Wednesday, March 30, 2016

Pain and Inflammation; Nociception and Cytokines

I'd like to start by marveling at a recent dramatic change in my fibromyalgia pain. After nearly nine years of intense burning pain through approximately 1/6 of my body I've now had 3 weeks of relief. On the left side of my body, my neck, shoulder girdle, pectoral, upper back, and the back of my head ached immensely. EVERY. WAKING. MOMENT. Currently that area feels normal, or occasionally tense - but no longer definitively painful. This is in large part due to decreasing systemic inflammation.

It shouldn't be a surprise that inflammation can cause pain. Everyone, not just fibromyalgia sufferers, has experienced the aching pains that accompany a flu. We've all noticed the localized pain that coincides with redness and swelling at the site of an injury. During inflammation the cytokines released by immune cells can stimulate nociceptors in the body.

Cytokines are signaling molecules released by immune cells in order to coordinate a response. Think of them as messages relayed by soldiers on a battlefield. Cytokines can also be released by other cells in the body in response to damage or threat. In this case they are similar to SOS messages from civilians.

Nociceptors are nerve cells that receive mechanical/electrical/chemical input and relay that input to the brain where it is transformed into the subjective experience of pain. They are analogous to the rods and cones in the eye that respond to photons and send a signal to the visual cortex, thereby giving rise to vision. You may have noticed that if you close your eyes and press firmly on your eyeballs you see some colors; the photoreceptors (rods and cones) are responding to a stimulus that they are not evolved to respond to, but they are responding nonetheless. Tinnitus is a similar phenomenon - noise generated in the absence of normal signal. A more mechanical analogy: sometimes electronic devices that are not radios will pick up signals from a radio station.

Enter the following quote from a biomedical study:
Today our understanding of this relationship is more detailed. When an antigen enters the body, local activation of immune cells leads to release of proinflammatory mediators, which are able to excite or lower thresholds of afferent nociceptive and afferent vagal nerve fibers [3]. If the neuronal signal strength is strong enough or if spillover of local inflammatory mediators into the circulation is robust enough, it signals to the brain, resulting in activation of the two major stress axes, the HPA axis and the SNS [3,4]. Cytokines like interleukin (IL)-1β [3,5] or tumor necrosis factor (TNF) [6] produced by locally activated innate immune cells are pivotal in this communication from immune system to central nervous system.

Afferent means a nerve fiber traveling from the body to the brain/central nervous system. *1

Thresholds. Neurons, including nociceptors, fire in an all-or-nothing fashion. They receive stimulation from neighboring neurons, or, in the case of nociceptors, from the adjacent environment. At any given moment, if the combined stimulation surpasses the threshold of the neuron it will depolarize and send an electrical signal down the length of its axon, thereby passing the message along to a distant neuron. If the stimulation is insufficient, no message will be sent. An analogy for thresholds: a sleeping person may not stir at all in response to quiet sounds, but a loud sound will awake them completely. If the thresholds for your afferent nociceptors are lowered, your experience of pain becomes akin to the hypersensitivity of a shallow sleeper.

The same cytokines mentioned in the above article (IL-1β and TNFα) can also enter the cerebrospinal fluid and lower the threshold of nociceptors in the spinal cord. This means that when a nociceptor in the periphery (e.g. skin or muscle) sends a message to a nociceptor in the spinal cord, that second nociceptor is more likely to pass that message along to the brain, where it is likely to be interpreted as pain.
The inflammatory milieu surrounding the nerve terminals in the skin contains numerous inflammatory mediators during CHS (Kondo et al., 1994; Westphal et al., 2003; Christensen and Haase, 2012), such as tumor necrosis factor alpha (TNFα) and interleukin-1β (IL-1β), which may be retrogradely transported to cell bodies of dorsal root ganglion neurons and contribute to the increased Na+ currents observed in this study. Indeed, TNFα and (IL-1β) have been demonstrated to augment TTX-sensitive and TTX-resistant Na+ currents in nociceptive dorsal root ganglion neurons (Binshtoket al., 2008; Czeschik et al., 2008).
(The dorsal root ganglion is the part of the spinal cord that relays pain signals. Na+ currents are electrical signals sent along axons. Axons are like long cables transmitting information from neuron to neuron.)

To add to the misery, it appears that long-term inflammation can alter the receptors on neurons, such that they remain hypersensitive even after proinflammatory cytokines are no longer present:

Following inflammation of the hindpaw, myelinated, CGRP-positive neurons projecting to the paw skin displayed elevated mechanical currents in response to mechanical stimuli. Conversely, muscle inflammation markedly amplified mechanical currents in myelinated, CGRP-negative neurons projecting to muscle. These data show, for the first time, that mechanically gated currents are amplified following in vivo tissue inflammation, and also suggest that mechanical sensitization can occur in myelinated neurons after inflammation.

Mechanical stimulation? Touch and pressure are forms of mechanical stimulation. This mechanical sensitization may therefore partly explain the presence of tender points in fibromyalgia sufferers. Incidentally, though my burning/aching pain is in remission, I still have the tender points. This dovetails with the notion that prolonged inflammation leads to physiological changes that persist even after the inflammation subsides.

 In future posts I'll explore:
 - how peripheral sensitization can lead to central sensitization
 - potential causes of inflammation in fibromyalgia
 - strategies to reduce inflammation
 - biomarkers for inflammation (e.g. blood tests)
 - other inflammatory conditions that are often comorbid with fibromyalgia (e.g. IBS, ME/CFS, Major Depression, and bipolar disorder)

*1 'Efferent' is the term for signals sent outwards from the brain.

The sympathetic nervous response in inflammation

Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain

Amplified Mechanically Gated Currents in Distinct Subsets of Myelinated Sensory Neurons following In Vivo Inflammation of Skin and Muscle

7/29/16 Addenda:

I just found out about the Fibro Friday link up over at , a great repository of FMS blogs and resources. I'll be sharing this post there for anyone interested in the biomolecular interactions in fibromyalgia.

A few more studies to look into (for the biomechanically-minded):

NLRP3 inflammasome is activated in fibromyalgia: the effect of coenzyme Q10.

MCP-1 and IL-8 as pain biomarkers in fibromyalgia: a pilot study.

Aaand, footage of me burning myself repeatedly with matches to demonstrate that it hurts very little in comparison to fibromyalgia. Skip to 3:30 for the worst burn and a brief explanation of cytokines and nociception.

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