Loss of cortical control over the descending pain modulatory system determines the development of the neuropathic pain state in rats

Abstract

The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemo-genetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.

Simultaneous Brain, Brainstem and Spinal Cord pharmacological-fMRI reveals endogenous opioid network interactions mediating attentional analgesia

“…This is similar to the previous finding from studies of placebo analgesia where naltrexone was shown to disrupt ACC-PAG communication which was also linked to the mediation of its analgesic effects (Eippert et al, 2009a). Activation of an analogous ACC-PAG pathway in rats has recently been shown to produce an analgesic effect mediated via an inhibition of activity at a spinal level indicating that it indeed represents a component of the descending analgesic system (Drake et al, 2021). Interestingly this study also found that this system failed in a chronic neuropathic pain model.…”

(2R,6R)-Hydroxynorketamine restores postsynaptic localization of AMPAR in the prelimbic cortex to provide sustained pain relief

“…Furthermore, such an effect is associated with reduced excitability of excitatory neurons in PrL, including the PAG-projecting neurons. These results provide a possible explanation for the impaired PrL-PAG connectivity detected in humans with chronic pain and animal models of chronic pain 32,33 . Our study establishes a new Bdnfdependent mechanism of central sensitization.…”

“…2). Such modulation enhances the PrL-vlPAG connectivity, which has been reported to be signi cantly suppressed in neuropathic pain 32 , leading to pain alleviation. Our study provides a molecular and neural circuit perspective for understanding the analgesic-like effects of R-HNK.…”

Indicators of central sensitization in chronic neuropathic pain after spinal cord injury

“…On the other hand, animal studies highlight the impact of decreased anti‐nociceptive mechanisms (Carlton et al, 2009), i.e. spinal disinhibition (Gwak et al, 2006; Zeilhofer, 2008) and loss of descending inhibition (Drake et al, 2021). In human research, the latter has been associated with the spatial extent of SCI‐NP (Gruener et al, 2016).…”