Chronic pain states result in activation and/or elevation in the number of certain calcium channels in nociceptive neurons [12
], for instance, the high-voltage gated N-channel [13
], the low-voltage gated T-channel [15
], the non-selective cation channel transient receptor potential cation channel subfamily V member 1 (TRPV1) [17
], etc. Although not specific to any one type of calcium channel, results from our study indicate that MEMRI can be used to functionally highlight and objectively identify active peripheral neuronal pathways in a rat model of neuropathic pain. MEMRI utilizes physiological changes, specifically ‘sensitization’ occurring in chronic pain to functionally highlight both the pain-sensing neurons and its contralateral non-injured neural counterpart.
We are able to demonstrate higher MEMRI signal in peripheral nerves in animals experiencing pain. However, we also observed an increase in T1-weighted signal enhancement on the non-injured side, contralateral to the nerve injury in the CCI group. Events that effect nonlesioned structures contralateral to a peripheral nerve lesion is a well documented phenomenon described in rats [19
]. Although the exact mechanism is not yet known, it has been shown that unilateral axotomy results in bilateral changes in levels of mRNA for cholecystokinin [20
], and bilateral changes in the neuropeptides galanin, neuropeptide Y and vasoactive intestinal polypeptide [21
]. These changes might be related to bilateral increases in trophic factors like nerve growth factor (NGF) that have been measured following unilateral axotomy [22
]. There are numerous studies that have found similar bilateral neuroinflammatory reaction in response to unilateral nerve injury while showing only ipsilateral mechanical allodynia [23
]. Further, studies indicate that after nerve injury, contralateral allodynia increases in a time-dependent manner, with a delayed onset, in the un-injured side [26
]. These studies suggest that behavioral manifestation of pain on the side contralateral to the nerve injury may follow more basic neuroinflammatory changes at the molecular and receptor level. Regardless of the exact mechanism, the increase in enhancement seen contralaterally to the source of pain in the CCI group on the 3D maximal intensity projections in our study is likely partly attributable to this phenomenon.
Additionally, the observation of enhancement contralateral to the site of injury might be considered a limitation of this method, but the fact that the image was obtained 24 hours after MnCl2 administration may indeed reflect manganese equilibrium attained in both the injured and contralateral nerves. If we were to obtain images relatively sooner (<24 hours), it may be possible to see preferential manganese accumulation in the ipsilateral injured nerve when compared to the contralateral nerve due to differential rates of manganese uptake. Ongoing experiments are currently addressing these issues and studying neural activity in both intact and injured peripheral nerves. We are also studying the effect of analgesic treatments on MEMRI signal.
Recognizing active nociceptive peripheral nerves using MEMRI may help inform diagnostic and therapeutic decisions. The diagnosis of peripheral nerve entrapment syndromes, such as carpal tunnel syndrome and piriformis syndrome, can potentially be aided by MEMRI when diagnosis can be challenging in early stages of the disease. Additionally, MEMRI may provide more objective decision support for fluoroscopy, computed tomography, or ultrasound-guided local anesthetic and steroid injections that are currently used to empirically treat a large variety of clinical pain disorders including low back pain, sciatica, post-surgical pain, post-traumatic neuralgia, etc.
In addition to helping guide therapeutic decisions, MEMRI can also be used to screen drug candidates for analgesia. Novel therapeutic strategies targeted on the peripheral mechanisms of neuropathic pain (for example, blocking ion channels in peripheral neurons, modulation of peripheral excitability via cannabinoid receptors, blocking glutamate receptors in spinal cord, blocking activated spinal neuroglia, etc) [28
] may find MEMRI to be a useful tool for evaluation of efficacy and local targeting.
Of note, manganese, which is essential for cell viability at normal levels, is toxic in humans at high concentrations [29
]. Chronic manganese exposure causes ‘manganism’ [34
], a movement disorder similar to Parkinson’s disease, which has limited its translation into the clinic. However, recent developments look promising for use in patients. For example, mangafodipir trisodium (MnDPDP; Teslascan) is an FDA-approved MRI contrast agent consisting of chelated manganese for MRI evaluation of the liver, which showed no significant adverse effects in its clinical trials [35
As technology advances and newer developments allow for manganese to provide contrast at lower concentrations, manganese-based imaging may emerge as the means of diagnosing and assessing the severity of neuropathic and other forms of chronic pain in human subjects in the future. MEMRI could potentially benefit living subjects with neuropathic and, perhaps, other chronic pain syndromes by offering scientists and health care providers a noninvasive tool to study pre-clinical and clinical pain syndromes, determine the effectiveness of systemic analgesics, and provide vital information useful in treating pain with image-guided regional nerve blockade or other novel minimally invasive approaches.