Time-dependent effect of epidural steroid on pain behavior induced by chronic compression of dorsal root ganglion in rats

Abstract

Although epidural steroid injection has been commonly used to treat radicular pain, its clinical efficacy remains controversial. In a rat model of radicular pain induced by chronic compression of lumbar dorsal root ganglion (CCD), we examined the effect of epidural steroid on CCD-induced pain behavior. Triamcinolone [a glucocorticoid receptor (GR) agonist] or RU38486 (a GR antagonist) was given epidurally once either on day 3 (early treatment) or day 10 (late treatment) after CCD. The results showed that 1) early treatment with triamcinolone and RU38486 alone, respectively, reduced and exacerbated mechanical allodynia and thermal hyperalgesia, 2) late treatment with triamcinolone alone failed to improve mechanical allodynia and only transiently attenuated thermal hyperalgesia, and 3) late treatment with RU38486 alone improved mechanical allodynia and thermal hyperalgesia in CCD rats. Moreover, a second dose of triamcinolone given on day 10 paradoxically exacerbated pain behavior in CCD rats that received a first dose of triamcinolone on day 3. These results indicate that the effect of epidural steroid on radicular pain may be time-dependent. Clinical implications for epidural steroid treatment are discussed in light of these preclinical findings.

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

“…Common to all the neuropathic pain models is a decrease in withdrawal threshold to mechanical or thermal stimulation, which is enhanced after exposure to stress. Studies using GR antagonists, such as mifepristone (MIFE), demonstrated that intrathecal administration could increase both mechanical and thermal withdrawal thresholds in the injured limb (Wang et al, 2004;Takasaki et al, 2005;Gu et al, 2007). Those results were also replicated with intrathecal administration of antisense oligodeoxynucleotides selective for GR (Wang et al, 2004;Dina et al, 2008).…”

“…Those results were also replicated with intrathecal administration of antisense oligodeoxynucleotides selective for GR (Wang et al, 2004;Dina et al, 2008). Conversely, administration of a GR agonist, dexamethasone or triamcinolone, mimicked stress-induced exacerbation of withdrawal threshold (Wang et al, 2004;Gu et al, 2007). Similarly, intrathecal dosing of an MR antagonist, spironolactone (SPIRO) or eplerenone, also reversed the allodynic responses (Gu et al, 2011;Dong et al, 2012).…”

Preclinical Studies of Low Back Pain

“…There are few preclinical studies directly examining behavioral effects of glucocorticoids delivered in or near the DRG, perhaps due to the difficulty in gaining access to the DRG in mice or rats. In two rat studies using a CCD model, the clinically used glucocorticoid triamcinolone applied epidurally reduced pain behaviors when given 3 days after the compression began [10,49]. However, different results were obtained when applying drugs at day 10; at this later time point, triamcinolone failed to improve pain behaviors while a glucocorticoid antagonist improved them [49].…”

“…Some of this effect may be due to direct effects on neurons, because eplerenone applied to small diameter cultured neurons in vitro could reverse some of the excitatory changes induced by DRG inflammation (Figure 3). In light of the study by Gu et al in which GR agonists had opposite effects at later time points [49], it will be important to determine if MR antagonists still have anti-nociceptive effects at later time points. In a study using an NP model, infiltration of the nerve root with the GR agonist dexamethasone at the time of NP application could block development of mechanical pain behaviors.…”

A Novel Nitronyl Nitroxide with Salicylic Acid Framework Attenuates Pain Hypersensitivity and Ectopic Neuronal Discharges in Radicular Low Back Pain

“…Amongst those, chronic compression of the dorsal root ganglion (CCD) model in rodents displayed dramatic pain hypersensitivity such as mechanical hypersensitivity (hyperalgesia and allodynia) and thermal hyperalgesia that mimic the pain symptom observed in low back pain patients [ 1 – 6 ]. Although epidural steroid injection and surgical intervention have been used both clinically and experimentally in many cases, radicular low back pain remains a common chronic pain condition that is sometimes refractory to current treatment modalities [ 7 , 8 ]. Therefore, development of new therapeutics is helpful and in urgent need towards the treatment of radicular low back pain.…”