Supraspinal And Spinal Mechanisms Of Morphine-Induced Hyperalgesia

Carol A. Arout


Morphine is the most prominent pharmacological treatment for moderate to severe pain in both acute and chronic paradigms. However, morphine notoriously elicits a paradoxical state of increased pain sensitivity known as hyperalgesia that complicates its use in clinical application. Research over the past three decades has reported that morphine-induced hyperalgesia is dose- and sex-dependent, and likely involves the synchronous activity of several neural networks beyond the opioid system. Whereas systemic, supraspinal, and spinal administration of morphine all cause hyperalgesia that is differentially reversible by N-methyl-D-aspartate receptor (NMDAR) antagonists or melanocortin-1 receptor (MC1R) antagonists, it is unknown as to whether or not these non-opioid systems that contribute to this state are located supraspinally or spinally. The current studies were performed with the goal of elucidating the precise location of regulatory action of this sex- and dose- dependent state of morphine hyperalgesia.

In all studies, outbred CD-1 male and female mice were pretreated with the general opioid receptor antagonist, naltrexone (NTX) 24 hours prior to morphine treatment. All mice were subsequently implanted with osmotic pumps, continuously dispensing a low (1.6mg/kg/24h) or high dose of morphine (40mg/kg/24h). As noted previously, mice of both sexes were hyperalgesic by Day 4 of continuous infusion of either morphine dose, a state that persisted through Day 6 of infusion. The first series demonstrated that NMDAR and MC1R systems that mediate this morphine-induced hyperalgesic state are located supraspinally, as intracerebroventricular injections of MK-801 and MSG606, respectively successfully reversed hyperalgesia during a one-hour testing period. A second series of studies investigated possible involvement of spinal systems. Whereas intrathecal MK-801 significantly reversed hyperalgesia in males at both doses, and females at the low morphine infusion dose, spinal administration of MSG606 significantly reduced hyperalgesia in females following continuous high dose morphine infusion. This indicates that the sex-dependent mechanism involved in morphine-induced hyperalgesia is located supraspinally and spinally, and either locus can independently modulate female-typical hyperalgesia.

A third series of studies investigated hormonally-regulated mechanisms involved in morphine-induced hyperalgesia. Ovariectomized females displayed male-typical patterns of hyperalgesia after i.c.v. and i.t. antagonist injection paradigms following continuous infusion of either dose of morphine on Day 4. On Day 6, NMDAR and MC1R antagonist injections were preceded by an acute systemic progesterone injection in ovariectomized female mice, and intact male mice. Following continuous morphine infusion, ovariectomized females displayed male-typical patterns of hyperalgesic reversal. However, following progesterone administration, hyperalgesia elicited by high doses of morphine was reversed by i.c.v. injection of MK-801 and MSG606 in both males and ovariectomized females. Conversely, following i.t. injections the data show that ovariectomized females are able to recruit the NMDAR or MC1R system, while males exclusively used the NMDAR system to mediate hyperalgesia. The current studies indicate that in terms of modulating morphine-induced hyperalgesia, there are both supraspinally- and spinally-regulated sex-dependent effects that mediate morphine-induced hyperalgesia.