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The clinical picture, but also neuroimaging findings, suggested the brainstem and midbrain structures as possible driving or generating structures in migraine.
Mas oncogene-related gene receptors (Mrg) are uniquely distributed in small and medium cells of trigeminal and dorsal root ganglia (DRG). The physiological and pharmacological properties of Mrg are unknown. We have shown that intermittent activation of MrgC prevents and reverses morphine tolerance. Now we observed that intrathecal (i.t.) administration of the MrgC agonist bovine adrenal medulla 8-22 (BAM8-22, 3 nmol) for 3 and 6 days reduced the potency of morphine analgesia by 1.5 and 3.5 folds, respectively. Daily administration of BAM8-22 for 6 days also significantly decreased the tail flick latency. The administration of another MrgC agonist (Tyr)-2-MSH-6-12 (MSH, 3 nmol) reduced morphine potency and the reduction was abolished following the co-administration of the protein kinase C (PKC) inhibitor chelerythrine chloride (CLT, 3 nmol). The chronic treatment with BAM8-22 or MSH increased the expression of PKC-gamma (PKCγ) in the cell membrane of spinal dorsal horn neurons and PKC-epsilon (PKCε) in the cell membrane and cytosol of DRG neurons. Moreover, the BAM8-22 treatment induced an increase in the expression of calcitonin gene-related peptide (CGRP) and neuronal nitric oxide synthase (nNOS) in small and medium cells in DRG. All of these responses were not seen when BAM8-22 or MSH was co-administered with the PKC inhibitor CLT (3 nmol) or GF-109203X (10 nmol). The present study suggested that the chronic activation of MrgC upregulated expressions of pronociceptive mediators via PKC signaling pathway leading to the suppression of antinociceptive property of morphine. These effects are opposite to those occurred when MrgC is activated acutely or moderately.
Repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) is increasingly being investigated as a means of alleviating chronic pain. However, rTMS interventions are typically initiated once pain has already become chronic and maladaptive patterns of neural activity are likely to have been established. A critical question is whether M1 rTMS applied soon after pain onset can prevent the development of maladaptive neural activity and promote recovery. This study investigated the effect of 5 consecutive days of excitatory M1 rTMS on pain, functional limitation, mechanical hyperalgesia, descending inhibitory pain control, and M1 organisation in the transition from acute to sustained pain. Thirty healthy participants attended 8 sessions over a 16-day period. On Days 0, 2, and 4, nerve growth factor was injected into the right forearm to induce progressively developing muscle soreness and mechanical hyperalgesia. Active or sham excitatory rTMS was delivered on Days 4-8. Clinical and neurophysiological outcomes were recorded on Days 0, 2, 4, 6, 8, 11 and 14. Active rTMS promoted recovery of muscle soreness, pain, and mechanical hyperalgesia when compared to sham rTMS (all between-group p < 0.05). Corticomotor excitability and descending inhibitory pain control did not differ between groups. These findings suggest that active excitatory M1 rTMS promotes recovery of muscle soreness, pain, and mechanical hyperalgesia in the transition from acute to sustained experimental pain. The analgesic effects of M1 rTMS do not appear to be modulated by descending inhibitory pain control or local changes in corticomotor excitability.
Intramuscular injection of Nerve Growth Factor (NGF) may influence the responsiveness of active chemo-sensitive channels affecting muscle pain sensitivity. This double-blinded crossover study in healthy humans assessed contraction-evoked pain responses and pain sensitivity during acute ischemia in the tibialis anterior (TA) muscle before and 24h after five distributed NGF injections (1μg, 4 cm interval) compared with control injections (isotonic-saline).
Persistent opioid use following total joint replacement (TJR) surgery is common; however, the association between pre-surgical opioid use and surgery type has not been established. The objective of this study was to determine the association between pre-surgery opioid use and persistent post-surgery opioid use in TJR patients compared to other elective surgical patients.
Exercise therapy such as motor control training (MCT) has been shown to reduce pain and disability in people with low back pain (LBP). It is unknown which patients are most likely to benefit. This longitudinal cohort study aimed to: (1) retrospectively examine records from a large cohort of patients who received MCT treatment, (2) identify potentially important predictors of response to MCT and (3) test the predictors on an independent (split) sample derived from the original cohort of patients, using one group to identify the predictors and the other to test them.
To estimate the prevalence of having at least one or two or more chronic health conditions among US adults with self-reported migraine or severe headaches.
Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of RVK4-40, a highly selective dopamine (DA) D receptor (DR) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of RVK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with RVK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D antagonism in reducing opioid reward, we used optogenetic approaches to examine intracranial self-stimulation (ICSS) maintained by optical activation of ventral tegmental area (VTA) DA neurons in DAT-Cre mice. Photoactivation of VTA DA in non-drug treated mice produced robust ICSS behavior. Lower doses of oxycodone enhanced, while higher doses inhibited, optical ICSS. Pretreatment with RVK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, RVK4-40 produced a modest dose-dependent reduction in optical ICSS. Pretreatment with RVK4-40 did not compromise the antinociceptive effects of oxycodone in rats, and RVK4-40 alone produced mild antinociceptive effects without altering open-field locomotion or rotarod locomotor performance. Together, these findings suggest RVK4-40 may permit a lower dose of prescription opioids for pain management, potentially mitigating tolerance and dependence, while diminishing reward potency. Hence, development of RVK4-40 as a therapy for the treatment of opioid use disorders and/or pain is currently underway.
"Other Primary Headaches" in the ICHD-3 encompasses activity-related headaches, headaches due to direct physical stimuli, epicranial headaches and a miscellanea, including hypnic headache and new daily-persistent headache. They can be primary or secondary and their etiologies differ depending on headache type. For instance, activity-related headaches can be induced by Valsalva maneuvers ("cough headache") or prolonged exercise ("exercise and sexual headaches"). Almost half of cough headaches are secondary to posterior fossa abnormality, whereas only 20% of exertional/sexual headaches are secondary, with subarachnoid hemorrhage the most frequent etiology. This article reviews the clinical diagnosis and management of these heterogeneous headaches.