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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.
Learn More >"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.
Learn More >In 2018, three calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies, erenumab, fremanezumab and galcanezumab, were approved in various parts of the world, including Europe and the US, and another, eptinezumab, is pending, for the prevention of migraine. In this article, episodic migraine treatment is reviewed, although these medicines are approved and are just as effective for chronic migraine. These new medicines usher a new phase in the preventive management of migraine with migraine-specific treatments. Data from phase III trials of CGRP pathway monoclonal antibodies have shown they are efficacious, with adverse effect rates comparable to placebo. The combination of clear efficacy and excellent tolerability will be welcome in an area where poor adherence to current preventives is common. Rimegepant, ubrogepant and lasmiditan are migraine-specific acute therapies yet to be approved by regulators. Phase III data for the respective CGRP receptor antagonists, the gepants, and the serotonin 5-HT receptor agonist, the ditan, have been positive and free of cardiovascular adverse effects. These medicines are not vasoconstrictors. When approved, they could meet the acute therapy demand of patients with cardiovascular risk factors where triptans are contraindicated. Beyond this, gepants will see the most disruptive development in migraine management in generations with medicines that can have both acute and preventive effects, the latter evidenced by data from the discontinued drug telcagepant and the early-phase drug atogepant. Moreover, one can expect no risk of medication overuse syndromes with gepants since the more patients take, the less migraines they have. During the next years, as experience with monoclonal antibodies grows in clinical practice, we can expect an evolution in migraine management to take shape. Clinicians will be able to offer treatment patients want rather than trying to fit migraineurs into therapeutic boxes for their management. Despite pessimistic susurrations of a largely addlepated form, many patients, and physicians, will welcome new options, and the challenges of new treatment paradigms, with optimism.
Learn More >Gene transcription regulation is critical for the development of spinal microgliosis and neuropathic pain after peripheral nerve injury. Using a model of chronic constriction injury (CCI) of the sciatic nerve, this study characterized the role of SET domain containing lysine methyltransferase 7 (SETD7) which monomethylates histone H3 lysine 4 (H3K4me1), a marker for active gene transcription. SETD7 protein expression in the spinal dorsal horn ipsilateral to nerve lesion was increased from one day to 14 days after CCI, concomitantly with the expression of inflammatory genes, Ccl2, Il-6 and Il-1β. The CCI-induced SETD7 expression was predominantly localized to microglia, as demonstrated by immunohistochemistry and western blot from magnetic activated cell sorted spinal microglia. SETD7 knockdown by intrathecal lentivirus shRNA delivery prior to CCI prevented spinal microgliosis and neuropathic pain, whereas lentiviral SETD7 transduction exacerbated these symptoms. In addition, SETD7 regulated H3K4me1 level and expression of inflammatory mediators both in CCI rats and in the HAPI rat microglia cell line. Accordingly, PFI-2, a specific inhibitor of SETD7 monomethylation activity, suppressed the lipopolysaccharides-induced amoeboid morphology of primary microglia and the expression of inflammatory genes, Ccl2, Il-6 and Il-1β. Moreover, intrathecal administration of PFI-2 alleviated CCI-induced neuropathic pain. However, this effect was observed in male but not in female rats. These results demonstrate a critical role of SETD7 in the development of spinal microgliosis and neuropathic pain subsequently to peripheral nerve injury. The pharmacological approach further suggests that SETD7 is a new target for the treatment of neuropathic pain. The underlying mechanisms may involve H3K4me1-dependent regulation of inflammatory gene expression in microglia.
Learn More >The clinical picture, but also neuroimaging findings, suggested the brainstem and midbrain structures as possible driving or generating structures in migraine.
Learn More >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.
Learn More >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.
Learn More >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).
Learn More >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.
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