Rostral Ventromedial Medulla Neurons That Project to the Spinal Cord Express Multiple Opioid Receptor Phenotypes

Marinelli, Silvia; Vaughan, Christopher W.; Schnell, Stephen A.; Wessendorf, Martin W.; Christie, MacDonald J.

doi:10.1523/jneurosci.22-24-10847.2002

Cited by 94 publications

(88 citation statements)

References 42 publications

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“…In vitro RVM recordings have shown that a large proportion of spinally projecting neurons respond directly to -opioid receptor (MOR) agonists, 19 which confirms the central role of the brainstem in opioid analgesia. 20,21 Moreover, many MOR-expressing spinally projecting neurons in the RVM stain positive for tryptophan hydroxylase, a marker of 5-HT content, and like-wise, many tryptophan hydroxylase-positive spinally projecting neurons respond to MOR agonists.…”

Section: Descending Modulatory Pathwaysmentioning

confidence: 87%

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

2009

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Summary:The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent ␣ 2 -adrenoceptor-mediated inhibitory system and 5-HT 3 (and likely also 5-HT 2 ) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control. Key Words: 5-HT receptors, 5-HT, serotonin, noradrenaline, RVM, rostral ventromedial medulla, opioidinduced hyperalgesia, neuropathy, fibromyalgia. PAIN, COMORBIDITIES, AND MONOAMINESPain and mood share certain neurological pathways in the CNS and have overlapping neurochemical bases, in particular their modulation by monoamine systems. This provides the substrate through which pain can influence mood, giving rise to comorbidities or secondary symptoms such as anxiety and depression, 1,2 and by the same continuum allows mood to exacerbate pain; indeed, patients with depression often present with symptoms that include medically unexplained pain, with the mean prevalence of such occurrence cited as 65%.1,3 Emotional facets of nociception play a significant role in the pain experience, with fear largely driving adaptive behaviors that enable avoidance of actual or impending harm. This therefore subserves the key function of pain, to protect the integrity and survival of an organism. Moreover, the role of emotions and state of mind in pain partly underlie the variable relationship between the intensity of damaging stimuli and perceived pain, such that at any given time and for any given nociceptive stimulus, painful response can be influenced by emotional state (the psychological context in which the stimulus is received), emotional trait (the psychological characteristics of the recipient), and cognitive set (attention and vigilance, for example).Depression is associated with abnormalities in the monoaminergic ...

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Section: Descending Modulatory Pathwaysmentioning

confidence: 87%

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

2009

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“…Because all three classes of opioid receptors are expressed in 5-HT neurons (4,31,32), it remains to be determined to what degree and in what way the loss of each individual opioid receptor in 5-HT neurons may have contributed to the altered behavioral phenotype of Lmx1b f/f/p mice. Obviously, it is possible that the attenuation of morphine analgesia in Lmx1b f/f/p mice could be due to a secondary change of MOR expression in other regions of the brain.…”

Section: Discussionmentioning

confidence: 99%

“…However, the role of the central 5-HT system in opioid analgesia is less clear. For the past several decades numerous pharmacological and behavioral studies have indicated that morphine-induced descending inhibition of nociceptive transmission depends on supraspinal 5-HT neurons (2)(3)(4). Despite these studies, many contradictory results concerning the role of central 5-HT neurons in morphine analgesia have also been reported, making it a long-standing controversial issue in pain research (5).…”

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confidence: 99%

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Zhao¹,

Gao²,

Sun³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Opioids remain the most effective analgesics despite their potential adverse effects such as tolerance and addiction. Mechanisms underlying these opiate-mediated processes remain the subject of much debate. Here we describe opioid-induced behaviors of Lmx1b conditional knockout mice (Lmx1b f/f/p ), which lack central serotonergic neurons, and we report that opioid analgesia is differentially dependent on the central serotonergic system. Analgesia induced by a opioid receptor agonist administered at the supraspinal level was abolished in Lmx1b f/f/p mice compared with their wild-type littermates. Furthermore, compared with their wild-type littermates Lmx1b f/f/p mice exhibited significantly reduced analgesic effects of and ␦ opioid receptor agonists at both spinal and supraspinal sites. In contrast to the attenuation in opioid analgesia, Lmx1b f/f/p mice developed tolerance to morphine analgesia and displayed normal morphine reward behavior as measured by conditioned place preference. Our results provide genetic evidence supporting the view that the central serotonergic system is a key component of supraspinal pain modulatory circuitry mediating opioid analgesia. Furthermore, our data suggest that the mechanisms of morphine tolerance and morphine reward are independent of the central serotonergic system. serotonin ͉ pain ͉ conditioned place preference ͉ behavior ͉ mouse

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“…Descending serotonergic pathways can be activated by ascending pathways involving neurokinin 1 receptor-positive projection neurons (Suzuki et al, 2002). Previous studies using combined electrophysiological and immunohistological approaches indicate that serotonergic descending pathways can also be disinhibited by MOR agonists (Marinelli et al, 2002). Disinhibition has a potentially rapid onset that could correspond well to the time course of the presently described immediate-onset facilitation.…”

Section: Withdrawal Ltp By Remifentanil Fentanyl and Morphinementioning

confidence: 73%

“…MORs are also expressed on neurons in various brain areas, including the rostral ventromedial medulla, that send descending projections to the spinal cord (Marinelli et al, 2002). MOR agonists may activate descending pathways that modulate spinal nociception.…”

Section: Introductionmentioning

confidence: 99%

Distinct Mechanisms Underlying Pronociceptive Effects of Opioids

Heinl¹,

Drdla-Schutting²,

Xanthos³

et al. 2011

J. Neurosci.

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In addition to analgesia, opioids may also produce paradoxical pain amplification [opioid-induced hyperalgesia (OIH)] either on abrupt withdrawal or during continuous long-term application. Here, we assessed antinociceptive and pronociceptive effects of three clinically used opioids at C-fiber synapses in the rat spinal dorsal horn in vivo. During 60 min of intravenous infusions of remifentanil (450), C-fiber-evoked field potentials were depressed and pairedpulse ratios (PPR) were increased, indicating a presynaptic inhibition by all three opioids. After withdrawal, postsynaptic responses were enhanced substantially for the remaining of the recording periods of at least 3 h. Withdrawal from remifentanil led to long-term potentiation (LTP) of synaptic strength in C-fibers via activation of spinal -opioid receptors (MORs) and spinal NMDA receptors (NMDARs). Fentanyl and morphine caused an enhancement of synaptic transmission at C-fibers, which involved two distinct mechanisms: (1) an opioid withdrawal LTP that also required activation of spinal MORs and NMDARs and that was associated with a decrease in PPR suggestive of a presynaptic mechanism of its expression, and (2) an immediate-onset, descending facilitation of C-fiber-evoked field potentials during and after intravenous infusion of fentanyl and morphine. Immediate-onset, descending facilitation was mediated by the activation of extraspinal MORs, descending serotonergic pathways, and spinal 5-hydroxytryptamine-3 receptors (5-HT 3 Rs). Our study identified fundamentally different pronociceptive effects of clinically used opioids and suggests that OIH can be prevented by the combined use of NMDAR and 5-HT 3 R antagonists.

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Rostral Ventromedial Medulla Neurons That Project to the Spinal Cord Express Multiple Opioid Receptor Phenotypes

Cited by 94 publications

References 42 publications

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward

Distinct Mechanisms Underlying Pronociceptive Effects of Opioids

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