Involvement of brain opioid receptors in the anti-allodynic effect of hyperbaric oxygen in rats with sciatic nerve crush-induced neuropathic pain

doi:10.1016/j.brainres.2013.08.050

Brain Research

Volume 1537, 6 November 2013, Pages 111-116

https://doi.org/10.1016/j.brainres.2013.08.050 Get rights and content

Highlights

•
Sciatic nerve crush produces a state of allodynia that lasts for up to 29 days after the procedure.
•
HBO₂ treatment seven days after nerve crush produces an antiallodynic effect.
•
Implantation of an Alzet^® osmotic minipump releasing 1.0 μg/h of naltrexone reversed the HBO₂-induced antiallodynia.

Abstract

Earlier research has demonstrated that hyperbaric oxygen (HBO₂) can produce an antinociceptive effect in models of acute pain. Recent studies have revealed that HBO₂ can produce pain relief in animal models of chronic pain as well. The purpose of the present investigation was to ascertain whether HBO₂ treatment might suppress allodynia in rats with neuropathic pain and whether this effect might be blocked by the opioid antagonist naltrexone (NTX). Male Sprague Dawley rats were subjected to a sciatic nerve crush under anesthesia and mechanical thresholds were assessed using an electronic von Frey anesthesiometer. The time course of the HBO₂-induced anti-allodynic effect in different treatment groups was plotted, and the area-under-the-curve (AUC) was determined for each group. Seven days after the nerve crush procedure, rats were treated with HBO₂ at 3.5 atm absolute (ATA) for 60 min and exhibited an anti-allodynic effect, compared to nerve crush-only control rats. Twenty-four hours before HBO₂ treatment, another group of rats was implanted with Alzet^® osmotic minipumps that continuously released NTX into the lateral cerebral ventricle for 7 days. These NTX-infused, HBO₂-treated rats exhibited an allodynic response comparable to that exhibited by rats receiving nerve crush only. Analysis of the AUC data showed that HBO₂ significantly reduced the nerve crush-induced allodynia; this anti-allodynic effect of HBO₂ was reversed by NTX. These results implicate opioid receptors in the pain relief induced by HBO₂.

Introduction

Inadequate management of pain may result in poor clinical outcomes and reduced quality of life for the patient. Effective treatment of chronic pain, in particular, presents a challenge to modern medicine. Pain relief is not an approved clinical indication of HBO₂ treatment (Gesell, 2008). Nonetheless, there is evidence that hyperbaric oxygen (HBO₂) treatment can mitigate both acute and chronic pain. There are observations in the literature that HBO₂ treatment can reduce pain in clinical patients who are afflicted with various chronic pains, including complex regional pain syndrome (CRPS) (Peach, 1995, Tuter et al., 1997, Kiralp et al., 2004), idiopathic trigeminal neuralgia (Gu et al., 2012), fibromyalgia (Yildiz et al., 2004), migraine (Wilson et al., 1998), cluster headache (Di Sabato et al., 1993) and other painful conditions (Dall'Era et al., 2006, Jones et al., 2006, Handschel et al., 2007).

Experimentally, HBO₂ treatment can reduce allodynia in rats with peripheral nerve injuries (Thompson et al., 2010, Li et al., 2011, Gu et al., 2012, Zhang et al., 2012) and experimental arthritis (Warren et al., 1979, Wilson et al., 2006, Wilson et al., 2007). Research from our laboratory demonstrated that HBO₂ treatment effectively reduced pain in animal models of acute pain (Ohgami et al., 2009, Zelinski et al., 2009a, Chung et al., 2010, Quock et al., 2011). Our results from these experiments show that HBO₂-induced antinociception is significantly attenuated by the opioid antagonist naltrexone (NTX). Hence, we concluded that HBO₂ treatment might lead to activation of central opioid receptors that can modulate pain.

The purpose of the present investigation was to determine whether the pain-relieving effect of HBO₂ treatment in chronic pain might also involve a central opioid pain-relieving mechanism.

Section snippets

Time course of the mechanical threshold

Fig. 1 compares the time course of the normalized mechanical thresholds in different treatment groups: control; nerve crush (NC) alone; nerve crush followed seven days later by a 60-min HBO₂ treatment at 3.5 atm absolute (ATA) (NC+HBO₂); nerve crush followed six days later by implantation of a continuously-releasing NTX osmotic minipump and, on the seventh day, by a 60-min HBO₂ treatment at 3.5 ATA (NC+NTX+HBO₂).

