Monomethyl fumarate inhibits pain behaviors and amygdala activity in a rat arthritis model

Abstract

Neuroplasticity in the amygdala, a brain center for emotions, leads to increased neuronal activity and output that can generate emotional-affective behaviors and modulate nocifensive responses. Mechanisms of increased activity in the amygdala output region (central nucleus, CeA) include increased reactive oxygen species, and so we explored beneficial effects of monomethyl fumarate (MMF), which can have neuroprotective effects through the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) anti-oxidant response pathway. Systemic (intraperitoneal) MMF dose-dependently inhibited vocalizations and mechano-sensitivity (hindlimb withdrawal reflexes) of rats in an arthritis pain model (kaolin/carrageenan-induced mono-arthritis in the knee). Stereotaxic administration of MMF into the CeA by microdialysis also inhibited vocalizations but had a limited effect on mechano-sensitivity, suggesting a differential contribution to emotional-affective versus sensory pain aspects. Extracellular single-unit recordings of CeA neurons in anesthetized rats showed that stereotaxic administration of MMF into the CeA by microdialysis inhibited background activity and responses of CeA neurons to knee joint stimulation in the arthritis pain model. MMF had no effect on behaviors and neuronal activity under normal conditions. The results suggest that MMF can inhibit emotional-affective responses in an arthritis pain model through an action that involves the amygdala (CeA).

Kappa opioid receptors in the central amygdala modulate spinal nociceptive processing through an action on amygdala CRF neurons

“…Extracellular single-unit recordings were made from neurons in the lateral-capsular division of the CeA in the right hemisphere as described previously [ 14 , 32 , 42 , 43 ]. Rats were anesthetized with isoflurane (3–4% induction, 2% maintenance; precision vaporizer, Harvard Apparatus, Holliston, MA).…”

“…The contribution of the amygdala to sensory aspects of pain such as hypersensitivity in pain models is less clear. Manipulations of amygdala activity provided evidence for dual pro- and anti-nociceptive effects [ 4 , 17 – 26 ] but others had little, if any effect on hypersensitivity [ 15 , 16 , 27 – 32 ]. The current view is that distinct amygdala circuits and cell types serve different functions related to different aspects of pain.…”

Fear extinction learning ability predicts neuropathic pain behaviors and amygdala activity in male rats

“…Extracellular single-unit recordings were made from neurons in the laterocapsular division of the CeA (CeLC) as described previously. 26 , 38 , 39 Recordings were made in SNL or sham rats four weeks post-surgery.…”

Small conductance calcium activated potassium (SK) channel dependent and independent effects of riluzole on neuropathic pain-related amygdala activity and behaviors in rats

“…Spinal withdrawal thresholds were measured in SNL and sham rats at least 45 min before brain slices were obtained to confirm presence of neuropathic hypersensitivity in SNL rats. This is a well-established protocol in our laboratory (see (Ji et al, 2017; Kiritoshi et al, 2016; Kiritoshi and Neugebauer, 2015)) and is unlikely to result in changes in neuronal responses as in vivo electrophysiology experiments using even noxious stimuli result in a return to baseline activity (see (Ji et al, 2015; Ji and Neugebauer, 2009; Kim et al, 2017)).…”