Decreased spinal cord opioid receptor mRNA expression and antinociception in a Theiler's murine encephalomyelitis virus model of multiple sclerosis

Abstract

Multiple sclerosis patients typically experience increased pain that is relatively insensitive to opiate treatment. The mechanistic basis for this increased nociception is currently poorly understood. In the present study, we utilized the Theiler's murine encephalomyelitis virus (TMEV) model of MS to examine possible changes in spinal cord opioid receptor mRNA over the course of disease progression. TMEV infection led to significantly decreased mu, delta and kappa opioid receptor mRNA expression as analyzed by quantitative real-time PCR in both male and female mice at days 90, 150 and 180 post-infection (PI). Since opioid receptor mRNA expression decreased in TMEV mice, we examined whether opiate analgesia is also altered. TMEV infected female mice had significantly decreased opiate analgesia in thermal nociceptive tests beginning at day 90 PI, while TMEV-infected male mice did not display significantly decreased opiate analgesia until day 120 PI. The novel finding that opioid receptor expression is significantly decreased in the spinal cord of TMEV mice could explain the increased nociception and loss of opiate analgesia observed in both TMEV mice and multiple sclerosis patients.

G protein-coupled receptors as therapeutic targets for multiple sclerosis

“…Preclinical investigations utilizing animal models, as well as clinical observations with MS patients, suggested alteration of endogenous opioid systems in the disease. In the TMEV model of MS, mRNA levels of the mu, delta, and kappa opioid receptors were significantly decreased in the spinal cord at days 90, 150, and 180 post infection [139]. The loss of opioid receptors might partially explain the common central neuropathic pain in MS patients [140].…”

Mechanisms and Pharmacology of Neuropathic Pain in Multiple Sclerosis

“…In two studies, thermal hyperalgesia after PLP 131–151 or TMV was similar between male and female mice (Aicher et al, 2004, Lynch et al, 2008). By contrast, TMEV mice develop mechanical allodynia faster in females than in males, despite the more rapid disease progression in males (Lynch et al, 2008). These findings support the idea, discussed below, that neuromuscular deficits do not prevent the study of pain hypersensitivity in EAE.…”

“…Both PLP 139–151 -induced relapsing-remitting EAE in SJL mice and MOG 33–55 -induced chronic EAE in C57BL/6 mice exhibited heat hypersensitivity during the chronic phase (day 35 to 45 after EAE induction) (Lu et al, 2012). TMEV infection also induced heat hypersensitivity in male and female SJL/J mice, as compared to control non-infected mice in the thermal tail-immersion test (Lynch et al, 2008). In a rat MBP model of EAE, heat hypersensitivity developed at the tail (Thibault et al, 2011).…”

“…Similarly, mechanical allodynia in male and female SJL/J mice occurs before or during the onset of motor deficits in the TMEV model (Lynch et al, 2008). Also, heat and cold hypersensitivity in rat MBP EAE models begins before the onset of motor dysfunction, and heat hyperalgesia continued even after clinical signs had disappeared (Thibault et al, 2011).…”

Social disruption alters pain and cognition in an animal model of multiple sclerosis

“…Prior research assessing pain sensitivity in the TMEV model relied on nociceptive reflex measures (Lynch et al, 2008a, Lynch et al, 2008b). While these measures provide information regarding spinal nociceptive processing (Gregory et al, 2013, Vierck et al, 2008), they do not reflect the affective experience of pain mediated by the brain (King et al, 2009, King et al, 1996, Meagher et al, 2001, Morgan et al, 1994, Qu et al, 2011, Vierck et al, 2008).…”