Engagement of descending inhibition from the rostral ventromedial medulla protects against chronic neuropathic pain

Abstract

A puzzling observation is why peripheral nerve injury results in chronic pain in some, but not all, patients. We explored potential mechanisms that may prevent the expression of chronic pain. Sprague Dawley (SD) or Holtzman (HZ) rats showed no differences in baseline sensory thresholds or responses to inflammatory stimuli. However, spinal nerve ligation (SNL)-induced tactile allodynia occurred in approximately 85% of SD and 50% of HZ rats, respectively. No apparent differences were observed in a survey of dorsal root ganglion or spinal neuropathic markers after SNL regardless of allodynic phenotype. SNL-induced allodynia was reversed by administration of lidocaine within the rostral ventromedial medulla (RVM), a site that integrates descending pain modulation via pain inhibitory (ie, OFF) and excitatory (ie, ON) cells. However, in SD or HZ rats with SNL but without allodynia, RVM lidocaine precipitated allodynia. Additionally, RVM lidocaine produced conditioned place preference in allodynic SD or HZ rats but conditioned place aversion in nonallodynic HZ rats. Similarly, RVM U69,593 (kappa opioid agonist) or blockade of spinal α(2) adrenergic receptors precipitated allodynia in previously nonallodynic HZ rats with SNL. All rats showed an equivalent first-phase formalin responses. However, HZ rats had reduced second-phase formalin behaviors along with fewer RVM OFF cell pauses and RVM ON cell bursts. Thus, expression of nerve injury-induced pain may ultimately depend on descending modulation. Engagement of descending inhibition protects in the transition from acute to chronic pain. These unexpected findings might provide a mechanistic explanation for medications that engage descending inhibition or mimic its consequences.

Figure 1

Baseline mechanical thresholds are not significantly different in SD and HZ rats. Following hindpaw CFA, similar magnitude and time course of decreased tactile (A) and noxious thermal (B) thresholds are observed in both strains.

Figure 2

A. Paw withdrawal thresholds of 783 SD rats were measured 10-14 days after SNL. Thresholds fell into a bimodal distribution, with 85% of SD rats indicating a low-threshold (allodynia) and 15% indicating a high-threshold (non-allodynic). B. Paw withdrawal thresholds of 185 HZ rats were measured 10-14 days after SNL. Thresholds fell into a bimodal distribution, with 51% of HZ rats indicating a low-threshold (allodynic) and 49% indicating a high-threshold (non-allodynic).

Figure 3

SD (A) or HZ (B) rats received RVM cannula 7 days prior to SNL or sham surgery. Non-allodynic SD or HZ rats received lidocaine (4% w/v; 0.5 μl) in the RVM producing a transient significant (p < 0.05) decrease in paw withdrawal thresholds indicating tactile allodynia. C. SD and HZ rats underwent conditioning to chambers that were paired to vehicle or lidocaine administered into the RVM. On day of testing, allodynic SD and HZ rats showed a preference (i.e., conditioned place preference) for the lidocaine-paired chamber, whereas the non-allodynic HZ rats showed aversion (i.e., conditioned place aversion) to the lidocaine-paired chamber. Sham-operated injected animals showed no differences from baseline. D. Data for CPP are shown as the difference in time spent in the lidocaine-paired chamber and vehicle-paired chamber.

Figure 4

A. HZ rats received sham surgery or SNL. SNL rats were separated into allodynic and non-allodynic groups and received U69593 (1 μg) into the RVM. Non-allodynic HZ rats demonstrated reversible significant (p < 0.05) decreases in paw withdrawal thresholds following RVM injection, indicating tactile allodynia. Allodynic and sham-operated HZ rats showed no changes from their baseline values. B. HZ rats received sham surgery or SNL. SNL rats were separated into allodynic and non-allodynic groups and received yohimbine (30 μg) intrathecally. Non-allodynic HZ rats demonstrated reversible significant (p < 0.05) decreases in paw withdrawal thresholds indicating tactile allodynia. Allodynic and sham-operated HZ rats showed no changes from their baseline values.

Figure 5

C-fiber drive differentially modulates RVM ON and OFF cell activity between SD and HZ rats. A. Behavioral responses to formalin injection into the hindpaw are shown. HZ rats showed a significant decrease in 2^nd phase behaviors compared to SD rats. The total number of OFF cell pauses (B) and ON cell bursts (C) lasting for more than 10 sec following the initial burst and pause from formalin injection were significantly decreased in HZ rats compared to SD rats. Representative ratemeters for SD ON cells (D), HZ ON cells (E), SD OFF cells (F) and HZ OFF cells (G) demonstrate differences in RVM neuron responses to formalin injection. Small arrows indicate time of thermal stimulation of the tail paired to tail flick and RVM neuron responses. Large arrows indicate formalin injection. ** p<0.01, *** p<0.001.