The role of endogenous opioid neuropeptides in neurostimulation-driven analgesia

Abstract

Due to the prevalence of chronic pain worldwide, there is an urgent need to improve pain management strategies. While opioid drugs have long been used to treat chronic pain, their use is severely limited by adverse effects and abuse liability. Neurostimulation techniques have emerged as a promising option for chronic pain that is refractory to other treatments. While different neurostimulation strategies have been applied to many neural structures implicated in pain processing, there is variability in efficacy between patients, underscoring the need to optimize neurostimulation techniques for use in pain management. This optimization requires a deeper understanding of the mechanisms underlying neurostimulation-induced pain relief. Here, we discuss the most commonly used neurostimulation techniques for treating chronic pain. We present evidence that neurostimulation-induced analgesia is in part driven by the release of endogenous opioids and that this endogenous opioid release is a common endpoint between different methods of neurostimulation. Finally, we introduce technological and clinical innovations that are being explored to optimize neurostimulation techniques for the treatment of pain, including multidisciplinary efforts between neuroscience research and clinical treatment that may refine the efficacy of neurostimulation based on its underlying mechanisms.

Keywords: analgesia; deep brain stimulation (DBS); neuromodulation; neurostimulation; opioid; pain; spinal cord stimulation (SCS); μ-opioid receptor.

FIGURE 1

Overview of three neural structures that have been targeted by neurostimulation therapies. Schematic of ascending (purple) and descending (blue) pain modulatory pathways (left). Middle: Macro level anatomy of the cortex, brainstem and spinal cord, showing key nodes in the ascending and descending pain modulatory pathways. Connections between the brainstem and spinal cord via the RVM are indicated. Right: Select synaptic connections and microcircuitry of the ACC, vlPAG and DH are shown. Mu-and delta-opioid receptors are expressed on cell bodies and pre-synaptic terminals of neurons throughout the pain neuraxis to modulate ascending and descending pain pathways. ACC, anterior cingulate cortex; RVM, rostroventromedial medulla; vlPAG, ventrolateral periaqueductal gray; LC, locus coeruleus; DH, dorsal horn.

FIGURE 2

Overview of neurostimulation modalities for the treatment of chronic pain. (Left) Schematic of application of neurostimulation devices for the treatment of chronic pain. (A) DBS electrodes are surgically targeted to specific brain nuclei (i.e., ACC, midline thalamus, PAG) with an external pulse generator. Following optimization of stimulation settings, the pulse generator and leads are internalized under the clavicle to deliver electrical stimulation to the brain. (B) With tDCS, small amounts of electric current are applied externally via electrodes held in place against the scalp. (C) rTMS is applied with an external electromagnetic coil to generate an electromagnetic field in the underlying cortical regions. Both tDCS and rTMS are applied for 20–60 min over repeated sessions without requiring anesthesia. (D) SCS employs implanted electrodes in the epidural space to apply electrical current to the spinal cord. Similar to DBS, SCS patients undergo a trial period to ensure adequate pain relief before the pulse generator and leads are internalized in the posterior flank. (Bottom) For all modalities, several properties of the stimulus waveform can be modulated, including the waveform shape, pulse amplitude, duration, and frequency, as well as whether it is applied continuously, in regular burst patterns or in a closed-loop manner in response to neural activity or patient control. DBS, deep brain stimulation; tDCS, transcranial direct current stimulation; rTMS, repeated transcranial magnetic stimulation; SCS, spinal cord stimulation; IPG, implanted pulse generator.