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Agonist binding in the extracellular region of the G protein-coupled adenosine A2A receptor increases its affinity to the G proteins in the intracellular region, and vice versa. The structural basis for this effect is not evident from the crystal structures of AR in various conformational states since it stems from the receptor dynamics. Using atomistic molecular dynamics simulations on four different conformational states of the adenosine A receptor, we observed that the agonists show decreased ligand mobility, lower entropy of the extracellular loops in the active-intermediate state compared with the inactive state. In contrast, the entropy of the intracellular region increases to prime the receptor for coupling the G protein. Coupling of the G protein to AR shrinks the agonist binding site, making tighter receptor agonist contacts with an increase in the strength of allosteric communication compared with the active-intermediate state. These insights provide a strong basis for structure-based ligand design studies.
Learn More >Residual lower limb pain after low back surgery (post-surgical sciatica) and complex regional pain syndrome involving a lower limb (CRPS) are separate conditions, but may share some mechanisms (e.g., tissue inflammation, neuro-immune disturbances and central neuro-plasticity). As adrenergically-evoked pain contributes, in part, to CRPS, whether an adrenergic mechanism also contributes to post-surgical sciatica was investigated in this study. Immunohistochemistry was used to identify α1-adrenoceptors (α1-AR) on nerve fibres and other targets in the affected and contralateral skin of 25 patients with post-surgical sciatica, and α1-AR expression was investigated in relation to pain and pinprick hyperalgesia after intradermal injection of the α1-AR agonist phenylephrine. In addition, quantitative sensory testing was performed on all four limbs and on each side of the forehead. α1-AR expression was greater in keratinocytes (but not blood vessels or nerve fibres) in the symptomatic than contralateral leg, and dermal nerve fibre density was reduced in both legs. However, distal adrenergic involvement in pain in post-surgical sciatica seems unlikely, as neither heightened α1-AR expression in keratinocytes nor reduced dermal nerve fibre density were associated with pain or hyperalgesia to intradermal phenylephrine injection. Sensitivity to pressure-pain, pinprick and cold-pain was greater in the ipsilateral than contralateral forehead of the entire cohort, but sensory disturbances were most pronounced in patients with additional CRPS-like features. Together, these findings suggest that bilateral distal neuropathy and central neuro-plastic changes are involved not only in the pathophysiology of CRPS but also in post-surgical sciatica. This may have treatment implications for patients with post-surgical sciatica.
Learn More >The dysfunctions of the mesolimbic cortical reward circuit have been proposed to contribute to migraine pain. Although supporting empirical evidence was mainly found in connection with primary rewards or in chronic migraine where the pain experience is (almost) constant. Our goal however was to investigate the neural correlates of secondary reward/loss anticipation and consumption using the monetary incentive delay task in 29 episodic migraine patients and 41 headache-free controls. Migraine patients showed decreased activation in one cluster covering the right inferior frontal gyrus during reward consumption compared to controls. We also found significant negative correlation between the time of the last migraine attack before the scan and activation of the parahippocampal gyrus and the right hippocampus yielded to loss anticipation. During reward/loss consumption, a relative increase in the activity of the visual areas was observed the more time passed between the last attack and the scan session. Our results suggest intact reward/loss anticipation but altered reward consumption in migraine, indicating a decreased reactivity to monetary rewards. The findings also raise the possibility that neural responses to loss anticipation and reward/loss consumption could be altered by the proximity of the last migraine attack not just during pre-ictal periods, but interictally as well.
Learn More >Vulvodynia is a common, recurrent, vulvar pain condition with debilitating consequences for affected women's health and quality of life. The heterogeneity of women suffering from vulvodynia as well as its uncertain and likely multifactorial etiology pose a significant challenge to identifying any kind of "gold standard" treatment. Thus, treatment providers must be well versed in the various options and the evidence for each. In this review, we begin with pharmacological treatments, followed by non-pharmacological treatments, surgery, and finally multimodal treatments. For each approach, we briefly discuss the method, mechanism of action, and empirical support for the treatment. In sum, pharmacological treatments that may be beneficial but require further research include antinociceptive agents (lidocaine, capsaicin), anti-inflammatory agents (corticosteroids, interferon), neuromodulating medications (anticonvulsants and antidepressants), hormonal agents, and muscle relaxants (e.g., botulinum toxin). There is strong evidence to support and recommend non-pharmacological interventions including psychological therapy, pelvic floor physical therapy, as well as surgery (i.e., vestibulectomy for provoked vestibulodynia) for the treatment of vulvodynia. We conclude this review with a discussion of issues that may have hindered progress of treatment efficacy and effectiveness, and recommendations for moving the field forward.
