Endogenous Opioid Peptides Acting at m-Opioid Receptors in the Dorsal Horn Contribute to Midbrain Modulation of Spinal Nociceptive Neurons

Budai, Dénes and Howard L. Fields. Endogenous opioid peptides horn nociceptive neurons remain unclear, largely because acting at m-opioid receptors in the dorsal horn contribute to midthe laminae that receive direct RVM input contain several brain modulation of spinal nociceptive neurons. J. Neurophysiol. different neural elements including the terminals of primary 79: 677–687, 1998. Activation of neurons in the midbrain periaafferent nociceptors, projection neurons, and both excitatory queductal gray (PAG) inhibits spinal dorsal horn neurons and and inhibitory local circuit interneurons (Light 1992; Willis produces behavioral antinociception in animals and analgesia in and Coggeshall 1991). humans. Although dorsal horn regions modulated by PAG activaAn important unresolved issue is the contribution of ention contain all three opioid receptor classes (m, d, and k) , as well dogenous opioids to the PAG-RVM circuit control of dorsal as enkephalinergic interneurons and terminal fields, descending horn nociceptive neurons. The dorsal horn regions that reopioid-mediated inhibition of dorsal horn neurons has not been demonstrated. We examined the contribution of dorsal horn ceive RVM input contain m, d, and k opioid receptors, as m-opioid receptors to the PAG-elicited descending modulation of well as enkephalinergic interneurons and terminal fields (Arnociceptive transmission. Single-unit extracellular recordings were vidsson et al. 1995a,b; Besse et al. 1991; Cheng et al. 1996; made from rat sacral dorsal horn neurons activated by noxious Fields et al. 1991; Mansour et al. 1995) and RVM axon heating of the tail. Microinjections of bicuculline (BIC) in the terminals contact enkephalinergic dorsal horn neurons (Cho ventrolateral PAG led to a 60–80% decrease in the neuronal reand Basbaum 1989b; Glazer and Basbaum 1984). Release sponses to heat. At the same time, the responses of the same of enkephalin at spinal levels has been demonstrated (Bourneurons to iontophoretically applied NMDA or kainic acid were goin et al. 1988; Collin et al. 1992; Dado et al. 1993; Tang not consistently inhibited. The inhibition of heat-evoked responses et al. 1989; Yaksh and Chipkin 1989). Furthermore, opioids by PAG BIC was reversed by iontophoretic application of the selective m-opioid receptor antagonists, D-Phe-Cys-Tyr-D-Trp-Orndirectly inhibit primary afferent nociceptors (Moises et al. Thr-Pen-Thr-NH2 (CTOP) and D-Phe-Cys-Tyr-D-Trp-Arg-Thr1994; Taddese et al. 1995; Werz et al. 1987) and nociceptive Pen-Thr-NH2 (CTAP). A similar effect was produced by naloxone; dorsal horn neurons (Glaum et al. 1994; Grudt and Williams however, naloxone had an excitatory influence on dorsal horn neu1994; Omote et al. 1990; Randic et al. 1995). Finally alrons in the absence of PAG-evoked descending inhibition. This is though some report that intrathecal naloxone does not antagthe first demonstration that endogenous opioids acting via spinal onize PAG-elicited antinociception (Aimone et al. 1987; m-opioid receptors contribute to brain stem control of nociceptive Fang and Proudfit 1996; Jensen and Yaksh 1984), others spinal dorsal horn neurons. The inhibition appears to result in part found that PAGor RVM-evoked antinociception is reduced from presynaptic inhibition of afferents to dorsal horn neurons. by intrathecal naloxone (Tseng and Tang 1989; Tortorici et al. 1996; Zorman et al. 1982) or naltrexone (Morgan et al.