Chronic Inflammatory Pain Prevents Tolerance to the Antinociceptive Effect of Morphine Microinjected into the Ventrolateral Periaqueductal Gray of the Rat

The ventrolateral periaqueductal gray (vlPAG) contributes to morphine antinociception and tolerance. Chronic inflammatory pain causes changes within the PAG that are expected to enhance morphine tolerance. This hypothesis was tested by assessing antinociception and tolerance following repeated microinjections of morphine into the vlPAG of rats with chronic inflammatory pain. Microinjection of morphine into the vlPAG reversed the allodynia caused by intraplantar administration of complete Freund's adjuvant and produced antinociception on the hot plate test. Although there was a gradual decrease in morphine antinociception with repeated testing, there was no evidence of tolerance when morphine- and saline-treated rats with hind paw inflammation were tested with cumulative doses of morphine. In contrast, repeated morphine injections into the vlPAG caused a rightward shift in the morphine dose-response curve in rats without hind paw inflammation, as would be expected with the development of tolerance. The lack of tolerance in complete Freund's adjuvant–treated rats was evident whether rats were exposed to repeated behavioral testing or not (experiment 2) and whether they were treated with 4 or 8 prior microinjections of morphine into the vlPAG (experiment 3). These data demonstrate that chronic inflammatory pain does not disrupt the antinociceptive effect of microinjecting morphine into the vlPAG, but it does disrupt the development of tolerance.PerspectiveThe present data show that induction of chronic inflammatory pain does not disrupt the antinociceptive effect of microinjecting morphine into the vlPAG, but it does attenuate the development of tolerance. This finding indicates that tolerance to opioids in rats with inflammatory pain is mediated by structures other than the vlPAG.