Mechanical thresholds temporarily increased in all three NC groups following the

Discussion

There are reports that HBO₂ treatment effectively relieved neuropathic pain in rats with peripheral nerve injury. Thompson et al. (2010) demonstrated that HBO₂ treatment could cause antinociception in two rat models of neuropathic pain, ligation of the L5 spinal nerve and chronic constriction injury (CCI) of the sciatic nerve. Rats were treated for 90 min with HBO₂ at 2.4 ATA daily for 14 consecutive days. HBO₂ treatment clearly improved mechanical thresholds (i.e., less hypersensitivity during

Conclusion

HBO₂ treatment causes an anti-allodynic effect in rats with sciatic nerve crush-induced neuropathic pain. The reversal of the anti-allodynic effect by centrally-administered NTX suggests that brain opioid mechanisms may be involved in the relief of neuropathic pain induced by HBO₂.

Animals

Male S/A albino rats, 160–180 g, were purchased from Simonsen Laboratories (Gilroy, CA) and used in this research. Experiments were approved by the Washington State University Institutional Animal Care and Use Committee (IACUC) with post-approval review and carried out in accordance with The Guide for the Care and Use of Laboratory Animals, 8th Edition (National Academies Press, Washington, DC, 2010). All measures to minimize pain or discomfort were taken by the investigators, including

Acknowledgments

This research was supported by NIH Grants GM-77153 and AT-007222 and the Allen I. White Distinguished Professorship from Washington State University.

References (36)

E. Chung et al.
Hyperbaric oxygen treatment induces a 2-phase antinociceptive response of unusually long duration in mice
J. Pain
(2010)
M.A. Dall'Era et al.
Hyperbaric oxygen therapy for radiation induced proctopathy in men treated for prostate cancer
J. Urol.
(2006)
F. Di Sabato et al.
Hyperbaric oxygen therapy in cluster headache
Pain
(1993)
A. George et al.
Wallerian degeneration after crush injury of rat sciatic nerve increases endo- and epineurial tumor necrosis factor alpha protein
Neurosci. Lett.
(2004)
A. George et al.
Thalidomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha, increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin
Pain
(2000)
S. Hara et al.
Effect of opioid peptide antisera on nitrous oxide antinociception in rats
Pharmacol. Biochem. Behav.
(1994)
M.M. Heinricher et al.
Descending control of nociception: specificity, recruitment and plasticity
Brain Res. Rev.
(2009)
K. Jones et al.
Treatment of radiation proctitis with hyperbaric oxygen
Radiother. Oncol.
(2006)
Y. Ohgami et al.
Nitrous oxide-induced NO-dependent neuronal release of β-endorphin from the rat arcuate nucleus and periaqueductal gray
Brain Res.
(2010)
Y. Ohgami et al.
Influence of hyperbaric oxygen on regional brain levels and spinal cord levels of nitric oxide metabolites in rat
Brain Res. Bull.
(2008)

P.S. Portoghese et al.

Binaltorphimine and nor-binaltorphimine, potent and selective kappa-opioid receptor antagonists

Life Sci.

(1987)

L.P. Quock et al.

The acute antinociceptive effect of HBO₂ is mediated by a NO-cyclic GMP-PKG-K_ATP channel pathway in mice

Brain Res.

(2011)

G. Sümen et al.

Hyperbaric oxygen treatment reduces carrageenan-induced acute inflammation in rats

Eur. J. Pharmacol.

(2001)

C.D. Thompson et al.

Hyperbaric oxygen treatment decreases pain in two nerve injury models

Neurosci. Res.

(2010)

H.D. Wilson et al.

Hyperbaric oxygen treatment is comparable to acetylsalicylic acid treatment in an animal model of arthritis

J. Pain

(2007)

H.D. Wilson et al.

Hyperbaric oxygen treatment decreases inflammation and mechanical hypersensitivity in an animal model of inflammatory pain

Brain Res.

(2006)

L.M. Zelinski et al.

A prolonged NO-dependent, opioid-mediated antinociceptive effect of hyperbaric oxygen in mice

J. Pain

(2009)

L.M. Zelinski et al.

Exposure to nitrous oxide stimulates a nitric oxide-dependent neuronal release of β-endorphin in ventricular cisternally-perfused rats

Brain Res.

