Genotype-dependent responsivity to inflammatory pain: the role of TRPV1 in the periaqueductal grey
Madasu, Manish Kumar
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The ability to experience pain is essential for survival, and to prevent potential tissue damage upon exposure to noxious stimuli. The periaqueductal grey - rostral ventromedial medulla – dorsal horn of the spinal cord (PAG-RVM-DH) pathway plays a pivotal role in pain processing and modulation. Antinociception caused by activation of this descending inhibitory pain pathway involves the PAG-mediated activation of neurons within the RVM. Negative affective state has a significant impact on pain, and genetic background is an important moderating influence on this interaction. The Wistar–Kyoto (WKY) inbred rat strain exhibits a stress-hyperresponsive, anxiety/depressive-like phenotype and also displays a hyperalgesic response to noxious stimuli, compared with Sprague-Dawley (SD) rats. Transient receptor potential subfamily V member 1 (TRPV1), a non-selective ligand-gated ion-channel activated by protons, capsaicin (active constituent of chilli peppers), and thermal stimuli, plays a key role within the midbrain PAG in regulating both aversive and nociceptive behaviour. The overall aim of the studies described in this thesis was to investigate the role of TRPV1 in the columns of the PAG in hyperalgesia to formalin-evoked inflammatory pain in WKY versus SD rats. TRPV1 mRNA expression was significantly lower in the dorsolateral (DL) PAG and higher in the lateral (L) PAG of WKY rats, compared with SD counterparts. There were no significant differences in TRPV1 mRNA expression in the ventrolateral (VL) PAG between the two strains. TRPV1 mRNA expression significantly decreased in the DLPAG and increased in the VLPAG of SD, but not WKY rats, upon intra-plantar formalin administration. Intra-DLPAG administration of either the TRPV1 agonist capsaicin, or the TRPV1 antagonist 5’-Iodoresiniferatoxin (5’-IRTX), significantly increased formalin-evoked nociceptive behaviour in SD rats, but not in WKY rats. The effects of capsaicin were likely due to TRPV1 desensitisation, given their similarity to the effects of 5’-IRTX. Intra-VLPAG administration of capsaicin or 5’-IRTX reduced nociceptive behaviour in a moderate and transient manner in SD rats, and similar effects were seen with 5’-IRTX in WKY rats. Intra-LPAG administration of 5’-IRTX reduced nociceptive behaviour in a moderate and transient manner in SD rats, but not in WKY rats. Pharmacological modulation of TRPV1 in the columns of the PAG had little effect on the levels of neurotransmitters and endocannabinoids/N-acylethanolamines in the RVM and dorsal horn of the spinal cord or on c-Fos expression in the dorsal horn. These results indicate that modulation of inflammatory pain by TRPV1 in the PAG occurs in a column-specific manner. The data also provide evidence for differences in the expression of TRPV1, and differences in the effects of pharmacological modulation of TRPV1 in specific PAG columns, between WKY and SD rats, suggesting that TRPV1 expression and/or functionality in the PAG plays a role in hyper-responsivity to noxious stimuli in a genetic background prone to negative affect.