Morphine effects within the rodent anterior cingulate cortex and rostral ventromedial medulla reveal separable modulation of affective and sensory qualities of acute or chronic pain

Abstract

Modulation of pain may result from engagement of opioid receptors in multiple brain regions. Whether sensory and affective qualities of pain are differentially affected by brain opioid receptor circuits remains unclear. We previously reported that opioid actions within the rostral anterior cingulate cortex (ACC) produce selective modulation of affective qualities of neuropathic pain in rodents, but whether such effects may occur in other areas of the ACC is not known. Here, morphine was microinjected into 3 regions of the ACC or into the rostral ventromedial medulla (RVM), and pain behaviors in naive, sham, or spinal nerve ligated (SNL) rats were evaluated. In naive animals, the tail-flick response was inhibited by RVM, but not ACC, morphine. Anterior cingulate cortex morphine did not affect tactile allodynia (the von Frey test) or mechanical (Randall-Selitto) or thermal (Hargreaves) hyperalgesia in spinal nerve ligated rats. In contrary, RVM morphine reduced tactile allodynia and produced both antihyperalgesic and analgesic effects against mechanical and thermal stimuli as well as conditioned place preference selectively in nerve-injured rats. Within the RVM, opioids inhibit nociceptive transmission reflected in both withdrawal thresholds and affective pain behaviors. Activation of mu opioid receptors within specific rostral ACC circuits, however, selectively modulates affective dimensions of ongoing pain without altering withdrawal behaviors. These data suggest that RVM and ACC opioid circuits differentially modulate sensory and affective qualities of pain, allowing for optimal behaviors that promote escape and survival. Targeting specific ACC opioid circuits may allow for treatment of chronic pain while preserving the physiological function of acute pain.

What goes up must come down: insights from studies on descending controls acting on spinal pain processing

“…Evoked mechanical activity was lower in the rostral anterior cingulate cortex yet higher in the rostral ventromedial medulla (RVM) reflecting functional connectivity between these two areas. These areas are in concordance with a preclinical study on morphine actions on sensory and affective pain measures in rodents (Gomtsian et al 2018). Most importantly the patient study (Soni et al 2019) revealed, in keeping with the ideas of a recruitment of the RVM facilitatory (presumably 5HT3 mediated) system in chronic pains (see Bannister and Dickenson 2016a;Bee and Dickenson 2008), that preoperative neuropathic-like pain and higher neural activity in the RVM were associated with moderate-to-severe long-term pain after arthroplasty.…”

Single-cell transcriptomic evidence for dense intracortical neuropeptide networks

“…Cortical neuropeptide signaling may be one such corner. While profound impacts of neuropeptide signaling are well-established in a wide range of non-mammalian and sub-cortical neural structures (Borbély et al, 2013; Burbach, 2011; Elphick et al, 2018; Grimmelikhuijzen and Hauser, 2012; Katz and Lillvis, 2014; Jan et al, 1979) and there certainly is an excellent literature on cortical neuropeptide signaling (Crawley, 1985; Férézou et al, 2007; Gallopin et al, 2006; Gomtsian et al, 2018; Hamilton et al, 2013; Liu et al, 2018; Mena et al, 2013; Mitre et al, 2018; Owen et al, 2013; Rossier and Chapouthier, 1982; Williams and Zieglgänsberger, 1981), published physiological results are surprisingly rare given the breadth of neuroscientific interest in cortex. The new transcriptomic data analyzed here suggest a possible explanation for this relative rarity.…”

Single-Cell Transcriptomic Evidence for Dense Intracortical Neuropeptide Networks

“…Light from single-cell transcriptomics is now beginning to illuminate dark corners of cellular neuroscience 424 that have long resisted mechanistic and functional analysis (Fan et al, 2018;Fishell and Kepecs, 2019; may be one such corner. While profound impacts of neuropeptide signaling are well-established in a wide 428 range of non-mammalian and sub-cortical neural structures (Borbély et al, 2013;Burbach, 2011;Elphick 429 et al, 2018;Grimmelikhuijzen and Hauser, 2012;Katz and Lillvis, 2014;Kuffler et al, 1979) and there 430 certainly is an excellent literature on cortical neuropeptide signaling (Crawley, 1985;Férézou et al, 2007;431 Gallopin et al, 2006;Gomtsian et al, 2018;Hamilton et al, 2013;Liu et al, 2018;Mena et al, 2013;Mitre 432 et al, 2018;Owen et al, 2013;Rossier and Chapouthier, 1982;Williams and Zieglgänsberger, 1981), 433 published physiological results are surprisingly rare given the breadth of neuroscientific interest in cortex.…”