(2009)

Cited by (31)

Hyperbaric oxygen produces a nitric oxide synthase-regulated anti-allodynic effect in rats with paclitaxel-induced neuropathic pain
2019, Brain Research
Citation Excerpt :
Preclinical studies have shown that HBO2 is efficacious in rodent models of neuropathic pain. HBO2 treatment ameliorated allodynia in rats with chronic constriction injury (CCI) (Thompson et al., 2010; Li et al., 2011; Han et al., 2013; Ding et al., 2017), L5 nerve ligation (Thompson et al., 2010) or sciatic nerve crush (Gu et al., 2012; Gibbons et al., 2013). Some studies have demonstrated an anti-inflammatory effect in HBO2-induced pain relief (Wilson et al., 2006, 2007; Li et al., 2011; Gu et al., 2012; Hui et al., 2013).
Research has demonstrated that hyperbaric oxygen (HBO₂) treatment produced relief of both acute and chronic pain in patients and animal models. However, the mechanism of HBO₂ antinociceptive effect is still elusive. Based on our earlier findings that implicate NO in the acute antinociceptive effect of HBO₂, the purpose of this study was to ascertain whether HBO₂-induced antinociception in a chronic neuropathic pain model is likewise dependent on NO. Neuropathic pain was induced in male Sprague Dawley rats by four injections of paclitaxel (1.0 mg/kg, i.p.). Twenty-four hours after the last paclitaxel injection, rats were treated for one day or four consecutive days with 60-min HBO₂ at 3.5 atmospheres absolute (ATA). Two days before HBO₂ treatment, some groups of rats were implanted with Alzet® osmotic minipumps that continuously infused a selective inhibitor of neuronal NO synthase (nNOS) into the lateral cerebral ventricle for 7 days. Mechanical and cold allodynia were assessed every other day, using electronic von Frey and acetone assays, respectively. Rats in the paclitaxel control group exhibited a mechanical or cold allodynia that was significantly reversed by one HBO₂ treatment for mechanical allodynia and four HBO₂ treatments for cold allodynic. In rats treated with the nNOS inhibitor, the effects of HBO₂ were nullified in the mechanical allodynia test but unaffected in the cold allodynia test. In summary, these results demonstrate that the antiallodynic effect of HBO₂ in two different pain tests is dependent on NO in the CNS.
Role of spinal GABA receptors in the acute antinociceptive response of mice to hyperbaric oxygen
2018, Brain Research
Citation Excerpt :
Clinically, HBO2 treatment is reportedly effective in a variety of off-label applications, including some chronic pain conditions such as complex regional pain syndrome (formerly reflex sympathetic dystrophy syndrome) (Katznelson et al., 2016; Kiralp et al., 2004; Peach, 1995), fibromyalgia syndrome (Efrati et al., 2015; Yildiz et al., 2004), migraine or cluster headache (Di Sabato et al., 1993; Myers and Myers, 1995; Wilson et al., 1998), myofascial pain syndrome (Kiralp et al., 2009) and idiopathic trigeminal neuralgia (Gu et al., 2012). In the preclinical setting, HBO2 has been shown to produce long-lasting pain relief in experimental animals (Chung et al., 2010; Gibbons et al., 2013; Warren et al., 1979). However, the mechanism through which HBO2 produces these effects is not, at present, fully characterized.
New pain treatments are in demand due to the pervasive nature of pain conditions. Hyperbaric oxygen (HBO₂) has shown potential in treating pain in both clinical and preclinical settings, although the mechanism of this effect is still unknown. The aim of this study was to investigate whether the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) is involved in HBO₂-induced antinociception in the central nervous system (CNS). To accomplish this goal, pharmacological interactions between GABA drugs and HBO₂ were investigated using the behavioral acetic acid abdominal constriction test. Western blotting was used to quantify protein changes that might occur as a result of the interactions. GABA_A but not GABA_B receptor antagonists dose-dependently reduced HBO₂ antinociception, while antagonism of the GABA reuptake transporter enhanced this effect. Western blot results showed an interaction between the pain stimulus and HBO₂ on expression of the phosphorylated β3 subunit of the GABA_A receptor at S408/409 in homogenates of the lumbar but not thoracic spinal cord. A significant interaction was also found in neuronal nitric oxide synthase (nNOS) expression in the lumbar but not thoracic spinal cord. These findings support the notion that GABA may be involved in HBO₂-induced antinociception at the GABA_A receptor but indicate that more study will be needed to understand the intricacies of this interaction.
