Contribution of Endogenous Enkephalins to the Enhanced Analgesic Effects of Supraspinal μ Opioid Receptor Agonists after Inflammatory Injury

Abstract

This study examined a mechanism responsible for the enhanced antihyperalgesic and antinociceptive effects of the opioid receptor agonist (ORA) [D-Ala 2 , NMePhe 4 , Gly 5 -ol]enkephalin (DAMGO) microinjected in the rostroventromedial medulla (RVM) of rats with inflammatory injury induced by injection of complete Freund's adjuvant (CFA) in one hindpaw. In rats injected with CFA 4 hr earlier, microinjection of the opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-PenThr-NH 2 (CTAP) in the RVM antagonized both the marginal enhancement of the potency of DAMGO and its antinociceptive effect. The ␦ opioid receptor antagonist naltriben (NTB) was without effect. In rats injected with CFA 2 weeks earlier, CTAP antagonized the effects of DAMGO to a lesser extent. However, NTB completely prevented the enhancement of the potency of DAMGO, whereas it did not antagonize DAMGO's antinociceptive effects. Microinjection of NTB alone, but not CTAP in the RVM of CFA-treated rats, enhanced the hyperalgesia present in the ipsilateral hindpaw and induced hyperalgesia in the contralateral, uninjured hindpaw. These results suggest that persistent inflammatory injury increased the release in the RVM of opioid peptides with preferential affinity for the ␦ opioid receptor, which can interact in a synergistic or additive manner with an exogenously administered opioid receptor agonist. Indeed, the levels of [Met 5 ]enkephalin and [Leu 5 ]enkephalin were increased in the RVM and in other brainstem nuclei in CFAtreated rats. This increase most likely presents a compensatory neuronal response of the CNS of the injured animal to mitigate the full expression of inflammatory pain and to enhance the antinociceptive and antihyperalgesic effects of exogenously administered opioid receptor analgesics. Key words: opioid receptor; ␦ opioid receptor; antinociception; complete Freund's adjuvant; hyperalgesia; nucleus raphe magnusPeripheral inflammatory injury alters the pharmacology and physiology of primary afferent fibers that convey tactile and nociceptive information (Noguchi et al., 1988;Schaible and Schmidt, 1988;Donaldson et al., 1992;Ji et al., 1995;Leslie et al., 1995;Neumann et al., 1996;Tanaka et al., 1998), as well as the pharmacology and physiology of the dorsal horn neurons on which they synapse (Hylden et al., 1989;Noguchi et al., 1989;Weihe et al., 1989;McCarson and Krause, 1994;Goff et al., 1998). More recently, peripheral inflammation has been recognized to also affect the efferent pain modulatory pathways. For example, persistent inflammatory injury can enhance either the inhibition or facilitation of spinal nociceptive transmission by medullary or pontine neurons (Schaible et al., 1991;Herrero and Cervero, 1996;Ren and Dubner, 1996;Tsuruoka and Willis, 1996;Urban et al., 1996Urban et al., , 1999Kauppila et al., 1998;Wei et al., 1998Wei et al., , 1999MacArthur et al., 1999;Terayama et al., 2000). Alterations in the activity of supraspinal neurons were inferred in most of these studies from lesion-induced changes in response...

Persistent pain model reveals sex difference in morphine potency

“…No change in morphine antinociception was noted in saline-treated animals, suggesting that the observed increase in morphine potency was due to the presence of persistent inflammation. Similar to the results obtained in the present study, Hurley and Hammond (27), also using a thermal stimulus, reported a significant increase in the antihyperalgesic potency of the agonist DAMGO, administered directly into the RVM, as a function of time postinflammation. More importantly, they reported that the antinociceptive potency of DAMGO, determined for the contralateral, uninflamed paw, was also progressively enhanced as a function of time postinjury, with the magnitude of enhancement paralleling the chronicity of the inflammation.…”

“…Several mechanisms have been proposed to account for persistent inflammation-induced changes in opioid potency, including upregulation of glutamate receptors in the RVM (24,25), increased MOR expression and second messenger coupling in the lumbar dorsal root ganglia (51,60), and increased release of endogenous opioids in several supraspinal sites, including the PAG and RVM (27,53,59). These results together suggest that in males, multiple mechanisms contribute to persistent pain-induced changes in opioid potency.…”

“…First, a number of studies in male rats have reported that the antihyperalgesic properties of opiates change in the presence of persistent inflammation, becoming more potent over time (26,33,54). Several mechanisms have been implicated, including changes in peripheral (55), spinal (18,49,50), and supraspinal (26,27) opioidergic circuits. Second, persistent pain influences the ovulatory cycle and, therefore, the hormonal status of females.…”

Morphine priming in rats with chronic inflammation reveals a dichotomy between antihyperalgesic and antinociceptive properties of deltorphin

“…Another possibility is that both effects have a joint central origin. Peripheral inflammation is known to increase the release of endogenous opioid peptides, both in the periphery (Cabot et al, 1997) and in the CNS (Millan et al, 1986(Millan et al, , 1988Iadarola et al, 1988;Hurley and Hammond, 2001;Parra et al, 2002). Specifically, unilateral inflammation of the hindlimb was reported to rapidly increase both the mRNA levels of dynorphin and enkephalin precursors (Iadarola et al, 1988;Noguchi et al, 1992) as well as the level of immunoreactive dynorphin (Iadarola et al, 1988;Millan et al, 1988;Parra et al, 2002).…”

“…Indeed, increased enkephalin immunoreactivity was reported in chronic inflammatory states (Faccini et al, 1984;Millan et al, 1986Millan et al, , 1988Hurley and Hammond, 2001). We sought to determine whether in the present chronic inflammation model, endogenous met-enkephalin levels were modified in the rat lumbar spinal cord.…”