Treadmill running and static stretching improve long-lasting hyperalgesia, joint limitation, and muscle atrophy induced by cast immobilization in rats

doi:10.1016/j.neulet.2012.11.009

Neuroscience Letters

Volume 534, 8 February 2013, Pages 295-300

https://doi.org/10.1016/j.neulet.2012.11.009 Get rights and content

Abstract

The effects of exercise on chronic pain induced by immobilization are incompletely understood. The purpose of this study was to investigate whether 30 min of treadmill running (TR; active exercise) and 10 min of static stretching (SS; passive exercise) of the immobilized hindlimb reduce widespread chronic pain, joint limitation, and hindlimb muscle atrophy induced by cast immobilization in rats. One hindlimb of Sprague Dawley (SD) rats was immobilized for 2 weeks with a cast, and remobilization was conducted for 7 weeks. MRI study showed that cast immobilization had induced inflammatory changes in the immobilized hindlimb, beginning as early as 2 h after cast removal; these changes continued for 2–3 days. Mechanical hyperalgesia in the calf and hindpaw developed as early as 2 h after cast removal and continued for 7 weeks. TR and SS were initiated 3 days after cast removal and were continued 3 times per week for 2 weeks. Both forms of exercise significantly inhibited mechanical hyperalgesia in the calf and hindpaw in immobilized rats. Range-of-motion limitations in the knee and ankle joints and calf muscle atrophy after cast removal were also decreased by both TR and SS. This study is the first to demonstrate the beneficial effect of TR and SS on widespread chronic pain, joint limitation, and muscle atrophy in a cast-immobilized rat model.

Highlights

► Two-week cast immobilization induced chronic hyperalgesia in the hindlimb of rats. ► The cast immobilization also induced joint limitation and calf muscle atrophy. ► Treadmill running and static stretching after cast removal counteracted these changes.

Introduction

It has been postulated that physical immobilization is one of the main contributors to long-lasting pain after trauma or surgery in an extremity [6], [20]. However, the mechanisms of sustained immobilization-induced chronic pain remain poorly understood. We have demonstrated that rats exposed to 2-week cast immobilization of 1 hindlimb exhibit local inflammatory changes and spontaneous pain in the immobilized hindlimb as well as long-lasting mechanical hyperalgesia in both the immobilized and contralateral hindlimbs (chronic post-cast pain; CPCP) [14]. In another study, we demonstrated that cast immobilization-induced ischemia/reperfusion injury with production of oxygen free radicals in the immobilized hindlimb leads to astrocyte activation in the bilateral spinal dorsal horn and, as a result, widespread hyperalgesia in rats with CPCP [13].

Exercise therapy is an effective treatment and the most widely used type of conservative treatment for various chronic pain in humans [7], [8], [21]. Exercise therapy includes two modalities: active (i.e., aerobic, muscle strengthening, and stabilizing exercises) and passive (i.e., stretching, manual therapy, and mobilization). Recent animal studies have reported that active aerobic exercise decreases neuropathic pain [3], [4], [9], [19] and musculoskeletal pain after muscle injury [1]. It has also been suggested that changes in central nervous system neurotransmitters and neuromodulators, such as endogenous opioids, are involved in the mechanism of exercise effects [11]. However, no concrete evidence exists for the effects of exercise on hyperalgesia after physical immobilization. The present study, therefore, aims to investigate the effects of treadmill running as active exercise on long-lasting mechanical hyperalgesia in CPCP rats. Passive exercise is also used to improve joint range of motion and muscle flexibility and to relieve musculoskeletal pain in humans. Thus, the second purpose of this study is to test effects of static stretching (i.e., passive exercise) on long-lasting mechanical hyperalgesia in rats with CPCP.

Parts of this study were presented in abstract form at the 14th World Congress of Pain, Milan, 2012 [23].

