Spinal μ-Opioid Receptor-Expressing Dorsal Horn Neurons: Role in Nociception and Morphine Antinociception

Abstract

The role of spinal cord -opioid receptor (MOR)-expressing dorsal horn neurons in nociception and morphine analgesia is incompletely understood. Using intrathecal dermorphin-saporin (Derm-sap) to selectively destroy MOR-expressing dorsal horn neurons, we sought to determine the role of these neurons in (1) normal baseline reflex nocifensive responses to noxious thermal stimulation (hotplate, tail flick) and to persistent noxious chemical stimulation (formalin) and (2) the antinociceptive activity of intrathecal and systemic morphine in the same tests. Lumbar intrathecal Derm-sap (500 ng) produced (1) partial loss of lamina II MOR-expressing dorsal horn neurons, (2) no effect on MOR-expressing dorsal root ganglion neurons, and (3) no change in baseline tail-flick and hotplate reflex nocifensive responses. Derm-sap treatment attenuated the antinociceptive action of both intrathecal and systemic morphine on hotplate responses. Derm-sap treatment had two effects in the formalin test: (1) increased baseline nocifensive responding and (2) reduced antinociceptive action of systemic morphine. We conclude that MOR-expressing dorsal horn neurons (1) are not essential for determining nocifensive reflex responsiveness to noxious thermal stimuli, (2) are necessary for full antinociceptive action of morphine (intrathecal or systemic) in these tests, and (3) play a significant role in the endogenous modulation of reflex nocifensive responses to persistent pain in the formalin test. Thus, one would predict that altering the activity of MOR-expressing dorsal horn neurons would be antinociceptive and of interest in the search for new approaches to management of chronic pain.

Spinal Synthesis of Estrogen and Concomitant Signaling by Membrane Estrogen Receptors Regulate Spinal κ- and μ-Opioid Receptor Heterodimerization and Female-Specific Spinal Morphine Antinociception

“…These areas also express opioid receptors, which localize to pre-synaptic terminals of primary sensory neurons as well as to their postsynaptic targets in laminae I and II (Kline and Wiley, 2008). In the present study, we found that MOR-IR neurons in the dorsal horn frequently expressed ER α .…”

Sex Differences in μ-Opioid Receptor Expression in the Rat Midbrain Periaqueductal Gray Are Essential for Eliciting Sex Differences in Morphine Analgesia

“…This suggests that in females, the PAG is not the primary anatomical substrate for the analgesic effects of morphine. Both the RVM (Porreca et al ., 2001; Burgess et al ., 2002) and the dorsal horn of the spinal cord (Kline & Wiley, 2008) contribute to morphine antihyperalgesia and perhaps these sites are more critical in females. In support, we have recently reported no differences in MOR expression within the lumbosacral spinal cord and similarly, no differences in ED 50 values for morphine when administered intrathecally (Ji et al ., 2006).…”

“…Thus, while vlPAG MOR obviously contributes to the effects of exogenous morphine, its reduction does not appear to alter endogenous pain modulation during inflammatory hyperalgesia suggesting that other pain inhibiting regions, including the RVM and spinal cord are involved. In support, previous studies have reported that DermSAP lesions of MOR-expressing neurons in the RVM (Porreca et al ., 2001; Burgess et al ., 2002) and dorsal horn neurons (Kline & Wiley, 2008) attenuate hyperalgesia in male rats. Together, these data indicate that the RVM and the dorsal horn of the spinal cord, but not the PAG, are essential for driving descending facilitation (Terayama et al ., 2000; Ren & Dubner, 2002; Dubner & Ren, 2004).…”

“…In addition, dermorphin has been shown to have a high binding affinity selective for the MOR (K i value of 0.7mM) and that conjugation to saporin does not significantly alter its binding affinity (K i value of 0.1nM; Porreca et al ., 2001). This technique has been previously been shown to result in a significant attenuation of MOR expression in the RVM (Porreca et al ., 2001) and the spinal cord (Kline & Wiley, 2008). Loss of MOR containing neurons was confirmed in the present study using both immunohistochemistry and autoradiography.…”

Activation of Mas Oncogene-Related G Protein–Coupled Receptors Inhibits Neurochemical Alterations in the Spinal Dorsal Horn and Dorsal Root Ganglia Associated with Inflammatory Pain in Rats

“…For example, substance P, which is coreleased from the central terminals, facilitates the relief of the Mg 21 block in the NMDA receptor, leading to the enhancement of NMDA receptor signaling (Khasabov et al, 2002;Suzuki et al, 2003). Other postsynaptic GPCRs that modulate NMDA receptors include metabotropic glutamate (D'Mello and Dickenson, 2008), CGRP (Yan and Yu, 2004), and m-opioid receptors (Gracy et al, 1997;Kline and Wiley, 2008). These receptors are known to couple to G q , G s , or G i proteins.…”