Background & Aims
Adverse events during early-life are increasingly implicated as a risk factor for chronic pain development.(1) The maladaptive effects of stress on metabolism are well established.(2) Stress can disrupt critical metabolic processes and energy metabolism, resulting in metabolic, cardiovascular, and mental disorders including metabolic syndrome and type 2 diabetes.(2) We hypothesize that chronic early-life stress (CES) alters the metabolic profile of rats after peripheral nerve injury. Therefore, the purpose of this study is to conduct high-resolution metabolic and behavioral profiling over the 14-day period following chronic constriction injury (CCI) of the sciatic nerve, to determine the effects of CES on metabolic and behavioral outcomes. A comprehensive metabolic assessment of the impact of CES on CCI could lead to a deeper understanding of the mechanisms by which stress influences pain development.
Methods
Timed-pregnant Sprague Dawley rats delivered without intervention. From postnatal day (PND) 2-9, litters were assigned to an impoverished environment with limited bedding (CES group) or a standard cage (STD group).(3) On PND10, all litters were housed in standard cages. All adult offspring underwent CCI surgery of the sciatic nerve on PND45.(4) Rats were then housed individually in Promethion metabolic cages with wheels, indirect calorimetry systems designed to obtain accurate and comprehensive metabolic and behavioral data. Metabolic (i.e., food consumption, energy expenditure (EE), respiratory exchange ratio (RER)) and behavior (i.e. wheel usage, ambulation) data were collected continuously throughout the 14 day post-CCI period. Baseline and post-surgical mechanical sensitivities were assessed on days (D) 3, 7, 10 and 14 after CCI. We evaluate each outcome for the effects of sex.
Results
As expected, CES rats had greater mechanical sensitivity than STD offspring, with a ?41% decrease in paw withdrawal threshold (PWT). CCI decreased PWT by ?30% in all rats. CES males consumed less food compared to STD on D3 (19.85±2.09 vs 22.26±1.46, p<0.05) and D14 (25.75±3.46 vs 30.74±1.85, p<0.010). CES females consumed less food compared to STD only on D3 (16.45±1.09 vs 21.98±1.71, p<0.001). We found no differences in water consumption, weight or wheel running distances in males or females post-CCI. CES females ambulated more around the cage on D3 compared to STD (140±44 vs 81±4, p<0.05), but these distances did not differ on D14. CES males experienced a decrease in total EE (58.5±6.5 vs 71.3±5.6, p<0.01) and resting EE (1.7±0.2 vs 2±0.2, p<0.05) compared with STD males on D14. We found no differences in CES females in EE measures. CES females showed increased active RER compared to STD on D3 (0.95±0.003 vs 0.97±0.01, p<0.001). CES had no effect on resting RER in males or females.
Conclusions
Growing evidence supports increased pain sensitivities following CES in animal models of chronic pain. However, the effects of CES on spontaneous behaviors and metabolism are limited and provide inconsistent findings.(5-7) Here, we continuously measure animal movements, eating behaviors, and metabolism for 14 days after CCI in adult offspring from CES or STD groups. Overall, we found modest metabolic effects and differences in cage activity of CES on post-CCI recovery, indicating that CES did not have a fundamental impact on the metabolic response to peripheral nerve injury in males or females. However, our data provide key measures of metabolism following nerve injury and the development of chronic pain in males and female rats.
References
(1) Melchior M, Kuhn P, Poisbeau P. The burden of early life stress on the nociceptive system development and pain responses. Eur J Neurosci. 2022 May;55(9-10):2216-2241.
(2)Kivimäki M, Bartolomucci A, Kawachi I. The multiple roles of life stress in metabolic disorders. Nat Rev Endocrinol. 2023 Jan;19(1):10-27.
(3)Molet J, Maras PM, Avishai-Eliner S, Baram TZ. Naturalistic rodent models of chronic early-life stress. Dev Psychobiol. 2014;56(8):1675-1688.
(4)Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87-107.
(5)Kuti D, Winkler Z, Horváth K, Juhász B, Szilvásy-Szabó A, Fekete C, Ferenczi S, Kovács KJ. The metabolic stress response: Adaptation to acute-, repeated- and chronic challenges in mice. iScience. 2022 Jun 30;25(8):104693.
(6)Harris RB, Palmondon J, Leshin S, Flatt WP, Richard D. Chronic disruption of body weight but not of stress peptides or receptors in rats exposed to repeated restraint stress. Horm Behav. 2006 May;49(5):615-25.
(7)Sadler DG, Treas L, Sikes JD, Porter C. A modest change in housing temperature alters whole body energy expenditure and adipocyte thermogenic capacity in mice. Am J Physiol Endocrinol Metab. 2022 Dec 1;323(6):E517-E528.
Presenting Author
Kayleigh A. Rodriguez
Poster Authors
Kayleigh Rodriguez
BSc
University of Arkansas for Medical Sciences
Lead Author
Mary Grace Bishop
BA
Arkansas Children's Research Institute, University of Arkansas for Medical Sciences
Lead Author
Laura Osborn
University of Arkansas for Medical Sciences
Lead Author
Dakota Redling
BS
Arkansas Children's Research Institute, University of Arkansas for Medical Sciences
Lead Author
James Sikes
BS
Arkansas Children's Research Institute
Lead Author
Craig Porter
PhD
Arkansas Children's Research Institute, University of Arkansas for Medical Sciences
Lead Author
Kimberly Stephens
University of Arkansas for Medical Sciences
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Post-surgical/Post-traumatic Chronic Pain