Background

Dynamic changes in neuronal activity and in noradrenergic locus coeruleus (LC) projections have been proposed during the transition from acute to chronic pain. Thus, the authors explored the cellular cFos activity of the LC and its projections in conjunction with spontaneous pain-like behavior in neuropathic rats.

Methods

Tyrosine hydroxylase:Cre and wild-type Long–Evans rats, males and females, were subjected to chronic constriction injury (CCI) for 2 (short-term, CCI-ST) or 30 days (long-term, CCI-LT), evaluating cFos and Fluoro-Gold expression in the LC, and its projections to the spinal cord (SC) and rostral anterior cingulate cortex (rACC). These tests were carried out under basal conditions (unstimulated) and after noxious mechanical stimulation. LC activity was evaluated through chemogenetic and pharmacologic approaches, as were its projections, in association with spontaneous pain-like behaviors.

Results

CCI-ST enhanced basal cFos expression in the LC and in its projection to the SC, which increased further after noxious stimulation. Similar basal activation was found in the neurons projecting to the rACC, although this was not modified by stimulation. Strong basal cFos expression was found in CCI-LT, specifically in the projection to the rACC, which was again not modified by stimulation. No cFos expression was found in the CCI-LT LCipsilateral (ipsi)/contralateral (contra)→SC. Chemogenetics showed that CCI-ST is associated with greater spontaneous pain-like behavior when the LCipsi is blocked, or by selectively blocking the LCipsi→SC projection. Activation of the LCipsi or LCipsi/contra→SC dampened pain-like behavior. Moreover, Designer Receptor Exclusively Activated by Designer Drugs (DREADDs)–mediated inactivation of the CCI-ST LCipsi→rACC or CCI-LT LCipsi/contra→rACC pathway, or intra-rACC antagonism of α-adrenoreceptors, also dampens pain-like behavior.

Conclusions

In the short term, activation of the LC after CCI attenuates spontaneous pain-like behaviors via projections to the SC while increasing nociception via projections to the rACC. In the long term, only the projections from the LC to the rACC contribute to modulate pain-like behaviors in this model.

Editor’s Perspective
What We Already Know about This Topic
  • Increasing evidence suggests the involvement of the noradrenergic locus coeruleus in the dynamic modulation of nociception
  • The role of neuronal projections from the locus coeruleus to the spinal cord and to the rostral anterior cingular cortex in the modulation of neuropathic pain over time is incompletely understood
What This Article Tells Us That Is New
  • In an experimental model of chronic constriction nerve injury in rats, a combination of genetic and histologic approaches revealed a biphasic time-dependent role for locus coeruleus neurons in modulating nociceptive responses
  • After 2 days of nerve injury, activation of locus coeruleus neurons projecting to spinal cord played a role in attenuating pain-like behavior while activation of locus coeruleus neurons projecting to the rostral anterior cingular cortex amplified nociceptive responses
  • After 30 days of nerve injury, only the projections from locus coeruleus neurons to the rostral anterior cingular cortex contributed to the modulation of pain-like behavior in this experimental model