Is the development of neuropathic pain and/or the loss of analgesic effects of morphine dependent upon the concentrations of central nitric oxide and nitroxyl, and are these effects mediated by the TLR4 receptor pathway?

BACKGROUND

• Neuropathic pain, the most diagnosed type of chronic pain in Australia affects approximately 7% of the population with highest                                                                                                                                                                                                             prevalence in patients aged 45-64 and sex difference varying depending on the underlying disease state (Pollack, A, et al., 2013). The total cost of chronic pain to the Australian economy was reported to be $34 billion, including $7 billion in health system costs (Access Economics, 2007).
• Neuropathic pain is defined as pain caused by a lesion of the peripheral or central nervous system (CNS) and can develop either post-surgically or from a variety of disease states ranging from diabetic neuropathy through to post-traumatic spinal cord injury. It is characterized by the presence of allodynia (pain generated from non-noxious stimuli) and hyperalgesia (heightened sense of pain to noxious stimuli) with patients frequently presenting with symptoms such as burning pain, stabbing pain or pins and needles. 
• Pain normally serves to guard against tissue injury, as it is imperative that the body is aware of potentially damaging stimuli. It also allows us to protect the damaged area as to facilitate tissue repair after injury.
• Neuropathic pain is a type of pathophysiological chronic pain state, and unlike other types of chronic pain such as nociceptive or inflammatory pain, is maladaptive, therefore neither protects or supports healing or repair (Costigan M, et al., 2009). 

NITROGEN SPECIES AND PAIN

         Nitric Oxide production                               Nitroxyl production:  DOI: 10.1016/j.niox.2016.04.006

Nitric oxide is able to act as a neurotransmitter following neuronal generation and release to signal during neuropathic pain, however it also acts via a neuronal- glial pathway with glial cells also able to produce nitric oxide in large amounts contributing to the development and maintenance of neuropathic pain. 

Nitroxyl, the protonated form of nitric oxide has also been implicated in neuropathic pain signalling, however the endogenous role has yet to be determined. Recently, Longhi-Balbinot et al (2016), demonstrated that administration of HNO donor was able to reduce pain sensitivity (hyperalgesia) by reducing the reactivity of spinal glia and expression of their associated cytokines. 

To be continued......Work in progress..........