Research reportDifferential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord
Graphical abstract
Introduction
The endogenous opioid system (EOS) is the pharmacological target for opioid analgesics. It is involved in the development and maintenance of pathological pain conditions including neuropathic pain. Treating neuropathic pain with opioids is often discouraging due to their lowered efficacy and high-doses required for opioid therapy (Bleeker, et al., 2001, Kupers et al., 1991, Law et al., 2000, MacPherson, 2002, Obara et al., 2004, Ossipov et al., 1995). Alteration in expression of the EOS genes (Mayer et al., 1999, Ossipov et al., 2000, Przewlocki and Przewlocka, 2001) causing rewiring of the nociceptive neural circuits in neuropathic pain conditions may account in part for the reduced efficacy of opioid drugs (Arner and Meyerson, 1988, Bleeker, et al., 2001, Kupers et al., 1991).
The EOS includes the proenkephalin (Penk), prodynorphin (Pdyn) and proopiomelanocortin (Pomc) genes that give rise to enkephalins, dynorphins and endorphins, respectively. These peptides act via δ-, κ- and µ-opioid receptors encoded by the Oprd1, Oprk1 and Oprm1 genes, respectively. The most consistent adaptive response in neuropathic animals is the upregulation of Pdyn gene transcription and dynorphin expression (Wagner et al., 1993, Wang et al., 2001). Pdyn mRNA levels were increased in the dorsal lumbar spinal cord after chronic constriction injury (Obara et al., 2009), and dynorphin immunoreactivity was elevated in the ipsilateral dorsal quadrant of the lumbar spinal cord in rats with ligations of the L5 and L6 spinal nerves (Kajander et al., 1990, Malan et al., 2000). Enhanced dynorphin expression may be pronociceptive (Caudle and Isaac, 1988, Wang et al., 2001) and promote morphine tolerance (Vanderah et al., 2000). The molecular basis for these non-opioid receptor mediated effects may formation of giant transient pores in plasma membrane causing profound long-lasting neuronal depolarisation (Maximyuk et al., 2015). On the other hand, dynorphins may block nociceptive signalling by activating κ-opioid receptors (Xu et al., 2004).
Less consistent and even controversial data were reported for other EOS genes (Hughes and Smith, 1994, Obara et al., 2009, Plantinga et al., 1992, Smith et al., 1994, van der Kraan et al., 1999). No changes and downregulation of the µ-opioid receptor (Oprm1) gene expression were identified (deGroot et al., 1997, Obara et al., 2009, Pol et al., 2006, Porreca et al., 1998, Zhang et al., 1998), while µ-opioid receptor protein and µ-receptor binding were increased in the lumbar spinal cord in animal models of neuropathic pain (Stevens et al., 1991, Truong et al., 2003). Either no changes or decreases in δ-opioid receptor (Oprd1) gene expression in the spinal cord after chronic constriction injury or sciatic nerve ligation were detected (Besse et al., 1992, Obara et al., 2009, Pol et al., 2006, Robertson et al., 1999, Stevens et al., 1991, Stone et al., 2004). The lack of changes or an increase in Oprk1 gene expression were also reported (Besse et al., 1992, Obara et al., 2009, Pol et al., 2006, Stevens et al., 1991). Expression of Penk mRNA in the lumbar spinal cord was down-regulated after sciatic nerve ligation (Obara et al., 2009), or not changed following complete transection of the sciatic nerve or sciatic nerve crush (Draisci et al., 1991).
In this study we re-examined whether the EOS expression patterns undergo adaptive changes in the ipsi- and contralesional domains of lumbar spinal cord of rats with spinal nerve ligation (SNL), a widely used neuropathic pain model (Chung et al., 2004). SNL-induced neuropathic pain and changes in processing of nociceptive and non-nociceptive stimuli in the spinal cord are controlled by the EOS (Podvin et al., 2016, Sun et al., 2017, Tseng et al., 2017). The opioid receptors are expressed in the dorsal and ventral spinal domains at similar levels (Kononenko et al., 2017) and may be involved in regulation of nociceptive motor reflexes. Therefore, the EOS mRNA levels in the ventral domains were also analysed. The left- and right-side unilateral neuropathy differently activates ipsilateral amygdala neurons, and produces different effects on anxiety and cognitive functions (Goncalves and Dickenson, 2012, Leite-Almeida et al., 2012). This side specificity may be underlined by lateralization of the dynorphin – κ-opioid receptor system in the amygdala (Nation et al., 2018, Xie et al., 2017). The expression patterns of the EOS genes were found to be strongly lateralized in the cervical spinal cord. Interregional co-expression patterns were side specific while intraregional co-expression profiles were differently affected by left- and right-side unilateral body injury (Kononenko et al., 2017). Therefore, in the present study, we also examined whether the left- and right-side SNL differently affects the balance in expression of EOS genes between ipsi- and contralesional spinal domains. The overall design included analyses of four groups of animals including two SNL groups with the left- and right-side nerve injury, and two groups with left- and right-side sham-operation (SO).
