Diffuse noxious inhibitory controls and brain networks are modulated in a testosterone-dependent manner in Sprague Dawley rats

Abstract

Diffuse noxious inhibitory control (DNIC), which involves endogenous pain modulation, has been investigated as a potential mechanism for the differences in pain modulation observed between men and women, though the literature shows contradictory findings. We used a capsaicin-induced DNIC behavioral assay and resting state functional magnetic resonance imaging (rsfMRI) to assess the effect of testosterone on pain modulation and related brain circuitry in rats. We hypothesized that testosterone is required for DNIC that leads to efficient pain inhibition by increasing descending pain modulation. Male, female, and orchidectomized (GDX) male rats had a capsaicin injection into the forepaw to induce DNIC and mechanical thresholds were observed on the hindpaw. rsfMRI scans were acquired before and after capsaicin injection to analyze the effects of DNIC on periaqueductal gray (PAG), anterior cingulate cortex (ACC) and nucleus accumbens (NAc) connectivity to the whole brain. The strength of DNIC was higher in males compared to females and GDX males. PAG connectivity with prelimbic cortex (PrL), ACC and insula was stronger in males compared to females and GDX males, whereas females and GDX males had increased connectivity between the right ACC, hippocampus and thalamus. GDX males also showed a stronger connectivity between right ACC and NAc, and right NAc with PrL, ACC, insula and thalamus. Our findings suggest that testosterone plays a key role in reinforcing the endogenous pain inhibitory system, while circuitries related to reward and emotion are more strongly recruited in the absence of testosterone.

Neurobiological mechanisms of TENS-induced analgesia

“…5). This observation matches the increased activity in multiple cortical regions projecting to the PAG during the analgesia caused by DNIC, which is triggered by intense somatosensory stimuli similar to the low-frequency and high-intensity TENS used in the present study (Da Silva et al., 2018). In addition to the recruitment of the PAG-RVM network, low-frequency and high-intensity TENS could recruit the DNIC system, through the activation of neurons in the subnucleus reticularis dorsalis (SRD) in the caudal-dorsal medulla (Villanueva et al., 1996; Youssef et al., 2016b).…”

Ablation of TRPV1+ Afferent Terminals by Capsaicin Mediates Long-Lasting Analgesia for Trigeminal Neuropathic Pain

“…Co-administration of capsaicin with calpain inhibitor MDL28170 (MD; 10 mM in 20 ml) into whisker pad area abolished capsaicin-induced analgesia for TNP compared with the injection of vehicle (Veh). Two-way RM ANOVA followed by Bonferroni post hoc test (CCI/Cap/Veh vs CCI/Cap/MDL); pp , 0.05, ppp , 0.01, pppp , 0.0005, ppppp , 0.0001. study, since capsaicin-induced analgesia was evident at 1 d after injection but not at 6 h. Capsaicin administration could also produce analgesia through diffuse noxious inhibitory control (DNIC; Da Silva et al, 2018). It is unlikely, however, that such DNIC effects contribute to the longlasting analgesia, since the time course of DNIC is transient (;30 min; Da Silva et al, 2018) and capsaicin-induced DNIC is lost following neuropathic injury (Phelps et al, 2019).…”

Neuroimaging of pain in animal models: a review of recent literature

“…The most commonly used brain imaging method in animals is MRI, which includes fMRI 1–3,9,17,22,35,37,40,46,56,61,64,75,84,85,88,89 and MEMRI 16,25,41,42,74 in the current literature of pain. Functional MRI usually uses the blood oxygenation level–dependent (BOLD) method as an indirect measure of neuronal activity associated with a task or stimulus, or using temporal interdependence of fMRI time series across regions to infer brain connectivity (see Refs.…”

“…Exclusion criteria for this review were studies that did not include brain imaging and did not assess pain. In that period, 18 animal neuroimaging studies have used fMRI, 1–3,9,17,22,35,37,40,46,56,61,64,75,84,85,88,89 whereas 10 other studies have used less commonly used techniques including 5 with MEMRI, 16,25,41,42,74 3 with PET, 19,44,78 and 2 with EEG. 48,72 There were no studies using diffusion tensor imaging or structural MRI in that period.…”