Accepted

Alleviating acute and chronic pain is a moral imperative for health professionals and health systems, and it requires adequate access to and use of essential opioid analgesics. However, this is still a neglected issue in global health, with striking inequalities in opioids availability between high and low- and middle-income countries. Countries most affected by lack of access are those with a fragile political situation and weak regulatory and healthcare systems. The main threats to accessibility, availability and affordability are situated at different levels: legislation and policy, financing, knowledge and cultural behavior, erroneous beliefs, and training and education. Among these threats, the lack of (adequate) training and education seems to be a cross-cutting issue. Exploring the current body of knowledge about training and educational activities related to use of opioid analgesics and palliative care, is helpful to understand gaps and to delineate priorities for setting up adequate interventions. When applied to West and Central Africa, this exercise reveals that there is little information (easily) available in the public domain. The African Palliative Care Association (APCA) appears to be the leading provider of capacity building activities in this region for key stakeholders, including national authorities, healthcare professionals and the general population; it is also very active in publishing and communicating about these issues. However, apart from APCA, there is little information on training programs' contents and long-term outcomes. Furthermore, trainings rarely target important stakeholders such as lawmakers, regulators, supply officers and the lay public (i.e., patients, caregivers, community leaders and members of the society as a whole). Hence, it is urgent to fill the existing gaps in training and educational activities to improve access to essential opioid analgesics in West and Central Africa, involving different stakeholders at the national and regional level. Furthermore, such experiences should be published and made publicly available to allow for mutual learning and further upscale.

Chronic pain affects 20 to 45% of the global population and is often associated with the development of anxio-depressive disorders. Treatment of this debilitating condition remains particularly challenging with opioids prescribed to alleviate moderate to severe pain. However, despite strong antinociceptive properties, numerous adverse effects limit opioid use in the clinic. Moreover, opioid misuse and abuse have become a major health concern worldwide. This prompted efforts to design original strategies that would efficiently and safely relieve pain. Targeting of opioid receptor heteromers is one of these. This review summarizes our current knowledge on the role of heteromers involving opioid receptors in the context of chronic pain and anxio-depressive comorbidities. It also examines how heteromerization in native tissue affects ligand binding, receptor signalling and trafficking properties. Finally, the therapeutic potential of ligands designed to specifically target opioid receptor heteromers is considered.

Gout is an inflammatory arthritis resulting from the deposition of monosodium urate crystals in and around joints. Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat acute gout. This is an update of a Cochrane Review first published in 2014.

Via the peripheral and autonomic nervous systems, the spinal cord directly or indirectly connects reciprocally with many body systems (muscular, intengumentary, respiratory, immune, digestive, excretory, reproductive, cardiovascular, etc). Accordingly, spinal cord injury (SCI) can result in catastrophe for multiple body systems including muscle paralysis affecting movement and loss of normal sensation, as well as neuropathic pain, spasticity, reduced fertility and autonomic dysreflexia. Treatments and cure for an injured spinal cord will likely require access of therapeutic agents across the blood-CNS (central nervous system) barrier. However, some types of repair within the CNS may be possible by targeting treatment to peripherally located cells or by delivering Adeno-Associated Viral vectors (AAVs) by peripheral routes (e.g., intrathecal, intravenous). This review will consider some future possibilities for SCI repair generated by therapeutic peripheral gene delivery. There are now six gene therapies approved worldwide as safe and effective medicines of which three were created by modification of the apparently nonpathogenic Adeno-Associated Virus. One of these AAVs, Zolgensma, is injected intrathecally for treatment of spinal muscular atrophy in children. One day, delivery of AAVs into peripheral tissues might improve recovery after spinal cord injury in humans; we discuss experiments by us and others delivering transgenes into nerves or muscles for sensorimotor recovery in animal models of SCI or of stroke including human Neurotrophin-3. We also describe ongoing efforts to develop AAVs that are delivered to particular targets within and without the CNS after peripheral administration using capsids with improved tropisms, promoters that are selective for particular cell types, and methods for controlling the dose and duration of expression of a transgene. In conclusion, in the future, minimally invasive administration of AAVs may improve recovery after SCI with minimal side effects.

Long-term potentiation (LTP) and long-term depression (LTD) in the spinal dorsal horn reflect activity-dependent synaptic plasticity and central sensitization in chronic pain. Tetanic high-frequency stimulation is commonly used to induce LTP in the spinal cord. However, primary afferent nerves often display low-frequency, rhythmic bursting discharges in painful conditions. Here, we determined how theta-burst stimulation (TBS) of primary afferents impacts spinal cord synaptic plasticity and nociception. We found that TBS induced more LTP, whereas tetanic stimulation induced more LTD, in mouse spinal lamina II neurons. TBS induced LTP, but not LTD, in 50% of excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2). By contrast, TBS induced LTD and LTP in 12%-16% of vesicular GABA transporter (VGAT)-expressing inhibitory neurons. Nerve injury significantly increased the prevalence of TBS-induced LTP in VGluT2-expressing, but not VGAT-expressing, lamina II neurons. Blocking NMDARs, inhibiting α2δ-1 with gabapentin, or α2δ-1 knockout abolished TBS-induced LTP in lamina II neurons. Also, disrupting the α2δ-1-NMDAR interaction with α2δ-1Tat peptide prevented TBS-induced LTP in VGluT2-expressing neurons. Furthermore, TBS of the sciatic nerve induced long-lasting allodynia and hyperalgesia in wild-type, but not α2δ-1 knockout, mice. TBS significantly increased the α2δ-1-NMDAR interaction and synaptic trafficking in the spinal cord. In addition, treatment with NMDAR antagonists, gabapentin, or α2δ-1Tat peptide reversed TBS-induced pain hypersensitivity. Therefore, TBS-induced primary afferent input causes a neuropathic pain-like phenotype and LTP predominantly in excitatory dorsal horn neurons via α2δ-1-dependent NMDAR activation. α2δ-1-bound NMDARs may be targeted for reducing chronic pain development at the onset of tissue/nerve injury.Spinal dorsal horn synaptic plasticity is a hallmark of chronic pain. Although sensory nerves display rhythmic bursting discharges at theta frequencies during painful conditions, the significance of this naturally occurring firing activity in the induction of spinal synaptic plasticity is largely unknown. In this study, we found that theta-burst stimulation (TBS) of sensory nerves induced LTP mainly in excitatory dorsal horn neurons and that the prevalence of TBS-induced LTP was potentiated by nerve injury. This TBS-driven synaptic plasticity required α2δ-1 and its interaction with NMDARs. Furthermore, TBS of sensory nerves induced persistent pain, which was maintained by α2δ-1-bound NMDARs. Thus, TBS-induced LTP at primary afferent-dorsal horn neuron synapses is an appropriate cellular model for studying mechanisms of chronic pain.