Michael Thacker

Pathophysiology of peripheral neuropathic pain: immune cells and molecules.

Damage to the peripheral nervous system often leads to chronic neuropathic pain characterized by spontaneous pain and an exaggerated response to painful and/or innocuous stimuli. This pain condition is extremely debilitating and usually difficult to treat. Although inflammatory and neuropathic pain syndromes are often considered distinct entities, emerging evidence belies this strict dichotomy. Inflammation is a well-characterized phenomenon, which involves a cascade of different immune cell types, such as mast cells, neutrophils, macrophages, and T lymphocytes. In addition, these cells release numerous compounds that contribute to pain. Recent evidence suggests that immune cells play a role in neuropathic pain in the periphery. In this review we identify the different immune cell types that contribute to neuropathic pain in the periphery and release factors that are crucial in this particular condition.

CCL2 is a key mediator of microglia activation in neuropathic pain states

While neuroimmune interactions are increasingly recognized as important in nociceptive processing, the nature and functional significance of these interactions is not well defined. There are multiple reports that the activation of spinal microglia is a critical event in the generation of neuropathic pain behaviors but the mediators of this activation remain disputed. Here we show that the chemokine CCL2, produced by both damaged and undamaged primary sensory neurons in neuropathic pain states in rats, is released in an activity dependent manner from the central terminals of these fibres. We also demonstrate that intraspinal CCL2 in naïve rats leads to activation of spinal microglia and neuropathic pain‐like behavior. An essential role for spinal CCL2 is demonstrated by the inhibition of neuropathic pain behavior and microglial activation by a specific neutralising antibody to CCL2 administered intrathecally. Thus, the neuronal expression of CCL2 provides a mechanism for immune activation, which in turn regulates the sensitivity of pain signaling systems in neuropathic pain states.

Cortical changes in chronic low back pain: Current state of the art and implications for clinical practice

There is increasing evidence that chronic pain problems are characterised by alterations in brain structure and function. Chronic back pain is no exception. There is a growing sentiment, with accompanying theory, that these brain changes contribute to chronic back pain, although empirical support is lacking. This paper reviews the structural and functional changes of the brain that have been observed in people with chronic back pain. We cast light on the clinical implications of these changes and the possibilities for new treatments but we also advise caution against concluding their efficacy in the absence of solid evidence to this effect.

Alterations in Resting-State Regional Cerebral Blood Flow Demonstrate Ongoing Pain in Osteoarthritis An Arterial Spin-Labeled Magnetic Resonance Imaging Study

OBJECTIVE Increasing evidence suggests a central nervous system (CNS) component underpinning persistent pain disease states. This study was undertaken to determine regional cerebral blood flow (rCBF) changes representing ongoing pain experienced by patients with painful osteoarthritis (OA) of the carpometacarpal (CMC) joint and to examine rCBF variability across sessions. We used pulsed continuous arterial spin labeling (pCASL), a perfusion magnetic resonance imaging (MRI) technique. METHODS The study included 16 patients with CMC OA and 17 matched controls. Two pCASL scans and numerical rating scale (NRS) estimates of ongoing pain were acquired in each of two identical sessions. Voxelwise general linear model analyses were performed to determine rCBF differences between OA and control groups, rCBF differences between sessions within each group, and whether sessionwise rCBF differences were related to variability in perceived ongoing pain. RESULTS In the OA group, rCBF increases representing ongoing pain were identified in the primary and secondary somatosensory, insula, and cingulate cortices; thalamus; amygdala; hippocampus; and dorsal midbrain/pontine tegmentum, including the periaqueductal gray/nucleus cuneiformis. Sessionwise rCBF differences in the OA group in the postcentral, rostral/subgenual cingulate, mid/anterior insula, prefrontal, and premotor cortices were related to changes in perceived ongoing pain. No significant sessionwise rCBF differences were observed in controls. CONCLUSION This is the first quantitative endogenous perfusion MRI study of the cerebral representation of ongoing, persistent pain due to OA. Observed rCBF changes potentially indicate dysregulated CNS appraisal and modulation of pain, most likely the maladaptive neuroplastic sequelae of living with painful OA. Understanding the neural basis of ongoing pain is likely to be important in developing novel treatment strategies.

Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen.

Abstract Nonopioid agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are the most commonly used class of analgesics. Increasing evidence suggests that cyclooxygenase (COX) inhibition at both peripheral and central sites can contribute to the antihyperalgesic effects of NSAIDs, with the predominant clinical effect being mediated centrally. In this study, we examined the cerebral response to ibuprofen in presurgical and postsurgical states and looked at the analgesic interaction between surgical state and treatment. We used an established clinical pain model involving third molar extraction, and quantitative arterial spin labelling (ASL) imaging to measure changes in tonic/ongoing neural activity. Concurrent to the ASL scans, we presented visual analogue scales inside the scanner to evaluate the subjective experience of pain. This novel methodology was incorporated into a randomized double-blind placebo-controlled design, with an open method of drug administration. We found that independent of its antinociceptive action, ibuprofen has no effect on regional cerebral blood flow under pain-free conditions (presurgery). However, in the postsurgical state, we observed increased activation of top–down modulatory circuits, which was accompanied by decreases in the areas engaged because of ongoing pain. Our findings demonstrate that ibuprofen has a measurable analgesic response in the human brain, with the subjective effects of pain relief reflected in two distinct brain networks. The observed activation of descending modulatory circuits warrants further investigation, as this may provide new insights into the inhibitory mechanisms of analgesia that might be exploited to improve safety and efficacy in pain management.

Anatomical and functional correlates of persistent pain in Parkinson's disease.

The pathophysiology of pain in Parkinsons disease (PD) is still poorly understood, although it is conceivable that supraspinal mechanisms may be responsible for pain generation and maintenance.

Pharmacologic Modulation of Hand Pain in Osteoarthritis: A Double‐Blind Placebo‐Controlled Functional Magnetic Resonance Imaging Study Using Naproxen

In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint.

Pharmacologic modulation of hand pain in osteoarthritis

In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint.

The close proximity of threat: altered distance perception in the anticipation of pain

Pain is an experience that powerfully influences the way we interact with our environment. What is less clear is the influence that pain has on the way we perceive our environment. We investigated the effect that the anticipation of experimental pain (THREAT) and its relief (RELIEF) has on the visual perception of space. Eighteen (11F) healthy volunteers estimated the distance to alternating THREAT and RELIEF stimuli that were placed within reachable space. The results determined that the estimated distance to the THREAT stimulus was significantly underestimated in comparison to the RELIEF stimulus. We conclude that pain-evoking stimuli are perceived as closer to the body than otherwise identical pain-relieving stimuli, an important consideration when applied to our decisions and behaviors in relation to the experience of pain.

Perceptual bias in pain: A switch looks closer when it will relieve pain than when it won’t

Summary Pain alters the way the environment is perceived. A pain‐relieving switch looks closer when you are experiencing pain than when you are not. Abstract Pain is fundamental to survival, as are our perceptions of the environment. It is often assumed that we see our world as a read‐out of the sensory information that we receive; yet despite the same physical makeup of our surroundings, individuals perceive differently. What if we “see” our world differently when we experience pain? Until now, the causal effect of experimental pain on the perception of an external stimulus has not been investigated. Eighteen (11 female) healthy volunteers participated in this randomised repeated‐measures experiment, in which participants estimated the distance to a switch placed on the table in front of them. We varied whether or not the switch would instantly stop a stimulus, set to the participant’s pain threshold, being delivered to their hand, and whether or not they were required to reach for the switch. The critical result was a strong interaction between reaching and pain [F(1, 181) = 4.8, P = 0.03], such that when participants experienced pain and were required to reach for a switch that would turn off the experimental stimulus, they judged the distance to that switch to be closer, as compared to the other 3 conditions (mean of the true distance 92.6%, 95% confidence interval 89.7%–95.6%). The judged distance was smaller than estimates in the other 3 conditions (mean ± SD difference >5.7% ± 2.1%, t(181) >3.5, P < 0.01 for all 3 comparisons). We conclude that the perception of distance to an object is modulated by the behavioural relevance of the object to ongoing pain.