Abstract
The use of morphine, the standard opioid drug, is limited by its undesirable effects, such as tolerance, physical dependence, and hyperalgesia (increased pain sensitivity). Clinical and preclinical studies have reported development of hyperalgesia after prolonged opioid administration or after a single dose of intrathecal (i.t.) morphine in uninjured rats. However, whether a single standard systemic morphine dose is sufficient to decrease the nociceptive threshold in rats is unknown. Here, we showed that a single morphine subcutaneous injection induces analgesia followed by a long-lasting delayed hyperalgesia in uninjured and PGE2 sensitized rats. The i.t injection of extracellular signal-regulated kinase (ERK) inhibitor blocked morphine-induced analgesia, without interfering with the morphine-induced hyperalgesia. However, i.t. injection of SB20358, a p38 inhibitor and SP660125, a JNK inhibitor, decreased the morphine-induced hyperalgesia. Consistently with the behavioral data, Western Blot analysis showed that ERK is more phosphorylated 1 h after morphine, i.e., when the analgesia is detected. Moreover, phospho-p38 and phospho-JNK levels are upregulated 96 h after morphine injection, time that coincides with the hyperalgesic effect. Intrathecal (i.t.) oligodeoxynucleotide (ODN) antisense to cAMP-responsive element binding protein (CREB) attenuated morphine-induced hyperalgesia. Real-time polymerase chain reaction (RT-PCR) analysis showed that CREB downstream genes expressions were significantly up-regulated 96 h after morphine injection in spinal cord. Together, our data suggest that central ERK is involved in the analgesic and hyperalgesic effects of morphine while JNK, p38, and CREB are involved in the morphine-induced delayed hyperalgesia.
Highlights
Opioids are effective analgesics for treating moderate to severe pain, but their use is limited due to adverse effects such as development of tolerance and paradoxical pain
Rats treated with morphine (5 mg/Kg), besides displaying analgesia, display a long-lasting decrease in the nociceptive threshold, starting at Day 4 (96 h) and lasting until Day 6 (144 h)
The results obtained for the systemic and intraplantar administration of morphine indicate that (a) a single systemic injection of morphine can induce a biphasic response in the nociceptive threshold of uninjured rats and (b) central mechanisms are involved in morphine-induced delayed hyperalgesia
Summary
Opioids are effective analgesics for treating moderate to severe pain, but their use is limited due to adverse effects such as development of tolerance and paradoxical pain. Several preclinical studies have reported that administration of opioids, such as morphine, either in very high or very low doses, increases sensitivity to noxious stimuli, i.e., hyperalgesia (Angst and Clark, 2006; Lee et al, 2011). Hyperalgesia is reported after repeated daily opioid administration (Corder et al, 2017) or after a single intrathecal injection of opioids in rats (Van Elstraete et al, 2005). Whether a single systemic administration of an intermediate opioid dose (i.e., a dose that induces analgesia without compromising the overall activity, such as, locomotion or respiratory functions) induces hyperalgesia is still controversial. Studies evaluating the effect of a single injection of opioid on the nociceptive threshold are still an unmet need and relevant for clinical practice
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