Section snippets

Animals

All experiments were conducted with the approval of the Animal Care Committee of Aichi Medical University and in accordance with the guidelines of the International Association for the Study of Pain for pain research in animals. Male Sprague Dawley rats (300–360 g, Japan SLC, Japan) were housed in standard transparent plastic cages (2–3 per cage) lined with sawdust under a 12/12-h light/dark cycle with free access to food and water. We attest that all efforts were made to minimize both the

MRI changes after cast removal

Fig. 1 illustrates the characteristic MRI patterns of both the immobilized and contralateral hindlimbs after cast removal. T2WI (A) and T1WI with Gd enhancement (C) showed dense hyperintensity in the calf skin (arrowheads) and interstitial region surrounding blood vessels (arrows) in the immobilized hindlimb. These high signals in the calf skin were observed 2 h after and 1 day after cast removal. In the interstitial region surrounding blood vessels, high signals appeared just after cast removal

Discussion

The present results are consistent with our recent observation that rats exposed to 2-week cast immobilization of the hindlimb exhibited local inflammatory changes, muscle atrophy, and long-lasting mechanical hyperalgesia in the immobilized hindlimb [14]. The present study further demonstrates that both TR (active exercise) and SS (passive exercise), which were conducted after muscle edema had subsided, reduced mechanical hyperalgesia in the calf, ROM limitation in the knee and ankle joints,

Conflict of interest statement

None of the authors have any conflicts of interest to declare.

Acknowledgments

We thank Drs. Hiroyuki Mizoguchi, Mariko Itoh (RIEM and Technical Center, Nagoya University, Aichi, Japan), and Kazuo Morio (Department of Radiology, Kochi University, Kochi, Japan) for providing technical assistance.

References (23)

M.K. Bement et al.
Low-intensity exercise reverses chronic muscle pain in the rat in a naloxone-dependent manner
Archives of Physical Medicine and Rehabilitation
(2005)
S.R. Chaplan et al.
Quantitative assessment of tactile allodynia in the rat paw
Journal of Neuroscience Methods
(1994)
S. Cobianchi et al.
Short- but not long-lasting treadmill running reduces allodynia and improves functional recovery after peripheral nerve injury
Neuroscience
(2010)
T.Z. Guo et al.
Substance P signaling contributes to the vascular and nociceptive abnormalities observed in a tibial fracture rat model of complex regional pain syndrome type I
Pain
(2004)
S. Ikeda et al.
Repetitive stretch induces c-fos and myogenin mRNA within several hours in skeletal muscle removed from rats
Archives of Physical Medicine and Rehabilitation
(2003)
M.J. Millan
Descending control of pain
Progress in Neurobiology
(2002)
A. Pertovaara
Noradrenergic pain modulation
Progress in Neurobiology
(2006)
D.A. Skyba et al.
Joint manipulation reduces hyperalgesia by activation of monoamine receptors but not opioid or GABA receptors in the spinal cord
Pain
(2003)
B. Vicenzino et al.
The initial effects of a cervical spine manipulative physiotherapy treatment on the pain and dysfunction of lateral epicondylalgia
Pain
(1996)
Y.W. Chen et al.
Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve
Anesthesia and Analgesia
(2012)

S. Golbidi et al.

Antioxidant and anti-inflammatory effects of exercise in diabetic patients

Experimental Diabetes Research

(2012)

Cited by (24)

