exacerbated orofacial pain behaviors, yet it remains unclear what anatomical substrate underlies progesterone's activity in the trigeminal system. Progesterone has been reported to exert protective effects through actions at intracellular progesterone receptors (iPR), membrane-progesterone receptors (mPR), or sigma 1 receptors (Sig-1R). Of these, the iPR and Sig-1R have been reported to have a role in pain. Progesterone can also have antinociceptive effects through its metabolite, allopregnanolone. Two enzymes, 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD), are required for the metabolism of progesterone to allopregnanolone. Both progesterone and allopregnanolone rapidly attenuate pain sensitivity, implicating action of either progesterone at Sig-1R and/or conversion to allopregnanolone which targets GABA receptors. In the present study, we investigated whether Sig-1 Rs are expressed in nociceptors within the trigeminal ganglia of cycling female rats and whether the two enzymes required for progesterone metabolism to allopregnanolone, 5α-reductase and 3α-hydroxysteroid dehydrogenase, are also present. Adult female rats from each stage of the estrous cycle were rapidly decapitated and the trigeminal ganglia collected. Trigeminal ganglia were processed by either fluorescent immunochemistry or western blotting to for visualization and quantification of Sig-1R, 5α-reductase, and 3α-hydroxysteroid dehydrogenase. Here we report that Sig-1Rs and both enzymes involved in progesterone metabolism are highly expressed in a variety of nociceptive sensory neuron populations in the female rat trigeminal ganglia at similar levels across the four stages of the estrous cycle. These data indicate that trigeminal sensory neurons are an anatomical substrate for the reported antinociceptive activity of progesterone via Sig-1R and/or conversion to allopregnanolone.
Learn More >Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes severe neuropathic pain typically encompassing cold allodynia and long-lasting mechanical allodynia. Endothelin has been shown to modulate nociceptive transmission in a variety of pain disorders. However, the action of endothelin varies greatly depending on many variables, including pain causes, receptor types (endothelin type A (ET) and B (ET) receptors) and organs (periphery and spinal cord). Therefore, in this study, we investigated the role of endothelin in a Sprague-Dawley rat model of oxaliplatin-induced neuropathic pain. Intraperitoneal administration of bosentan, a dual ET/ET receptor antagonist, effectively blocked the development or prevented the onset of both cold allodynia and mechanical allodynia. The preventive effects were exclusively mediated by ET receptor antagonism. Intrathecal administration of an ET receptor antagonist prevented development of long-lasting mechanical allodynia but not cold allodynia. In marked contrast, an intraplantar ET receptor antagonist had a suppressive effect on cold allodynia but only had a partial and transient effect on mechanical allodynia. In conclusion, ET receptor antagonism effectively prevented long-lasting mechanical allodynia through spinal and peripheral actions, while cold allodynia was prevented through peripheral actions.
Learn More >To develop and implement criteria for description of post COVID syndrome based on analysis of patients presenting for evaluation at Mayo Clinic Rochester between November 2019 and August 2020.
Learn More >Adult rats that experienced neonatal limited bedding (NLB), a form of early-life stress, experience persistent muscle mechanical hyperalgesia. Since there is a growing recognition that the gut microbiome regulates pain and nociception, and that early-life stress produces a long-lasting impact on the gut microbiome, we tested the hypothesis that persistent muscle hyperalgesia seen in adult NLB rats could be ameliorated by interventions that modify the gut microbiome. Adult NLB rats received probiotics, either GG (10 billion CFU/150 ml) or De Simone Formulation (DSF) (112.5 billion CFU/150 ml mixture of 8 bacterial species), in their drinking water, or non-absorbable antibiotics, rifaximin or neomycin, admixed with cookie dough, to provide 50 mg/kg. Mechanical nociceptive threshold in the gastrocnemius muscle was evaluated before and at several time points after administration of probiotics or antibiotics. Adult NLB rats fed probiotics or DSF, antibiotics, as well as rats fed non-absorbable antibiotics rifaximin or neomycin, had markedly attenuated muscle mechanical hyperalgesia. We hypothesize that persistent skeletal muscle hyperalgesia produced by NLB stress may be, at least in part, due to a contribution of the gut microbiome, and that modulation of gut microbiome using probiotics or non-absorbable antibiotics, may be novel therapeutic approaches for the treatment of chronic musculoskeletal pain.
Learn More >Projection neurons in the spinal dorsal horn relay sensory information to higher brain centres. The activation of these populations is shaped by afferent input from the periphery, descending input from the brain, and input from local interneuron circuits. Much of our recent understanding of dorsal horn circuitry comes from studies in transgenic mice; however, information on projection neurons is still based largely on studies in monkey, cat, and rat. We used viral labelling to identify and record from mouse parabrachial nucleus (PBN) projecting neurons located in the dorsal horn of spinal cord slices. Overall, mouse lamina I spinoparabrachial projection neurons (SPBNs) exhibit many electrophysiological and morphological features that overlap with rat. Unbiased cluster analysis distinguished 4 distinct subpopulations of lamina I SPBNs, based on their electrophysiological properties that may underlie different sensory signalling features in each group. We also provide novel information on SPBNs in the deeper lamina (III-V), which have not been previously studied by patch clamp analysis. These neurons exhibited higher action potential discharge frequencies and received weaker excitatory synaptic input than lamina I SPBNs, suggesting this deeper population produces different sensory codes destined for the PBN. Mouse SPBNs from both regions (laminae I and III-V) were often seen to give off local axon collaterals, and we provide neuroanatomical evidence they contribute to excitatory input to dorsal horn circuits. These data provide novel information to implicate excitatory input from parabrachial projection neuron in dorsal horn circuit activity during processing of nociceptive information, as well as defining deep dorsal horn projection neurons that provide an alternative route by which sensory information can reach the PBN.
Learn More >In late 2019, a novel coronavirus SARS-CoV-2 (COVID-19) spread unchecked across the world's population. With tens of millions infected, the long-term consequences of COVID-19 infection will be a major health care focus for years after the contagion subsides. Most complications stem from direct viral invasion provoking an over-exuberant inflammatory response driven by innate immune cells and activation of the clotting cascade causing thrombosis. Injury to individual organs and their protective linings are frequent presentations in respiratory, cardiovascular, and neurological systems. Reviewing the historical context of postviral fatiguing symptoms seems relevant to understanding reports of uneven recoveries and persistent symptoms that are emerging as "long-haul COVID-19." The pandemic is also an unprecedented sociocultural event, transforming how people consider their health, gather in groups, and navigate their daily lives. The unprecedented sociocultural stresses of the pandemic will have an invisible, ubiquitous, and predictable impact on neurologic, endocrine, and immune functioning, even in people untouched by the virus. COVID-19 may also have a surprise or two in store, with unique clinical presentations and novel mechanisms of injury which are yet to clearly emerge. Although challenging and unfortunate, these times also represent a unique opportunity to start to unravel the physiology that underlie how viruses may trigger cancers, neurological disease, and postviral fatiguing syndromes.
Learn More >Most patients with amputation (up to 80%) suffer from phantom limb pain postsurgery. These are often multimorbid patients who also have multiple risk factors for the development of chronic pain from a pain medicine perspective. Surgical removal of the body part and sectioning of peripheral nerves result in a lack of afferent feedback, followed by neuroplastic changes in the sensorimotor cortex. The experience of severe pain, peripheral, spinal, and cortical sensitization mechanisms, and changes in the body scheme contribute to chronic phantom limb pain. Psychosocial factors may also affect the course and the severity of the pain. Modern amputation medicine is an interdisciplinary responsibility.
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