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Migraine is a complex neurovascular disorder that is one of the leading causes of disability and a reduced quality of life. Even with such a high societal impact, our understanding of the cellular and molecular mechanisms that contribute to migraine headaches are poorly understood. To address this complex disorder, several groups have performed genome-wide associated studies (GWAS) to elucidate migraine susceptibility genes, with many identifying TRPM8, a cold-sensitive cation channel expressed in peripheral afferents innervating the trigeminovascular system, and the principal mediator of cold and cold pain associated with injury and disease. Interestingly, these migraine-associated single nucleotide polymorphisms (SNPs) reside in noncoding regions of TRPM8, with those correlated with reduced migraine risk exhibiting lower TRPM8 expression and decreased cold sensitivity. Nonetheless, as a role for TRPM8 in migraine has yet to be defined, we sought to address this gap in our knowledge using mouse genetics and TRPM8 antagonism to determine if TRPM8 channels or neurons are required for migraine-like pain (mechanical allodynia and facial grimace) in inducible migraine models. Our results show that both evoked and spontaneous pain behaviors are dependent on both TRPM8 channels and neurons, as well as required in both acute and chronic migraine models. Moreover, inhibition of TRPM8 channels prevented acute but not established chronic migraine-like pain. However, chronic pain could not be prevented with TRPM8 inhibition. These results are consistent with its association with migraine in genetic analyses and establish that TRPM8 channels are a component of the underlying mechanisms of migraine.
Learn More >Central neuropathic pain is a core clinical sign of syringomyelia in humans and Cavalier King Charles Spaniel (CKCS) dogs. This histopathological study used spinal cords from CKCS with syringomyelia to investigate: 1) whether specific structural cervical spinal cord entities involved in nociception are affected by loss of neuroparenchyma or other pathological changes in CKCS with pain-related behaviour and phantom scratching, 2) if pain related behaviour or phantom scratching correlated with loss of a specific anatomical entity or upregulation of glia cells, and 3) if syringomyelia-related lesions affected specific functional spinal cord units of nociception.Spinal cord segments C1-C8 from CKCS with MRI-confirmed syringomyelia and clinical signs of pain and phantom scratch (n=8) were compared to CKCS without syringomyelia (n=4). Dogs with unilateral scratching (n=7) had a volume loss (P=0.043) of the dorsal horn laminae I-III in the ipsilateral side compared to the contralateral dorsal horn. A clear pattern of ipsilateral changes in the dorsal root entry zone characterised by deafferentation and reorganization of first-order axons into deeper laminae was found in cases with lateralised scratching. Significant changes in cell number density were not found for astrocytes or microglia, suggesting that the dogs represented cases of end-stage syringomyelia and thus could not reveal astrogliosis and microgliosis, which may be involved in the early phases of syrinx development and phantom scratch.The present relationship between clinical findings and dorsal horn and pain pathway pathology in CKCS suggests that these dogs may be of interest as a supplement to experimental model pain research.
Learn More >The objective of this study was to determine the associations among migraine disability assessment scores, healthcare resource utilization (HCRU; medical visits and pharmacy use) and direct medical costs among people with episodic migraine in a real-world setting.
Learn More >Epidural stimulation of the motor cortex (eMCS) was devised in the 1990s, and has now largely supplanted thalamic stimulation for neuropathic pain relief. Its mechanisms of action involve activation of multiple cortico-subcortical areas initiated in the thalamus, with involvement of endogenous opioids and descending inhibition toward the spinal cord. Evidence for clinical efficacy is now supported by at least 7 RCTs; benefits may persist up to 10 years, and can be reasonably predicted by preoperative use of non-invasive repetitive magnetic stimulation (rTMS). rTMS first developed as a means of predicting the efficacy of epidural procedures, then as an analgesic method on its own right. Reasonable evidence from at least 6 well-conducted RCTs favours a significant analgesic effect of high-frequency rTMS of the motor cortex in neuropathic pain (NP), and less consistently in widespread/fibromyalgic pain. Stimulation of the dorsolateral frontal cortex (DLPFC) has not proven efficacious for pain, so far. The posterior operculo-insular cortex is a new and attractive target but evidence remains inconsistent. Transcranial direct current stimulation (tDCS) is applied upon similar targets as rTMS and eMCS; it does not elicit action potentials but modulates the neuronal resting membrane state. tDCS presents practical advantages including low cost, few safety issues, and possibility of home-based protocols; however, the limited quality of most published reports entails a low level of evidence. Patients responsive to tDCS may differ from those improved by rTMS, and in both cases repeated sessions over a long time may be required to achieve clinically significant relief. Both invasive and non-invasive procedures exert their effects through multiple distributed brain networks influencing the sensory, affective and cognitive aspects of chronic pain. Their effects are mainly exerted upon abnormally sensitised pathways, rather than on acute physiological pain. Extending the duration of long-term benefits remains a challenge, for which different strategies are discussed in this review.
