Inhibition of α9α10 nicotinic acetylcholine receptors prevents chemotherapy-induced neuropathic pain
- Proceedings of the National Academy of Sciences of the United States of America
- Published 11 months ago
Opioids are first-line drugs for moderate to severe acute pain and cancer pain. However, these medications are associated with severe side effects, and whether they are efficacious in treatment of chronic nonmalignant pain remains controversial. Medications that act through alternative molecular mechanisms are critically needed. Antagonists of α9α10 nicotinic acetylcholine receptors (nAChRs) have been proposed as an important nonopioid mechanism based on studies demonstrating prevention of neuropathology after trauma-induced nerve injury. However, the key α9α10 ligands characterized to date are at least two orders of magnitude less potent on human vs. rodent nAChRs, limiting their translational application. Furthermore, an alternative proposal that these ligands achieve their beneficial effects by acting as agonists of GABAB receptors has caused confusion over whether blockade of α9α10 nAChRs is the fundamental underlying mechanism. To address these issues definitively, we developed RgIA4, a peptide that exhibits high potency for both human and rodent α9α10 nAChRs, and was at least 1,000-fold more selective for α9α10 nAChRs vs. all other molecular targets tested, including opioid and GABAB receptors. A daily s.c. dose of RgIA4 prevented chemotherapy-induced neuropathic pain in rats. In wild-type mice, oxaliplatin treatment produced cold allodynia that could be prevented by RgIA4. Additionally, in α9 KO mice, chemotherapy-induced development of cold allodynia was attenuated and the milder, temporary cold allodynia was not relieved by RgIA4. These findings establish blockade of α9-containing nAChRs as the basis for the efficacy of RgIA4, and that α9-containing nAChRs are a critical target for prevention of chronic cancer chemotherapy-induced neuropathic pain.
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.Molecular Psychiatry advance online publication, 15 October 2013; doi:10.1038/mp.2013.130.
AIMS: To review the recreational use of ketamine (“Special K”; KET) and explore the recent diffusion of its new derivative methoxetamine (“Special M”; MXE). METHODS: The literature search on the nonclinical/recreational use of KET and MXE was carried out in a range of medical databases. Considering the limitations of peer-reviewed information, data were integrated with a qualitative assessment of a range of websites, drug fora, and other online resources including e-newsgroups, chat rooms, mailing lists, e-newsletters, and bulletin boards. RESULTS: The recreational use of KET has started since its discovery in 1962. This was due to its rapid onset, short duration of action, and peculiar psychotropic effects (“K-hole”). The latter effect ranges from confusion to dissociation and depersonalization (near-death experience). However, KET abuse is often associated with physical and psychological side effects, of which the worst is urological/bladder toxicity. Recently, MXE has emerged as a legal and “bladder-friendly” KET alternative. MXE presents with the same dissociative effect of KET, but with slower onset and longer duration of action. However, MXE seems to be associated with worse side effects than KET, ranging from mood disturbances/suicidal attempts to acute cerebellar toxicity. CONCLUSIONS: After 50 years of its discovery, KET has led to the emergence of MXE. However, this latter derivative does not appear to be a safer alternative to KET itself.
BACKGROUND: Neuropathic pain is severely debilitating and resistant to pharmacological approaches; therefore, the study of therapies to complement its treatment is especially relevant. In a case report study, light-emitting diode therapy (LEDT) has shown analgesic activity as well as reduced the expression of pro-inflammatory cytokines in a rabbit osteoarthritis model and in calcaneal tendinitis in rats. Although LEDT stimulated morphofunctional recovery after nerve injury in rats, its effect against neuropathic pain has not been tested. METHODS: To that purpose, mice under anaesthesia were subjected to the sciatic nerve crush (SNC) model. On the seventh post-operative day, after determining analgesic dose (energy density in joules), LEDT (950 nm, 80 mW/cm(2) , 2.5 J/cm(2) ) was irradiated, daily for a period of 15 days, on the skin over the crush site. RESULTS: Compared with the SNC group, LEDT reduced mechanical hypersensitivity but not cold hypersensitivity which is induced by SNC, decreased spinal cord and sciatic nerve levels of tumour necrosis factor alpha (TNF-α) but did not alter interleukin (IL)-1β and IL-10 levels, and finally, failed to accelerate motor functional recovery and morphological nerve regeneration. CONCLUSION: Taken together, these data provide first-hand evidence of LEDT effectiveness against neuropathic pain induced by SNC, with corresponding decrease of pro-inflammatory cytokine levels, both in the sciatic nerve and in the spinal cord, although at a small analgesic dose, LEDT failed to accelerate nerve regeneration.
