One putative dynorphin metabolic fragment corresponding to Leu-Enk-Arg-Arg (m/z 867) was upregulated by 54% in the HD group compared to the LD group but showed no significant correlation with LID severity (Fig. 7B; expressed as % of intact side, mean 6 SEM; HD 170618, LD 110615; p,0.01 HD vs. LD; p = 0.07 and correlation coefficient R = 0.59;). Additionally, a putative metabolic product of aNeo (aNeo (1-7); m/z 840) displayed a 45% elevation in peak intensity without a significant correlation with dyskinesia ( Fig. 7C; mean 6 SEM, HD 148612, LD 102615; p,0.05; p = 0.08 and correlation coefficient R = 0.54). Notably, we could not detect any changes in peak intensities for Dyn A(1-17, m/z 2145), Dyn A(1-8, m/z 981), and substance P (m/z 1347; Fig. 7 D, E). Leu-Enk (m/z 555) was not detected in this study most probably due to the limit of detection in the low molecular weight region. Another way to effectively reduce opioid receptor activation of dynorphins is by removing the first N-terminal tyrosine [35]. Metabolic fragments corresponding to the des-tyrosine forms of Dyn A(1-8), aNeo, and Dyn B were observed in SN but displayed no treatment-induced changes (Supplemental Fig. S2).   Dyskinesia is associated with high levels of dynorphin Bimmunoreactivity in the lateral SN Confirming the MALDI IMS data, Dyn B-immunoreactive axons densely innervated the substantia nigra and the hippocampus adjacent to the ventral midbrain (cf. Fig. 8 and Fig. 4). In highdyskinetic animals, Dyn B immunoreactivity was elevated by 63% in the lateral SN ( Fig. 8B; p,0.001, HD vs. LD, and HD vs. LC group). A smaller increase by 39% was detected in the medial part of SN (p,0.05, HD vs. LD, mean % optical density 6 SEM, HD 130613, LD 93 6 8). Indeed, Dyn B immunoreactivity in the medial part showed a weak but still significant correlation with cumulative dyskinesia score (p,0.05 R = 0.61, **data** not shown), however, the strongest correlation was localized to the lateral part of SN (p,0.001, R = 0.83, **data** not shown). This is strikingly similar to that observed from the MALDI IMS experiment (R = 0.80, p,0.01). Indeed, a linear correlation between the MALDI Dyn B peak intensity and the corresponding optical density of Dyn B immunoreactivity was observed ( Fig. 8C; p,0.05, R = 0.73).