Chemogenetic management of neuropathic pain.

Neuropathic pain syndromes can result from injury to the peripheral or CNS and are characterized by ongoing, often burning pain, dysaesthesias and intense pain that can be provoked by normally innocuous stimulation (Colloca et al., 2017). Mechanical allodynia and cold hypersensitivity predominate. Common peripheral neuropathic pains include post-herpetic neuralgia, diabetic neuropathic pain, phantom limb pain and painful radiculopathy. Central neuropathic pain can also occur post-stroke, after spinal cord injury and in patients with multiple sclerosis. Unlike tissue injury-induced inflammatory pains, neuropathic pains do not respond to non-steroidal anti-inflammatory drugs and are generally poorly responsive to opioids, largely because the high doses required generate intolerable adverse effects, and because of the potential for misuse. As hyperexcitability and ectopic firing of injured peripheral afferents and consequent hyperactivity of CNS circuits are major contributors to neuropathic pain (Haroutounian et al., 2014), anticonvulsant drugs are often used to manage the pain. The mantra in the field, however, is that even the first-line approach to treating neuropathic pain, namely the gabapentinoids, is on average only 30% effective in 30% of patients. In this issue of Brain, Weir and co-workers report preclinical studies of a novel adeno-associated virus (AAV)-based chemogenetic therapy to treat peripheral nerve injury-induced neuropathic pain (Weir et al., 2017). The rationale for the authors’ approach derived, in part, from the observation that most peripheral neuropathic pains, including phantom limb pain, can be relieved by local anaesthetics that target damaged, hyperexcitable peripheral afferents (Haroutounian et al., 2014; Vaso et al., 2014). Unfortunately, the local anaesthetic action is short-lived and limited by cardiac, motor and CNS side effects. Weir et al. therefore adopted an alternate strategy to silence hyperactive sensory neurons. Their approach followed previous work that examined CNS neurons transfected with a modified, heteromeric invertebrate glutamate-gated chloride channel (GluCl). The modified channel does not respond to the endogenous neurotransmitter, glutamate, but is readily activated by ivermectin (IVM), a well-tolerated broad spectrum anti-parasitic agent. A low dose of IVM acting on the modified GluCl channel can silence mammalian CNS neurons in vivo for days (Lerchner et al., 2007). Weir et al. took advantage of a GluCl channel that had been optimized to increase incorporation of the beta subunit, which, together with a required alpha subunit, forms the functional channel (Frazier et al., 2013). Because AAV-directed channel expression can be targeted to neurons of interest (e.g. those critical to the transmission of the ‘pain’ message), the therapeutic window can be greatly increased, even after systemic IVM administration, compared to traditional systemic analgesic drug approaches. The authors first completed a comprehensive in vitro characterization of the channel in dissociated dorsal root ganglion (DRG) sensory neurons electroporated with GluCl plasmid DNA. The intrinsic properties of the transfected cells, studied by whole cell patch clamp, did not differ from control neurons; however, a low IVM dose silenced the cells in response to current injection. In parallel studies, using ratiometric Ca + imaging, the authors demonstrated that IVM inhibited K + -evoked depolarization of sensory neurons, as well as the responses to the TRP channel agonists capsaicin and menthol, which target sensory neurons directly (Julius, 2013). IVM also inhibited action potential generation in induced pluripotent stem cell-derived human DRG cells expressing the GluCl channel. Interestingly, IVM-induced silencing does not result from hyperpolarization. Because intracellular Cl levels can be relatively high in sensory neurons compared to CNS neurons (Gilbert et al., 2007), increasing transmembrane Cl flux via the GluCl channel does not produce the expected BRAIN 2017: 140; 2522–2529 | 2522