Hyperbaric oxygen treatment suppresses withdrawal signs in morphine-dependent mice
2016, Brain Research
Citation Excerpt :
Other studies have been able to precipitate withdrawal in morphine-dependent mice with much lower doses of naloxone (Ho et al., 1972; Friedler et al., 1972). One reason for selection of 5.0 mg/kg of naloxone as our dose for precipitating withdrawal was a previous finding from our laboratory that HBO2-induced antinociception in rodents was sensitive to antagonism by both opioid antagonist drugs as well as rabbit antisera against selected endogenous opioid peptides, namely dynorphin (Zelinski et al., 2009; Heeman et al., 2013; Gibbons et al., 2013). This suggests that a mechanism of HBO2-induced antinociception is stimulation of neuronal release of opioid peptides.
Hyperbaric oxygen (HBO₂) therapy reportedly reduces opiate withdrawal in human subjects. The purpose of this research was to determine whether HBO₂ treatment could suppress physical signs of withdrawal in opiate-dependent mice. Male NIH Swiss mice were injected s.c. with morphine sulfate twice a day for 4 days, the daily dose gradually increasing from 50 mg/kg on day 1 to 125 mg/kg on day 4. On day 5, withdrawal was precipitated by i.p. injection of 5.0 mg/kg naloxone. Mice were observed for physical withdrawal signs, including jumping, forepaw tremor, wet-dog shakes, rearing and defecation for 30 min. Sixty min prior to the naloxone injection, different groups of mice received either a 30-min or 60-min HBO₂ treatment at 3.5 atm absolute. HBO₂ treatment significantly reduced naloxone-precipitated jumping, forepaw tremor, wet-dog shakes, rearing and defecation. Based on these experimental findings, we concluded that treatment with HBO₂ can suppress physical signs of withdrawal syndrome in morphine-dependent mice.
Endogenous opiates and behavior: 2013
2014, Peptides
This paper is the thirty-sixth consecutive installment of the annual review of research concerning the endogenous opioid system. It summarizes papers published during 2013 that studied the behavioral effects of molecular, pharmacological and genetic manipulation of opioid peptides, opioid receptors, opioid agonists and opioid antagonists. The particular topics that continue to be covered include the molecular-biochemical effects and neurochemical localization studies of endogenous opioids and their receptors related to behavior, and the roles of these opioid peptides and receptors in pain and analgesia; stress and social status; tolerance and dependence; learning and memory; eating and drinking; alcohol and drugs of abuse; sexual activity and hormones, pregnancy, development and endocrinology; mental illness and mood; seizures and neurologic disorders; electrical-related activity and neurophysiology; general activity and locomotion; gastrointestinal, renal and hepatic functions; cardiovascular responses; respiration and thermoregulation; and immunological responses.
Complex Hippocampal Response to Thermal Skin Injury and Protocols with Hyperbaric Oxygen Therapy and Filipendula ulmaria Extract in Rats
2024, International Journal of Molecular Sciences
Simultaneous Administration of Hyperbaric Oxygen Therapy and Antioxidant Supplementation with Filipendula ulmaria Extract in the Treatment of Thermal Skin Injuries Alters Nociceptive Signalling and Wound Healing
2023, Medicina (Lithuania)

View all citing articles on Scopus

¹: Authors contributed equally to this paper.

View full text

Research ReportInvolvement of brain opioid receptors in the anti-allodynic effect of hyperbaric oxygen in rats with sciatic nerve crush-induced neuropathic pain

Highlights

Abstract

Introduction

Section snippets

Time course of the mechanical threshold

Discussion

Conclusion

Animals

Acknowledgments

J. Pain

J. Urol.

Pain

Neurosci. Lett.

Pain

Pharmacol. Biochem. Behav.

Brain Res. Rev.

Radiother. Oncol.

Brain Res.

Brain Res. Bull.

Life Sci.

Brain Res.

Eur. J. Pharmacol.

Neurosci. Res.

J. Pain

Brain Res.

J. Pain

Brain Res.

Research Report
Involvement of brain opioid receptors in the anti-allodynic effect of hyperbaric oxygen in rats with sciatic nerve crush-induced neuropathic pain