Static stretching of the ankle prevents cold hypersensitivity associated with limb immobilization in model mice
2023, Journal of Orthopaedic Science
Limb immobilization is considered to contribute to limb pain including hyperalgesia. Approximately 50% of patients with such chronic limb pain complain that their abnormal pain worsens after exposure to cold. However, there have been few studies on the relationship between limb immobilization and cold hypersensitivity. The aim of this study was to examine whether limb immobilization induces cold hypersensitivity, and whether physical exercise such as ankle stretching prevents its induction in model mice.
We used forty-four 8-week-old male C57Bl/6J mice, consisting of 32 immobilized mice and 12 control mice. The bilateral hind limbs of the mice were immobilized by a thermoplastic cast. After limb-immobilization for 1 week, changes in mechanical, thermal and cold hypersensitivity, and the expression levels of TRPV1, TRPA1, TRPM8, IL-1β, IL-6, and TNFα in the spinal cord, dorsal root ganglia and the affected hind paw were evaluated in comparison with those in the control mice. In addition, we examined the effect of ankle stretching on the hypersensitivity and expression levels in the limb-immobilized mice.
Mechanical, thermal and cold hypersensitivity were significantly increased in the limb-immobilized mice. In addition, ankle stretching during the immobilization period significantly prevented the increases in those hypersensitivities. There were no significant differences in the expression levels of TRPV1, TRPA1 and TRPM8 among the control, and limb-immobilized mice with and without ankle stretching. The expression levels of IL-1 and IL-6 were significantly increased in the immobilized hind limb paw. Furthermore, ankle stretching significantly prevented the increases in their expression levels.
Limb-immobilization induced cold hypersensitivity as well as mechanical and thermal hypersensitivity, and ankle stretching significantly prevented the hypersensitivity induction in the model mice. It would be of great interest to clarify whether a patient with limb-immobilization experiences cold hypersensitivity and whether ankle stretching might prevent hypersensitivity induction in the future.
Conflicting time-dependent effects of treadmill exercise on joint contracture after anterior cruciate ligament reconstruction in rats
2022, Tissue and Cell
Citation Excerpt :
Moreover, the ROM before myotomy in the ACLR + EX group recovered to the levels seen in the ACLR + SED group at four weeks post-surgery, although it was significantly smaller than the ACLR + SED group at two weeks post-surgery. Previous studies reported that treadmill exercise after joint immobilization facilitates ROM recovery before myotomy in rat knee and ankle joints (Morimoto et al., 2013; Sakakima et al., 2004). After ACL reconstruction, treadmill exercise performed during the residual arthrofibrosis phase will positively affect both myogenic and arthrogenic contracture.
We examined the time-dependent differences in the effects of treadmill exercise on joint contracture after anterior cruciate ligament (ACL) reconstruction. Rats received ACL reconstructive surgery. After surgery, rats were reared with or without treadmill exercise (60 min/day) starting at 3 days (when inflammatory reactions are active) or 14 days (when inflammatory reactions have subsided) post-surgery. Untreated rats were used as controls. Data were collected at two or four weeks post-surgery. The range of motion (ROM) decreased following surgery at both time points and treadmill exercise during the first two weeks post-surgery further decreased the ROM. Moreover, treadmill exercise during first two weeks post-surgery upregulated the pro-inflammatory cytokine interleukin-1β gene in the joint capsule and aggravated joint capsule fibrosis. For exercise started at 14 days post-surgery, the ROM recovered to control levels at four weeks post-surgery. In addition, delayed exercise contributed to resolving inflammatory and fibrotic reactions. Treadmill exercise initiated soon after surgery aggravates joint contracture via enhanced inflammatory and fibrotic reactions in the joint capsule. Conversely, exercise initiated after active inflammation has subsided facilitates joint capsule reorganization and increases joint ROM. Therefore, aggressive exercise should be started only after active inflammation is resolved to improve joint contracture following ACL reconstruction.
Suppression of TGF-beta activity with remobilization attenuates immobilization-induced joint contracture in rats
2021, Injury
Citation Excerpt :
However, it is still controversial whether passive movements are effective in the rehabilitation process of joint contracture [43,44]. In contrast to passive joint movement, recent research showed that spontaneous active movement of joints during remobilization may have beneficial effects on immobilization-induced joint contracture [45,46]. In the present study, we found that joint extension ROM was partially recovered after remobilization compared to the immobilized group, indicating that active motion could moderately relieve the limited joint ROM.
Joint contracture is a common complication of joint injury. This study aimed to assess the effect of inhibiting the transforming growth factor-β (TGF-β) signaling during joint immobilization and remobilization on immobilization-induced joint contracture in rats.
The knees of rats were immobilized using Kirschner wires following trauma to the femoral condyles to generate joint contracture. After immobilization, levels of TGF-β and passive extension range of motion (ROM) were measured at different time points, joints were histologically analyzed by hematoxylin and eosin (H&E) and Masson trichrome staining, and the expression of inflammatory or fibrosis-related mediators, including interleukin-1β (IL-1β), phosphorylated Smad2/3 (p-Smad2/3), α-smooth muscle actin (α-SMA) and collagen types I (Col 1) and III (Col 3), were examined in joint capsules using immunohistochemistry and quantitative real‐time polymerase chain reaction (qRT-PCR). Rats were also treated with LY2157299, a TGF-β receptor I kinase inhibitor, at different stages of immobilization and remobilization.
