Non‐stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll‐like receptor 4 (TLR4)

Abstract

Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)-naltrexone, (+)-naloxone, and (-))-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by (+)-naloxone and (-))-naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)-naloxone and (-))-naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-))-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-))-opioid agonists suppress pain.

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…Naloxone is also an opioid receptor antagonist with similar affinity to mu opioid receptors as naltrexone, but relatively lower affinity to kappa and delta opioid receptors. Each of these medications is available in two isomers: the (À) isomer is the common opioid receptor antagonist form of each drug, whereas the (+) isomer does not bind (or has significantly reduced binding affinity) to opioid receptors (Hutchinson et al, 2008(Hutchinson et al, , 2011. However, both the (+) and (À) forms of each drug are antagonists at the Toll-like receptor 4 (TLR4; Hutchinson et al, 2008).…”

“…Each of these medications is available in two isomers: the (À) isomer is the common opioid receptor antagonist form of each drug, whereas the (+) isomer does not bind (or has significantly reduced binding affinity) to opioid receptors (Hutchinson et al, 2008(Hutchinson et al, , 2011. However, both the (+) and (À) forms of each drug are antagonists at the Toll-like receptor 4 (TLR4; Hutchinson et al, 2008). Interestingly, despite its inability to antagonize opioid receptors, (+) naloxone was found to reduce stimulant-induced locomotor activity (Chatterjie, Alexander, Sechzer, & Lieberman, 1996;Chatterjie, Sechzer, Lieberman, & Alexander, 1998), which is congruent with findings suggesting that TLR4 contributes to the acute effects of drugs of abuse (Hutchinson et al, 2012) and the ability of opioid receptor antagonists to affect such responses (Wu et al, 2012).…”

Behavioral Models of Pain States Evoked by Physical Injury to the Peripheral Nerve

“…39 Pain behaviors last between 2 weeks to 3 months, depending on the laboratory, 28,40,41 and was first reported to be exclusively ipsilateral. 42 However, there are now reports of bilateral pathological pain after CCI, 43,44 although initial reports indicated only ipsilateral thermal hyperalgesia. Motor deficits parallel loss of peripheral axons, 45 and motor disturbances and damage to motor axons may extend to the contralateral "noninjured" nerve.…”

Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment

“…[98][99][100][101][102][103] It is now clear that glia-to-neuron signaling via toll-like receptor 4 (TLR-4) can play a causal role in the initiation and maintenance of pathological pain. [104][105][106][107] The toll-like receptors (TLRs) are a family of innate immune pattern recognition receptors, which respond to a wide variety of pathogen-derived and tissue damage-related ligands. 108 The TLR-4 receptor, which is primarily expressed upon microglia, 109 is an important contributor to activation of these cells, although expression on astrocytes, endothelial cells and neurons has also been reported.…”