Individual Differences in Acute Pain-induced Endogenous Analgesia Predict Time to Resolution of Postoperative Pain in the Rat

Abstract

Background Chronic post-surgical pain (CPSP), a significant public health problem, occurs in 10-50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of CPSP. The relationship between CPM and recovery from surgery has not been examined in preclinical models. Methods CPM was assessed in individual rats and correlated with each animal’s time course of recovery of hypersensitivity following partial spinal nerve ligation (pSNL). The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine β hydroxylase conjugated saporin (DβH-saporin) to ablate these pathways. Behavioral hypersensitivity, static weight bearing and spinal glial activation were measured after pSNL. Results The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001, r = 0.660). CPM induced release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or DβH-saporin. DβH-saporin also slowed recovery and enhanced spinal glial activation following pSNL surgery. Ongoing activation of these pathways was critical to sustained recovery, since intrathecal DβH-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery. Conclusions Collectively, these studies provide a clear back-translation from clinical observations of CPM and CPSP and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

Pupil responses and pain ratings to heat stimuli: Reliability and effects of expectations and a conditioning pain stimulus

“…We anticipated, but did not observe, that the conditioning stimulus would induce increased LC activity as measured by increased pupil diameter and that this increased activity would result in release of norepinephrine in the spinal cord causing analgesia and correlating with the strength of CPM on pain report (Peters et al, 2015). This was not observed and, in contrast to this hypothesis, the resting pupil diameter just prior to the test stimulus while the foot was in the water correlated negatively with the strength of CPM.…”

“…As such, we explored in the current study the potential moderation of PDR on changes in pain report during cued learning of pain intensity and in potential surprise when a signal tied to pain intensity is false. Finally, conditioned pain modulation (CPM), wherein a continuous noxious stimulus produces heterotopic analgesia to another noxious test stimulus, is due in part to activation of LC projections to the spinal cord in rodents (Peters et al, 2015), and we explored whether changes in pupil diameter and PDR correlated with the strength of CPM.…”

Disruption of Spinal Noradrenergic Activation Delays Recovery of Acute Incision-Induced Hypersensitivity and Increases Spinal Glial Activation in the Rat

“…Clinical studies have measured individual endogenous analgesia triggered by a painful stimulus using conditioned pain modulation (CPM) and show that a weak CPM response preoperatively correlates with a greater incidence of persistence of pain for months or years following thoracotomy 65 and abdominal surgery 61 . We recently demonstrated that descending spinal noradrenergic activity is an important component of CPM and also important to speed of resolution of mechanical hypersensitivity following partial nerve injury in rats 44 . However, this model may not be predictive of recovery from surgery that does not involve injury to major peripheral nerves, as chronic pain can develop in patients in the absence of obvious signs of nerve injury.…”

Reporting of Preclinical Research in Anesthesiology

“…However, the need for these procedures is underscored by changes in animal behavior due to seasonal changes in the source of the protein in commercial animal chow 9 and large inter-individual animal variability in behaviors prior to and after surgery. 10 Additionally, we now know that environmental influences can alter subsequent biology and physiology via epigenetic and other mechanisms, despite presumed identical genomes. Similarly, experimenter blinding is essential whenever possible given that unintentional experimenter bias can influence measurements as evidenced by the fact that effect sizes of interventions are lower in studies when blinding is performed.…”