TGF-β1 levels in the serum and the number of p-Smad2/3⁺ cells in the joint capsule were significantly elevated after immobilization. ROM decreased during the 6 weeks of immobilization and partly recovered after remobilization. After treatment with LY2157299 during immobilization, the restricted ROM moderately increased, but this effect was stronger when combined with active motion. Mechanistically, the expression of IL-1β, TGF-β, fibrosis-related factors, and the density of collagen significantly decreased after treatment with LY2157299.
Inhibiting TGF-β signaling paired with active motion effectively attenuated the formation of immobilization-induced joint contracture in rats.
Modest Amounts of Voluntary Exercise Reduce Pain- and Stress-Related Outcomes in a Rat Model of Persistent Hind Limb Inflammation
2017, Journal of Pain
Citation Excerpt :
Although sedentary inflamed rats experienced ongoing deficits in weight-bearing over the 3-week period, inflamed rats engaging in voluntary running exhibited a steady improvement in weight-bearing capacity of the ipsilateral paw, achieving basal levels by 3 weeks post-CFA. In studies using forced exercise paradigms, although not all groups describe complete exercise-induced reversal of hypersensitivity to von Frey stimulation, most produce progressive improvements over spans of a few days to more than 5 weeks.9,11,18-24,35,54,63,69,82,93,102,103,112,132 Strikingly, development of the CFA-induced thermal hypersensitivity observed in the sedentary inflamed group was prevented by only 1 week of voluntary running.
Aerobic exercise improves outcomes in a variety of chronic health conditions, yet the support for exercise-induced effects on chronic pain in humans is mixed. Although many rodent studies have examined the effects of exercise on persistent hypersensitivity, the most used forced exercise paradigms that are known to be highly stressful. Because stress can also produce analgesic effects, we studied how voluntary exercise, known to reduce stress in healthy subjects, alters hypersensitivity, stress, and swelling in a rat model of persistent hind paw inflammation. Our data indicate that voluntary exercise rapidly and effectively reduces hypersensitivity as well as stress-related outcomes without altering swelling. Moreover, the level of exercise is unrelated to the analgesic and stress-reducing effects, suggesting that even modest amounts of exercise may impart significant benefit in persistent inflammatory pain states.
Modest levels of voluntary exercise reduce pain- and stress-related outcomes in a rat model of persistent inflammatory pain, independently of the amount of exercise. As such, consistent, self-regulated activity levels may be more relevant to health improvement in persistent pain states than standardized exercise goals.
Sensorial, structural and functional response of rats subjected to hind limb immobilization
2015, Life Sciences
Citation Excerpt :
These changes may explain the diminished sensorial response in the disuse animals stimulated with Von Frey filaments, involving major axon fibers, or the augmented animals' response to painful thermal stimulus, which involves minor fibers. The literature also shows an increased pain reaction in disuse models using nerve injury [7] and cast immobilization [17]. In addition, an increased neuronal excitability was demonstrated in immobilized skeletal muscle [1], which could also support the hyperresponsiveness to thermal stimuli observed in this investigation.
This study analyzed the sensorial, structural and functional response of rats subjected to paw immobilization.
Animal pelvis, hip, knee and ankle were immobilized using waterproof tape during two weeks for assessment of sensorial response to thermal (hot plate test) and mechanical stimuli (Von Frey test), motor system structure (histology and radiography) and muscle function (soleus contractility).
Disuse animals became more responsive to thermal stimuli (49%), although less responsive to mechanical challenge (58%). Disuse animals showed local injuries such as reduction in muscle fiber diameter (16.7% in gastrocnemius, 5.7% in soleus), contractile activity (55% of the control maximal tonic contraction) and tibia cortical thickness (9.3%), besides increased nitrite:protein ratio, suggestive of protein degradation. Disuse also evoked systemic adaptations that include increase in serum lactate dehydrogenase (36.1%) and alkaline phosphatase (400%), but reduction in calcium (8.4%) and total serum protein (5.5%), especially albumin (34.2%).
Two weeks of functional paw disuse leads to local and systemic harmful adaptive changes in sensorial and structural systems. This study brings new insights into nervous and motor system mechanism associated with therapeutic limb immobilization in muscle and skeletal pathological conditions.
Regular Low-Intensity Exercise Prevents Cognitive Decline and a Depressive-Like State Induced by Physical Inactivity in Mice: A New Physical Inactivity Experiment Model
2022, Frontiers in Behavioral Neuroscience

View all citing articles on Scopus

¹: These authors contributed equally to this work.

View full text

Treadmill running and static stretching improve long-lasting hyperalgesia, joint limitation, and muscle atrophy induced by cast immobilization in rats

Abstract

Highlights

Introduction

Section snippets

Animals

MRI changes after cast removal

Discussion

Conflict of interest statement

Acknowledgments

Archives of Physical Medicine and Rehabilitation

Journal of Neuroscience Methods

Neuroscience

Pain

Archives of Physical Medicine and Rehabilitation

Progress in Neurobiology

Progress in Neurobiology

Pain

Pain

Exercise training attenuates neuropathic pain and cytokine expression after chronic constriction injury of rat sciatic nerve

Anesthesia and Analgesia

Antioxidant and anti-inflammatory effects of exercise in diabetic patients

Experimental Diabetes Research