The role of the endocannabinoid system in the emotional modulation of pain
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Fear-conditioned analgesia (FCA) is the robust suppression of pain that occurs upon reexposure to a context previously paired with an aversive stimulus. FCA is mediated by activation of the descending inhibitory pain pathway. The medial prefrontal cortex (mPFC) in rodents is typically subdivided into three subregions; the infralimbic (IL), prelimbic (PrL) or anterior cingulate (ACC) cortices. While evidence exists of a role for the endocannabinoid system in the mPFC in FCA, further investigation is warranted. Moreover, few studies have investigated the role of genetic background on the emotional modulation of pain. The Wistar Kyoto (WKY) rat strain represents a useful model to investigate the role of genetic background on FCA. This rat strain displays an anxiodepressive-like phenotype and is highly sensitive to both stress and pain. The overall aims of the work described in this thesis were (1) to further examine the role of the endocannabinoid system in the three subregions of the mPFC in FCA and (2) to compare FCA, conditioned fear and pain-related behaviour in WKY versus Sprague Dawley (SD) rats and investigate the role of the endocannabinoid system in the mPFC in the differential behavioural profile of these two strains. FCA was modelled by combining the formalin test of persistent pain with classical Pavlovian fear conditioning to context in rats. Male Lister-Hooded rats were used for the initial studies. On conditioning days, rats received footshocks (10x1s, 0.4mA) spaced 1 minute apart in a conditioning arena. Control rats received no footshocks and were placed in the conditioning arena for an equivalent amount of time (10-minutes). 23.5 hours later, rats received an intraplantar injection of formalin (2.5%, 50µl) into the right hind paw. 30-minutes later rats were re-exposed to the contextually aversive footshock arena and behaviours were recorded for 30-minutes. In some of these experiments, rats had guide cannulae implanted into the left and right IL, PrL and ACC approximately one week before testing. On the day of testing, 15 minutes prior to re-exposure to the arena, depending on the experiment, rats received bilateral intracerebral microinjections of the fatty acid amide hydrolase (FAAH) inhibitor, URB597, or the CB1 receptor antagonist, AM251, or the monoacylglycerol lipase inhibitor (MAGL), MJN110, or the CB2 receptor antagonist, AM630, or a combination of AM251+URB597 or MJN110+AM251 or MJN110+AM630. Additional experiments compared FCA in male WKY and SD rats and examined the role of AEA and CB1 in the IL of WKY and SD rats in response to inflammatory pain. Rats were implanted with cannulae into the left and right IL approximately one week before testing. Formalin-evoked nociceptive behaviour was measured for 1 hour following bilateral intra-IL microinjection of the AEA analog methanandamide, mAEA, or URB597 or AM251 or the CB1 agonist ACEA. In the ACC, neither FAAH inhibition nor CB1 antagonism had any effect on the expression of FCA or contextually induced fear. Intra-IL, PrL or ACC administration of the MAGL inhibitor MJN110 significantly attenuated the expression of FCA, effects unopposed by coadministration of the CB1 antagonist, AM251. MJN110 elevated levels of 2-AG in the ACC but not in the IL or PrL. The attenuation of FCA by intra-ACC MJN110 was blocked by coadministration with the CB2 antagonist, AM630. Alone, AM630 significantly reduced formalin-evoked nociceptive behaviour in non-fear-conditioned but not fear-conditioned rats. These data provide new evidence to support a role for MAGL substrates in the IL, PrL ACC, in the modulation of FCA. The data suggest that FCA is attenuated by 2 AG-CB2 receptor signalling in the ACC, and that CB2 receptors in the ACC may facilitate formalin-evoked nociceptive behaviour. WKY rats exhibited reduced expression of FCA and increased formalin-evoked nociceptive behaviour compared to SD rats; suggesting an impairment in the descending inhibitory pain pathway of this strain. WKY rats also had lower levels of AEA in the IL cortex, compared with SD rats. In SD rats, intra-IL administration of m-AEA and URB597 reduced formalin-evoked nociceptive behaviour an effect not seen in WKY rats. Intra-IL administration of AM251 and ACEA had no effect on formalin-evoked nociceptive behaviour in either SD or WKY rats. These results indicate differences in the endocannabinoid system in the IL of WKY rats compared to SD controls, which may account for the hyperalgesic phenotype exhibited by this strain. In conclusion, the data provide further evidence for an important physiological role of the endocannabinoid system within the mPFC in FCA, and formalin-evoked nociceptive behaviour. This work enhances our understanding of the mechanisms underlying emotional modulation of pain and may facilitate the development of new therapeutic strategies for pain and fear-related disorders and their co-morbidity.
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