Section snippets
Results
First, we examined whether effects of SNL on paw withdrawal thresholds differed significantly from those of SO, suggesting behavioural signs of mechanical allodynia correlative with neuropathic pain. Second, we analysed the EOS expression levels in the left (L) and right (R) halves of dorsal and ventral domains (L-DD, L-VD, R-DD, and R-VD) in the left- and right-side SNL and SO groups. Third, we evaluated whether molecular parameters analysed are associated with the hind paw withdrawal
Discussion
Patterns of the SNL induced changes in expression of the EOS genes were complex and different among the genes; between the dorsal and ventral spinal domains; between the left and right operations; and between the spinal cord sides. The robust effect was upregulation of Pdyn in the ipsilesional DD after the left and right-side SNL. Other significant effects were dependent on the side of nerve ligation, and different in left and right sides of the spinal cord. Thus μ-opioid receptor (Oprm1) was
Animal treatments and surgery
Male Sprague Dawley rats (Harlan, Indianapolis, IN) weighing between 225 and 300 g were maintained in cages in a climate-controlled room on a 12 h light/dark cycle with ad libitum access to food and water. All testing procedures were performed in accordance with the policies and recommendations of the International Association for the Study of Pain and the National Institutes of Health guidelines for the handling and use of the laboratory animals and were approved by the Institutional Animal
Acknowledgments
This work was supported by Grants from the Swedish Science Research Council (VR), the Swedish Council for Working Life and Social Research (FORTE), and the Swedish Research Council Formas (to G.B.); the Swedish Institute (Visby Program; to O.K. and G.B.). The authors declare no conflicts of interest.
References (59)
- et al.
Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain
Pain
(1988) Met-enkephalin-induced release into the blood of a factor causing postural asymmetry
Peptides
(1986)- et al.
Opioids induce postural asymmetry in spinal rat: the side of the flexed limb depends upon the type of opioid agonist
Brain Res.
(1989) Regulation of opioid binding sites in the superficial dorsal horn of the rat spinal cord following loose ligation of the sciatic nerve: comparison with sciatic nerve section and lumbar dorsal rhizotomy
Neuroscience
(1992)Inefficacy of high-dose transdermal fentanyl in a patient with neuropathic pain, a case report
Eur. J. Pain
(2001)Quantitative assessment of tactile allodynia in the rat paw
J. Neurosci. Methods
(1994)- et al.
No DREAM, no pain. Closing the spinal gate
Cell
(2002) - et al.
The reorganization of mu opioid receptors in the rat dorsal horn following peripheral axotomy
Neurosci. Lett.
(1997) Up-regulation of opioid gene expression in spinal cord evoked by experimental nerve injuries and inflammation
Brain Res.
(1991)- et al.
Dynorphin induces partially reversible paraplegia in the rat
Eur. J. Pharmacol.
(1983)
RNA integrity and the effect on the real-time qRT-PCR performance
Mol. Aspects Med.
Mouse strains that lack spinal dynorphin upregulation after peripheral nerve injury do not develop neuropathic pain
Neuroscience
Upregulation of the pro-opiomelanocortin gene in motoneurons after nerve section in mice
Brain Res. Mol. Brain Res.
Dynorphin increases in the dorsal spinal cord in rats with a painful peripheral neuropathy
Peptides
Morphine differentially affects the sensory and affective pain ratings in neurogenic and idiopathic forms of pain
Pain
Differential effects of left/right neuropathy on rats’ anxiety and cognitive behavior
Pain
Extraterritorial neuropathic pain correlates with multisegmental elevation of spinal dynorphin in nerve-injured rats
Pain
Local peripheral effects of mu-opioid receptor agonists in neuropathic pain in rats
Neurosci. Lett.
