Kevin A. Keay

Pain modulation is a fundamental survival mechanism that prioritises, shapes, and suppresses nociceptive inputs to optimise behaviour. Although acute pain signals potential or actual tissue damage, sustained pain can impair essential behaviours, necessitating modulatory circuits that dynamically regulate nociception according to context and motivational state. These systems are deeply conserved, embedded within primitive spinal and brainstem structures, and capable of powerful modulation independent of cortical input, although higher regions such as the prefrontal cortex can influence their function. Decades of work have sought to identify these core modulatory circuits to advance basic understanding and develop strategies for clinically meaningful hypoalgesia. More recently, dysfunction within these circuits has been implicated in chronic pain, driving efforts to characterise how their organisation and function change during persistent pain states. Although most mechanistic insights come from animal studies, human neuroimaging, particularly since the advent of functional magnetic resonance imaging, has begun to map their location and engagement during pain modulation. Early work focused on forebrain regions due to the limited spatial resolution of standard MRI, but ultra-high-field functional magnetic resonance imaging now enables mm ³ -scale investigation of brainstem nuclei. This review synthesises evidence from animal and human studies to outline the best-characterised modulatory pathway, consisting of projections from the midbrain periaqueductal gray to the rostral ventromedial medulla and onward to the dorsal horn/spinal trigeminal nucleus, and highlights recent work detailing its organization.

Brain imaging studies have identified structural alterations in individuals with chronic neuropathic pain, particularly in regions involved in sensory, emotional, and cognitive processing. However, most studies remain cross-sectional, leaving the temporal progression of these changes during pain chronification unclear. This gap is critical, as both neural and non-neural cells undergo dynamic changes during pain chronification. The primary aim of this study was to track longitudinally regional brain volume and density changes before and after induction of orofacial neuropathic pain in male rats, using a chronic constriction injury of the infraorbital nerve (ION-CCI). This model enables assessment of changes in the spinal trigeminal nucleus (SpVn). T2-weighted magnetic resonance imaging scans were acquired 7 d prior to injury and then at +2, +7, +14, and +28 d, in ION-CCI ( n = 11), sham-injured ( n = 6), and naive ( n = 8) groups. Voxel-based and deformation-based morphometry were used to identify early- and late-onset density and volumetric changes, respectively. Early after injury, transient, bidirectional volume and/or density changes in the ipsilateral primary somatosensory cortex (S1), contralateral SpVn, and bilateral dorsomedial periaqueductal gray, ipsilateral retrosplenial and contralateral prelimbic cortices, were observed. In contrast, late-onset changes were more widespread, with volume increases observed bilaterally in the SpVn pars interpolaris (SpVo), in the ipsilateral dorsomedial SpVn (SpVdm), bilateral lateral hypothalamus, and contralateral amygdalo-hippocampal complex, and volume decreases in contralateral retrosplenial, prelimbic, and bilateral S1 cortices. These findings reveal early dynamic reorganization of sensory and sensory-modulatory brain regions, followed by sustained structural alterations across trigeminal brainstem nuclei, limbic-hypothalamic systems, and higher-order cortical networks.

Chronic neuropathic pain represents a significant global health burden and is hypothesized to be maintained by an altered astrocyte‐neuron interplay. Evidence of astrocyte contributions to neuropathic pain are derived from both post‐mortem immunohistochemical analyses and in vivo pharmacological studies. These data cannot provide insights into dynamic changes in astrocytes within an individual as pain develops. Here, we present the first use of [ ¹⁸ F]‐SMBT‐1, a radioisotope that binds monoamine oxidase‐B (MAO‐B) in reactive astrocytes, in a longitudinal (35 days) study of the development of orofacial neuropathic pain. We used the chronic constriction injury of the infraorbital nerve (ION‐CCI) to produce orofacial neuropathic pain in adult male Sprague–Dawley rats, which we compared to both sham‐injury and anesthesia controls. Between 14 and 28 days following ION‐CCI, increases in SMBT‐1 binding occurred in: the trigeminal nerve, ganglion and the spinal trigeminal nucleus; as well as the nucleus accumbens and dorsal striatum. Increased MAO‐B expression in these regions was confirmed using immunohistochemical analysis. MAO‐B expression was also confirmed in the ION, the trigeminal ganglion, and trigeminal root entry zone. These data provide evidence of regional and temporally specific increases in astrocyte reactivity, which may be critical for establishing chronic orofacial neuropathic pain. Longitudinal mapping of changes in astrocyte reactivity during the development of chronic orofacial neuropathic pain will provide an opportunity to test the potential of astrocyte specific compounds delivered at specific time points following nerve injury, to determine the key brain regions that could be targeted to prevent and/or reverse the development of chronic neuropathic pain.

Body procurement at The University of Sydney has a long history. Anatomy legislation (1881 Anatomy Act) modeled on the British Anatomy Act 1832 legalized procurement of unclaimed bodies from public institutions for anatomical dissection at licensed Schools of Anatomy, effectively conferring the University of Sydney an exclusive license until the 1960s. This study documents the procurement of 7609 bodies between 1883 and 1983, of which 4084 were unclaimed. Until the 1930s, bodies were predominantly from public asylums, with a small number from psychiatric asylums, hospitals and morgues. Donors were uncommon as were female bodies, reflecting prevailing societal antipathy toward anatomical dissection, the characteristics of asylum residents, and academic attitudes to the dissection of the female body. The individuals whose bodies sustained medical education were diverse in origin and circumstances: ex‐convicts, immigrants, miners, Chinese indentured laborers, Indigenous Australians and locally born individuals. Although the law provided a limited right of objection, asylum residents were poorly positioned to exercise it. Mirroring practice across the Western World, their classification as “unclaimed” reflected legal procedure and poverty, institutionalization, separation from family, discriminatory and inaccurate record‐keeping, and Colonial‐era assumptions of social worth. Little consideration was given to their cultural beliefs, preferences and rights. The University shifted to a body donation program in the 1940s as the availability of unclaimed bodies diminished. This shift was rapid; the last unclaimed body was received in 1961.

Placebo analgesia is widely believed to rely on psychological, genetic, and biological factors. Whilst these factors have been assessed in single expressions of this phenomenon, few have documented its consistency over time, limiting understanding of its stability, and by extension, consideration in non-experimental settings. Here we show in 30 control participants by combining magnetic resonance imaging and a longitudinal design spanning five sessions, the psychological and neural substrates underpinning Placebo Analgesia response consistency.