Interactions with pain-related systems - Towards new electrical treatments for chronic pain

Abstract: Background. Persistent intolerable pain is still an unsolved issue with a huge socioeconomic impact. To develop appropriate treatments, it is crucial to understand the complex mechanisms underlying pain and how they change during sustained pain stimuli or during pathological conditions. In particular, it is essential to clarify how the endogenous analgesic centres which are present in the brain, such as periaqueductal grey (PAG) matter and dorsal raphe nuclei (DRN) in the brainstem, modulate pain by interfering with the nociceptive information. Deep brain stimulation of these areas can elicit potent analgesia. However, it has not been possible to exploit its full analgesic potential due to the insufficient stimulation specificity of the state-of-the-art probes.Aim. To address this challenge, we developed and implanted in rodents, a novel probe for high-definition brain stimulation (HDBS) based on the spread in 3D of ultra-flexible microelectrodes in PAG/DRN. The probe comprised 16 ultra-flexible microelectrodes embedded in a gelatine needle-like probe. The main aim was to elucidate whether stimulation of individually selected microelectrodes can selectively activate the anti-nociceptive pathways without activating networks that provoke side effects.Methodology. The selection of an appropriate microelectrode subset and stimulation intensity was done by monitoring the withdrawal reflexes elicited by CO2 laser stimuli and by simultaneous behavioural observations in awake freely moving animals. To evaluate the effect of HDBS in PAG/DRN on the nociceptive pathways related to pain perception, microelectrode recordings were made in cortical areas known to be involved in the sensory-discriminative and affective aspects of pain. Clinically relevant aspects such as potency, specificity, sustainability, reliability of HDBS as well as efficacy in conditions with hypersensitivity to nociceptive stimuli (hyperalgesia) were assessed by recording nociceptive-evoked cortical responses, withdrawal reflexes, gait and normal behaviours. To assess the presence of side effects, HDBS effect on intracortical spontaneous activity, brain states (ECoGs), behaviour in an open field, and the tactile input to cortex was also investigated. The tissue reactions to the implanted stimulation probe and the probe placement were evaluated using immunohistochemistry. In addition, we investigated whether tissue reactions related to probe implantation can be mitigated by incorporating PLGA-nanoparticles loaded with an anti-inflammatory drug, minocycline, and embedded into a gelatine vehicle.Results. For all the animals with verified placement within or nearby PAG/DRN, it was possible to individually select a microelectrode subset and stimulation intensity, which strongly inhibit nociceptive-evoked withdrawal reflexes without noticeable side effects. The selected microelectrode combinations also reduced nociceptive-evoked cortical responses (related to both discriminative and affective pain) in normal conditions and during hyperalgesia. The HDBS-induced analgesia could be sustained for at least 4 hours and did not provoke significant side effects on behaviour, spontaneous activity, and brain states and it had a minor effect on the tactile afferent pathway to the cortex. Histological analysis showed minimal tissue reactions and neuronal death around the stimulation implant. Minocycline containing PLGA nanoparticles significantly reduced glial reactions without signs of toxicity. Conclusions. These results show that granular and high-resolution PAG/DRN stimulation enables potent, specific, safe, and durable analgesia by blocking the nociceptive-evoked motor, sensory and affective responses without significant activation of pathways provoking adverse side effects. Therefore, HDBS in PAG/DRN holds great promise as an efficient treatment of intractable chronic pain disorders.