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.
Highlights
The adage that “pain inhibits pain” is underpinned by diffuse noxious inhibitory controls (DNIC)—a descending pain modulatory mechanism, recruited by a distant noxious stimulus, that can suppress firing of convergent second‐order sensory neurones (Le Bars, Dickenson, & Besson, 1979)
Pre‐operative patients with low conditioned pain modulation (CPM) levels were at greater risk of developing chronic post‐operative pain (Wilder‐Smith, Schreyer, Scheffer, & Arendt‐Nielsen, 2010; Yarnitsky et al, 2008), consistent with animal data demonstrating that susceptibility to pain chronicity after nerve injury related to the ability to engage descending inhibitory pathways (De Felice et al, 2011; Xu, Kontinen, & Kalso, 1999)
We investigated whether the infralimbic (ILC) region of the medial prefrontal cortex forms part of DNIC circuitry in rats with functional DNIC, and in a model of neuropathy characterised by an absence of DNIC (Bannister, Lockwood, Goncalves, Patel, & Dickenson, 2017; Bannister et al, 2015)
Summary
The adage that “pain inhibits pain” is underpinned by diffuse noxious inhibitory controls (DNIC)—a descending pain modulatory mechanism, recruited by a distant noxious stimulus, that can suppress firing of convergent second‐order sensory neurones (Le Bars, Dickenson, & Besson, 1979). Drawing parallels with rodent studies, tapentadol restores absent DNIC in neuropathic rats (Bannister, Patel, Goncalves, Townson, & Dickenson, 2015), but fails to enhance functional DNIC in uninjured rats (Lockwood & Dickenson, 2019). DNIC is partly mediated via an opioidergic mechanism (Le Bars, Chitour, Kraus, Dickenson, & Besson, 1981), and opioidergic interneurones in the DRt receive projections from multiple cortical regions (Martins et al, 2015a). These interneurones might be recruited during DNIC, and we investigated this possibility by inhibiting with naloxone. We investigated whether the infralimbic (ILC) region of the medial prefrontal cortex (mPFC) forms part of DNIC circuitry in rats with functional DNIC, and in a model of neuropathy characterised by an absence of DNIC (Bannister, Lockwood, Goncalves, Patel, & Dickenson, 2017; Bannister et al, 2015)
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