Learn More >Increased glucocorticoids characterise acute pain responses, but not the chronic pain state, suggesting specific modifications to the hypothalamic-pituitary-adrenal (HPA)-axis preventing the persistent nature of chronic pain from elevating basal glucocorticoid levels. Individuals with chronic pain mount normal HPA-axis responses to acute stressors, indicating a rebalancing of the circuits underpinning these responses. Preclinical models of chronic neuropathic pain generally recapitulate these clinical observations, but few studies have considered that the underlying neuroendocrine circuitry may be altered. Additionally, individual differences in the behavioural outcomes of these pain models, which are strikingly similar to the range of behavioural subpopulations that manifest in response to stress, threat and motivational cues, may also be reflected in divergent patterns of HPA-axis activity, which characterises these other behavioural subpopulations. We investigated the effects of sciatic nerve chronic constriction injury (CCI) on adrenocortical and hypothalamic markers of HPA-axis activity in the subpopulation of rats showing persistent changes in social interactions after CCI (Persistent Effect) and compared them with rats that do not show these changes (No Effect). Basal plasma corticosterone did not change after CCI and did not differ between groups. However, adrenocortical sensitivity to adrenocorticotropic hormone (ACTH) diverged between these groups. No Effect rats showed large increases in basal plasma ACTH with no change in adrenocortical melanocortin 2 receptor (MC R) expression, whereas Persistent Effect rats showed modest decreases in plasma ACTH and large increases in MC R expression. In the paraventricular nucleus of the hypothalamus of Persistent Effect rats, single labelling revealed significantly increased numbers of corticotropin releasing factor (CRF) +ve and glucocorticoid receptor (GR) +ve neurons. Double-labelling revealed fewer GR +ve CRF +ve neurons, suggesting a decreased hypothalamic sensitivity of CRF neurons to circulating corticosterone in Persistent Effect rats. We suggest that in addition to rebalancing the HPA-axis, the increased CRF expression in Persistent Effect rats contributes to changes in complex behaviours, and in particular social interactions.
Learn More >To review the chemistry, pharmacodynamics, pharmacokinetics, efficacy, safety, and tolerability profile of small molecule CGRP receptor antagonists for the preventive treatment of migraine.
Learn More >Persistent pain is a leading cause of disability worldwide yet implementation of clinical guidelines that recommend a biopsychosocial approach remains a challenge in clinical practise. Limited pain understanding amongst clinicians may be partly responsible for this.
Learn More >Neuropathic pain (NP) is a chronic condition that affects ~ 1% of the general population globally. Several conditions such as chronic diabetes, herpes zoster (HZ), cancer, HIV, stroke, multiple sclerosis, physical compression or damage of nerves and certain surgical procedures can lead to neuropathy and related pain. The condition is difficult to treat with traditional analgesic drugs. Typically, non-traditional analgesics are used in treating pain in this condition such as antidepressants and antiepileptic drugs. Opioids are useful in some patients, but the risk of addiction and the risk of both short-term and long-term adverse effects make it a low priority drug class in the treatment of NP. In the current review we discuss the pharmacology and pharmaceutical care aspects of various classes of drugs used in the treatment of NP, counselling points for these drug classes, and future prospects in the treatment of NP.
Learn More >The purpose of this review was to summarize current reports regarding emotional problems in children and adolescents with primary headaches. Emotional problems include those related to personality, psychiatric, and neurodevelopmental disorders.
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