A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

Abstract

Diffuse noxious inhibitory controls (DNIC) are a mechanism of endogenous descending pain modulation and are deficient in a large proportion of chronic pain patients. However, the pathways involved remain only partially determined with several cortical and brainstem structures implicated. This study examined the role of the dorsal reticular nucleus (DRt) and infralimbic (ILC) region of the medial prefrontal cortex in DNIC. In vivo electrophysiology was performed to record from dorsal horn lamina V/VI wide dynamic range neurones with left hind paw receptive fields in anaesthetised sham‐operated and L5/L6 spinal nerve‐ligated (SNL) rats. Evoked neuronal responses were quantified in the presence and absence of a conditioning stimulus (left ear clamp). In sham rats, DNIC were reproducibly recruited by a heterotopically applied conditioning stimulus, an effect that was absent in neuropathic rats. Intra‐DRt naloxone had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. In addition, intra‐DRt naloxone blocked DNIC in sham rats, but had no effect in SNL rats. Intra‐ILC lidocaine had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. However, differential effects were observed in relation to the expression of DNIC; intra‐ILC lidocaine blocked activation of DNIC in sham rats but restored DNIC in SNL rats. These data suggest that the ILC is not directly involved in mediating DNIC but can modulate its activation and that DRt involvement in DNIC requires opioidergic signalling.

Developments in Understanding Diffuse Noxious Inhibitory Controls: Pharmacological Evidence from Pre-Clinical Research

“…For instance, systemic administration of naloxone abolishes DNIC 31,32 and DCN 14,15,30,33 expression in naïve rats. This recapitulates the involvement of opioidergic mechanisms from the DRt or MdD where naloxone also abolished DNIC expression, 24,30 but not those from the RVM, where DNIC were not affected by microinjected naloxone. 30 However, it is still unclear if the systemic effect of naloxone is mediated by other cerebral, spinal (or possibly) joint mechanisms, as the drug is distributed throughout the body within minutes.…”

“…For instance, naloxone dosed in the medullary reticularis dorsalis nucleus (MdD) abolished DCN in rats with muscle inflammation, 30 and so did its injection in the dorsal reticular nucleus (DRt). 24 Intriguingly, in neuropathic animals lacking DNIC expression, microinjection of naloxone to the DRt restored DNIC. 24 These studies advocate for the complexity of interactions for pharmacological systems in terms of the functionality of DNIC pathways.…”

“…24 Intriguingly, in neuropathic animals lacking DNIC expression, microinjection of naloxone to the DRt restored DNIC. 24 These studies advocate for the complexity of interactions for pharmacological systems in terms of the functionality of DNIC pathways.…”

“…Regarding higher brain centres, Patel and Dickenson previously reported that lidocaine inhibition of the infralimbic (ILC) region of the medial prefrontal cortex abolishes DNIC expression in healthy rats, while restoring DNIC expression in SNL animals. 24 Focusing on the mesencephalon, morphine injected in the medioventral periaqueductal grey (MV-PAG) abolished DNIC expression in healthy animals. 25 Previously, Phelps et al demonstrated that microinjection of norbinaltorphimine (nor-BNI), a κ-opioid receptor (KOR) antagonist, into the right central nucleus of amygdala (RCeA) restored DCN and DNIC expression in neuropathic animals.…”

Conditioned pain modulation affects the N2/P2 complex but not the N1 wave: A pilot study with laser‐evoked potentials

“…Although CPM is not influenced by stimuli location, it seems to be better evaluated by heterotopic nociceptive conditioning stimulation (HNCS) in which the stimuli are applied to two separate and remote body areas (Klyne et al., 2015). CPM/DNIC likely reflects the net balance between descending inhibitory and facilitatory signalling (Patel & Dickenson, 2020). There is a spino‐bulbo‐spinal loop involving brainstem structures (Bouhassira et al., 1992; Le Bars et al., 1981) that inhibits pain transmission at the spinal cord dorsal horn (Le Bars et al., 1979).…”