Local peripheral opioid effects and expression of opioid genes in the spinal cord and dorsal root ganglia in neuropathic and inflammatory pain
Pain
Inhibition by spinal morphine of the tail-flick response is attenuated in rats with nerve ligation injury
Neurosci. Lett.
Expression of the pro-opiomelanocortin gene in dorsal root ganglia, spinal cord and sciatic nerve after sciatic nerve crush in the rat
Brain Res. Mol. Brain Res.
Expression of opioid receptors and c-fos in CB1 knockout mice exposed to neuropathic pain
Neuropharmacology
Spinal opioid mu receptor expression in lumbar spinal cord of rats following nerve injury
Brain Res.
Opioids in chronic pain
Eur. J. Pharmacol.
Effects of sciatic nerve injuries on delta -opioid receptor and substance P immunoreactivities in the superficial dorsal horn of the rat
Eur. J. Pain
Spinal motor actions of the mu-opioid receptor agonist DAMGO in the cat
Neurosci. Res.
Bilateral and differential changes in spinal mu, delta and kappa opioid binding in rats with a painful, unilateral neuropathy
Pain
Effects of peripheral nerve injury on delta opioid receptor (DOR) immunoreactivity in the rat spinal cord
Neurosci. Lett.
Expression of melanocortin receptors and pro-opiomelanocortin in the rat spinal cord in relation to neurotrophic effects of melanocortins
Brain Res. Mol. Brain Res.
Cited by (15)
Research Trends and Hotspots of Neuromodulation in Neuropathic Pain: A Bibliometric Analysis
2023, World NeurosurgeryThe active second-generation proteasome inhibitor oprozomib reverts the oxaliplatin-induced neuropathy symptoms
2020, Biochemical PharmacologyCitation Excerpt :Selective α7 nAChR agonists prevent receptor downregulation and reduce hypersensitivity. Interestingly, the pain relieving effect of α7 nAChR agonists parallels a spinal decrease of dynorphin A [13], an endogenous kappa opioid receptor agonist that strongly contributes to neuropathic pain [14,15]. Other cellular functions have been associated with the activation and sensitization of pain signaling in sensory neurons.
Endogenous Opiates and Behavior: 2018
2020, PeptidesCitation Excerpt :Spinal pentazocine-induced antinociception was mediated by KOR and negatively modulated by MOR [731]. Both left and right spinal nerve ligation in the lumbar cord upregulated ipsilateral PDYN expression; PENK expression upregulation was dependent on the side of the lesion [509]. Lappaconitine, a C18-diterpenoid alkaloid, exhibited antihypersesnitivity in chronic pain through stimulation of spinal DYN A expression [838].
Differential suppression of the ipsi- and contralateral nociceptive reflexes in the neonatal rat spinal cord by agonists of µ-, δ- and κ-opioid receptors
2019, Brain ResearchCitation Excerpt :Molecular studies also demonstrate the pain-associated bilateral changes in the expression of immediate early, neuropeptide and glutamate system genes in the dorsal and ventral horns of the spinal cord (Herdegen et al., 1991; Sluka et al., 1992; Williams et al., 1990). A complex pattern of changes in expression of the opioid genes specific for the contra- and ipsilesional sides in the dorsal and ventral spinal domains is induced by unilateral neuropathy (Kononenko et al., 2018). In spite of solid behavioral and physiological evidence for the phenomenon, little is known about the neurotransmitter control of the bilateral nociceptive processing.
Activation of alpha7 acetylcholine receptors reduces neuropathic pain by decreasing dynorphin A release from microglia
2019, Brain ResearchCitation Excerpt :The advantage for endogenous opioid analgesia is less tolerance and addiction. However, dynorphin A, an endogenous kappa opioid receptor agonist, has been reported a contributor of the neuropathic pain (Kononenko et al., 2018). A mouse strain that lacks spinal dynorphin A up-regulation after peripheral nerve injury did not show neuropathic pain behaviors (Gardell et al., 2004).
The left–right side-specific endocrine signaling in the effects of brain lesions: questioning of the neurological dogma
2022, Cellular and Molecular Life Sciences