Dextromethorphan (DXM) in combination with antihistamines and/or pseudoephedrine is widely available as an over-the-counter remedy commonly used for relief of colds and cough. In supratherapeutic amounts, DXM can be extremely activating. These cough preparations have been adopted by many young users of recreational drugs for their psychoactive effects. When used in amounts exceeding those recommended, this practice, known as “robotripping,” may result in a manic toxidrome of psychomotor agitation, hostility, grandiose behavior, hallucinations, paranoia, and panic. A case illustration of this phenomenon is described and implications of this phenomenon discussed. There are few reports associating DXM use with bipolar symptomatology.
Methoxetamine (MXE) is a ketamine analog sold online that has been subject to widespread abuse for its dissociative and hallucinogenic effects. Previous studies have shown that MXE has high affinity for the phencyclidine (PCP) binding site located within the channel pore of the NMDA receptor (NMDAR), but little is known about its behavioral effects. Dissociative anesthetics such as ketamine and PCP produce a characteristic behavioral profile in rats that includes locomotor hyperactivity and disruption of prepulse inhibition (PPI) of acoustic startle.
Honey plus coffee versus systemic steroid in the treatment of persistent post-infectious cough: a randomised controlled trial
- Primary care respiratory journal : journal of the General Practice Airways Group
- Published over 4 years ago
Persistent post-infectious cough (PPC) is a cough that remains after a common cold or an upper respiratory tract infection for more than three weeks or perhaps for many months. Two of the suggested treatments for PPC are systemic steroid and honey plus coffee.
Ketamine for prehospital trauma analgesia in a low-resource rural trauma system: a retrospective comparative study of ketamine and opioid analgesia in a ten-year cohort in Iraq
- Scandinavian journal of trauma, resuscitation and emergency medicine
- Published about 2 years ago
Opioid analgesics are used in most trauma systems, and only a few studies report on the use of ketamine for prehospital analgesia. In a low-cost rural trauma system in Iraq paramedics have been using prehospital ketamine analgesia for ten years. This study aims to evaluate the effects of prehospital analgesia on physiologic trauma severity indicators and compare the effect of ketamine and pentazocine on those indicators.
Opioids are good painkillers, but many patients treated with opioids as painkillers developed a secondary addiction. These patients need to stop misusing opioids, but the mild-to-severe clinical symptoms associated with opioid withdrawal risk increasing their existing pain. In such cases, ketamine, which is used by anaesthetists and pain physicians to reduce opioid medication, may be an effective agent for managing opioid withdrawal.
The unique pharmacology of remifentanil makes it a popular intra-operative analgesic. Short-acting opioids like remifentanil have been associated with acute opioid tolerance and/or opioid-induced hyperalgesia, two phenomena which have different mechanisms and are pharmacologically distinct. Clinical studies show heterogeneity of remifentanil infusion regimens, durations of infusion, maintenance of anaesthesia, cumulative dose of remifentanil and pain measures, which makes it difficult to draw conclusions about the incidence of acute tolerance or hyperalgesia. However, it appears that intra-operative remifentanil infusion rates of above 0.25 μg.kg(-1) .min(-1) are associated with higher postoperative opioid consumption, suggesting tolerance. Infusion rates greater than 0.2 μg.kg(-1) .min(-1) are characterised by lower mechanical/pressure/cold/pain thresholds, which suggests hyperalgesia. The use of concurrent multimodal analgesia, especially N-methyl-D-aspartate receptor antagonists, may be an effective preventive strategy. The clinical significance and long-term consequences of these entities is still uncertain.