Suppression of Pain in the Late Phase of Chronic Trigeminal Neuropathic Pain Failed to Rescue the Decision-Making Deficits in Rats.

Suresh Kanna Murugappan,Heung Yan Wong,Li Xie,Zafar Iqbal,Ying Li,Zhuogui Lei,Aruna Surendran Ramkrishnan

doi:10.3390/ijms22157846

Suresh Kanna Murugappan, Heung Yan Wong + Show 5 more

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https://doi.org/10.3390/ijms22157846

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Abstract

Trigeminal neuropathic pain (TNP) led to vital cognitive functional deficits such as impaired decision-making abilities in a rat gambling task. Chronic TNP caused hypomyelination in the anterior cingulate cortex (ACC) associated with decreased synchronization between ACC spikes and basal lateral amygdala (BLA) theta oscillations. The aim of this study was to investigate the effect of pain suppression on cognitive impairment in the early or late phases of TNP. Blocking afferent signals with a tetrodotoxin (TTX)-ELVAX implanted immediately following nerve lesion suppressed the allodynia and rescued decision-making deficits. In contrast, the TTX used at a later phase could not suppress the allodynia nor rescue decision-making deficits. Intra-ACC administration of riluzole reduced the ACC neural sensitization but failed to restore ACC-BLA spike-field phase synchrony during the late stages of chronic neuropathic pain. Riluzole suppressed allodynia but failed to rescue the decision-making deficits during the late phase of TNP, suggesting that early pain relief is important for recovering from pain-related cognitive impairments. The functional disturbances in ACC neural circuitry may be relevant causes for the deficits in decision making in the chronic TNP state.

Highlights

Infraorbital nerve chronic constriction injury (ION-CCI) is a well-established chronic trigeminal neuropathic pain (TNP) injury animal model that produces prolonged mechanical allodynia and hyperalgesia, and is usually difficult to treat by analgesics and surgical intervention
By multiple-electrode array recordings in awake rats, we showed that chronic constriction injury (CCI)-induced alterations in the phase locking of anterior cingulate cortex (ACC) spikes to the phase of theta oscillations in the basal lateral amygdala (BLA) in the late phase of TNP, revealing decreased synchronization between ACC spikes and BLA theta oscillations [6]
Both infraorbital nerve (ION)-CCI and sham rats showed a decrease in body weight gain on day 4 following surgery, after which their body weight gain increased in a similar pattern for 30 days

Summary

Introduction

Infraorbital nerve chronic constriction injury (ION-CCI) is a well-established chronic trigeminal neuropathic pain (TNP) injury animal model that produces prolonged mechanical allodynia and hyperalgesia, and is usually difficult to treat by analgesics and surgical intervention. Cumulative evidence suggests that TNP affects cognitive functions, but little is known about the underlying mechanisms. An enhanced responsiveness of nociceptive neurons in the spinal trigeminal nucleus (SpV) to afferent input (i.e., central sensitization) has been well demonstrated [1,2,3]. FMRI studies have shown enhanced activation of the SpV, thalamus, and anterior cingulate cortex (ACC) in patients with TNP [4,5], suggesting dysfunction of the brainstem sensory components and higher brain emotional pain system. We provided direct electrophysiological evidence of synaptic changes in the SpV and higher brain regions in the TNP state [6]. We characterized that long-term enhancement of synaptic transmission occurs in the SpV after trigeminal nerve injury. Afferent hyperactivity is a critical contributor for development of synaptic plasticity within a few hours after nerve injury [7]

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