Agonist-dependent attenuation of μ-opioid receptor-mediated G-protein activation in the dorsal root ganglia of neuropathic rats

Abstract

Besides generally accepted lower analgesic potencies of opioids in neuropathic pain, our recent pharmacological reports have demonstrated that the effectiveness of the micro-opioid receptor (MOR) agonists in neuropathy might depends upon the chemical/structural property of these compounds (alkaloid vs. peptides). Such findings prompted us to investigate the changes in MOR mRNA expression (estimated by PCR) as well as MOR functional activity (examined by [(35)S]GTPgammaS binding) in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) of neuropathic rats at different time points after sciatic nerve ligation. We found that the spinal MOR mRNA level and agonist-stimulated [(35)S]GTPgammaS binding were not affected by nerve injury. In contrast, down-regulation of MOR mRNA in the ipsilateral side of DRG developed 3 (approximately 63% reduction) and 14 (approximately 89% reduction) days after the ligation. The decrease was paralleled with pronounced reduction in the stimulation of [(35)S]GTPgammaS binding by morphine (approximately 37-39%). Thus, neuropathy-induced specific dysfunction of MOR to activate G-protein together with changes in the MOR synthesis might be related, at least in part, to diminish analgesic efficacy of morphine in neuropathic pain. Interesting observations from current studies are linked to endomorphins (EMs), which do not affect the G protein stimulation of MOR after nerve ligation. This intriguing property of EMs, together with previously reported high analgesic efficacy of these compounds indicate that chemically/structurally different MOR agonists, particularly morphine versus EMs, may differentially interact with receptors causing distinct pharmacological effects in chronic pain.

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

“…Similar effects were observed after PSL (Rashid et al, 2004;Pol et al, 2006), although -receptor immunoreactivity (analyzed by Western blot) was enhanced in another study (Walczak et al, 2005). After CCI, there was no strict correlation between -receptor mRNA and protein levels, in that mRNA was unchanged (Truong et al, 2003) or down-regulated (Obara et al, 2009(Obara et al, , 2010, whereas the number of -receptor-expressing neurons was enhanced (Truong et al, 2003) or unaltered (Kolesnikov et al, 2007). In the same model, a reduction (by 37-39%) of the stimulation of G protein coupling to -receptors by morphine, but not by endomorphins, was reported (Obara et al, 2010).…”

“…After CCI, there was no strict correlation between -receptor mRNA and protein levels, in that mRNA was unchanged (Truong et al, 2003) or down-regulated (Obara et al, 2009(Obara et al, , 2010, whereas the number of -receptor-expressing neurons was enhanced (Truong et al, 2003) or unaltered (Kolesnikov et al, 2007). In the same model, a reduction (by 37-39%) of the stimulation of G protein coupling to -receptors by morphine, but not by endomorphins, was reported (Obara et al, 2010). -Receptor mRNA was unchanged after PSL , lowered after CCI (Obara et al, 2009), and enhanced in animals with hypersensitivity after transection of the sacral nerve (Sung et al, 2000).…”

“…␦-Receptor mRNA was not altered after PSL or down-regulated after CCI (Obara et al, 2009). All these changes were observed 2 to 28 days after surgeries in lumbar DRG ipsilateral to the nerve injury compared with the contralateral DRG of injured animals (Zhang et al, 1998b;Truong et al, 2003;Pol et al, 2006) or to DRG of naive or sham-operated animals (Zhang et al, 1998b;Sung et al, 2000;Rashid et al, 2004;Kohno et al, 2005;Walczak et al, 2005;Pol et al, 2006;Obara et al, 2009Obara et al, , 2010. ␦-Receptor protein was examined in a CCI-resembling model, in which a loose polyethylene cuff is placed around the sciatic nerve (Mosconi and Kruger model) (Kabli and Cahill, 2007).…”

Why mu‐opioid agonists have less analgesic efficacy in neuropathic pain?

“…Alternatively, several peripheral dysregulations that operate after nerve lesion and may contribute to the reduction in systemic morphine potency have been also suggested. Drastic decrease of MOR expression in dorsal root ganglia (DRG) neurons due to primary afferent fibres damage was reported years ago (Li, Kaneko, & Mizuno, 1996;Obara et al, 2010;Ossipov et al, 1995b;Rashid et al, 2004;Zhang, Bao et al, 1998). More recently, epigenetic alterations have been suggested to be responsible for this down-regulation of MOR gene expression in the DRG and in the dorsal horn of the spinal cord, leading to limited morphine effectiveness (Rivat, 2016;Uchida, Ma, & Ueda, 2010;Uchida, Matsushita, Araki, Mukae, & Ueda, 2015;Zhang et al, 2016).…”

Modulation of neuropathic-pain-related behaviour by the spinal endocannabinoid/endovanilloid system

“…CCI of the sciatic nerve is a commonly used neuropathic pain model that causes hypersensitivity to radiant heat stimuli (i.e. hyperalgesia) [98][99][100] and nociceptive responses to typically non-nociceptive stimuli (e.g. allodynia), including touch [101,102] and cold [102,103].…”