Learn More >Chronic pain is a common public health problem that has a detrimental impact on patient health, quality of life (QoL), and function, and poses a substantial socioeconomic burden. Evidence supports redefinition of chronic pain as a distinct disease entity, not simply a symptom of injury or illness. Chronic pain conditions are characterized by three types of pain pathophysiology – i.e., nociceptive, neuropathic, and centralized pain/central sensitization -influenced by a cluster of coexisting psychosocial factors. Negative risk/vulnerability factors, e.g., mood or sleep disturbances, and positive resilience/protective factors, e.g., social/interpersonal relationships and active coping, interact with pain neurobiology to determine patients' unique pain experience. Viewing chronic pain through a biopsychosocial lens, instead of a purely biomedical one, clinicians need to adopt a practical integrated management approach. Thorough assessment focuses on the whole patient (not just the pain), including comorbidities, cognitive/emotional/behavioral characteristics, social environment, and QoL/functional impairment. As for other complex chronic illnesses, the treatment plan for chronic pain can be developed based on pain subtype and psychosocial profile, incorporating pharmacotherapy and self-management modalities. Preferred pharmacologic treatment of conditions primarily associated with nociception (e.g., osteoarthritis) includes acetaminophen and non-steroidal anti-inflammatory drugs, whereas preferred pharmacologic treatment of conditions primarily associated with neuropathy or central sensitization (e.g., fibromyalgia) includes tricyclic compounds, serotonin norepinephrine reuptake inhibitors, and αδ ligands. Education, exercise, cognitive behavioral therapy, and many other non-pharmacological approaches, alone or combined with pharmacotherapy, have been shown to be effective for any type of pain, although they remain underutilized due to lack of awareness of their benefits and reimbursement obstacles.
Learn More >Acute inflammation induces sensitization of nociceptive neurons and triggers the accumulation of calcium permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in the dorsal horn of the spinal cord. This coincides with behavioral signs of acute inflammatory pain, but whether CP-AMPARs contribute to chronic pain remains unclear. To evaluate this question, we first constructed current-voltage (IV) curves of C-fiber stimulus-evoked, AMPAR-mediated EPSCs in lamina II to test for inward rectification, a key characteristic of CP-AMPARs. We found that the intraplantar injection of complete Freund's adjuvant (CFA) induced an inward rectification at 3 d that persisted to 21 d after injury. Furthermore, the CP- AMPAR antagonist IEM-1460 (50 μM) inhibited AMPAR-evoked Ca transients 21d after injury but had no effect in uninflamed mice. We then used a model of long-lasting vulnerability for chronic pain that is determined by the balance between latent central sensitization (LCS) and mu opioid receptor constitutive activity (MOR). When administered 21 d after the intraplantar injection of CFA, intrathecal administration of the MOR inverse agonist naltrexone (NTX, 1 μg, i.t.) reinstated mechanical hypersensitivity, and superfusion of spinal cord slices with NTX (10 μM) increased the peak amplitude of AMPAR-evoked Ca transients in lamina II neurons. The CP-AMPAR antagonist naspm (0-10 nmol, i.t.) inhibited these NTX-induced increases in mechanical hypersensitivity. NTX had no effect in uninflamed mice. Subsequent western blot analysis of the postsynaptic density membrane fraction from lumbar dorsal horn revealed that CFA increased GluA1 expression at 2 d and GluA4 expression at both 2 and 21 d post-injury, indicating that not just the GluA1 subunit, but also the GluA4 subunit, contributes to the expression of CP-AMPARs and synaptic strength during hyperalgesia. GluA2 expression increased at 21 d, an unexpected result that requires further study. We conclude that after tissue injury, dorsal horn AMPARs retain a Ca permeability that underlies LCS. Because of their effectiveness in reducing naltrexone-induced reinstatement of hyperalgesia and potentiation of AMPAR-evoked Ca signals, CP-AMPAR inhibitors are a promising class of agents for the treatment of chronic inflammatory pain.
Learn More >Despite being one of the most common presenting dermatological symptoms, itching continues to perplex health care professionals because it is notoriously difficult to control.
Learn More >Previous studies have reported that certain bacteria exert visceral antinociceptive activity in visceral pain and may also help to relieve neuropathic and inflammatory pain.
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