Segmental Chiropractic Spinal Manipulation Does not Reduce Pain Amplification and the Associated Pain-Related Brain Activity in a Capsaicin-Heat Pain Model

Musculoskeletal injuries lead to sensitization of nociceptors and primary hyperalgesia (hypersensitivity to painful stimuli). This occurs with back injuries, which are associated with acute pain and increased pain sensitivity at the site of injury. In some cases, back pain persists and leads to central sensitization and chronic pain. Thus, reducing primary hyperalgesia to prevent central sensitization may limit the transition from acute to chronic back pain. It has been shown that spinal manipulation (SM) reduces experimental and clinical pain, but the effect of SM on primary hyperalgesia and hypersensitivity to painful stimuli remains unclear. The goal of the present study was to investigate the effect of SM on pain hypersensitivity using a capsaicin-heat pain model. Laser stimulation was used to evoke heat pain and the associated brain activity, which were measured to assess their modulation by SM. Eighty healthy participants were recruited and randomly assigned to one of the four experimental groups: inert cream and no intervention; capsaicin cream and no intervention; capsaicin cream and SM at T7; capsaicin cream and placebo. Inert or capsaicin cream (1%) was applied to the T9 area. SM or placebo were performed 25 min after cream application. A series of laser stimuli were delivered on the area of cream application (1) before cream application, (2) after cream application but before SM or placebo, and (3) after SM or placebo. Capsaicin cream induced a significant increase in laser pain (p < 0.001) and laser-evoked potential amplitude (p < 0.001). However, SM did not decrease the amplification of laser pain or laser-evoked potentials by capsaicin. These results indicate that segmental SM does not reduce pain hypersensitivity and the associated pain-related brain activity in a capsaicin-heat pain model.

Neural Processing of Pain and Itch

Pain is defined as “An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage,” while itch can be defined as “an unpleasant sensation that evokes the desire to scratch.” These sensations are normally elicited by noxious or pruritic stimuli that excite peripheral sensory neurons connected to spinal circuits and ascending pathways involved in sensory discrimination, emotional aversiveness, and respective motor responses. Specialized molecular receptors expressed by cutaneous nerve endings transduce stimuli into action potentials conducted by C- and Aδ-fiber nociceptors and pruriceptors into the outer lamina of the dorsal horn of the spinal cord. Here, neurons selectively activated by nociceptors, or by convergent input from nociceptors, pruriceptors, and often mechanoreceptors, transmit signals to ascending spinothalamic and spinoparabrachial pathways. The spinal circuitry for itch requires interneurons expressing gastrin-releasing peptide and its receptor, while spinal pain circuitry involves other excitatory neuropeptides; both itch and pain are transmitted by ascending pathways that express the receptor for substance P. Spinal itch- and pain-transmitting circuitry is segmentally modulated by inhibitory interneurons expressing dynorphin, GABA, and glycine, which mediate the antinociceptive and antipruritic effects of noxious counterstimulation. Spinal circuits are also under descending modulation from the brainstem rostral ventromedial medulla. Opioids like morphine inhibit spinal pain-transmitting circuits segmentally and via descending inhibitory pathways, while having the opposite effect on itch. The supraspinal targets of ascending pain and itch pathways exhibit extensive overlap and include the somatosensory thalamus, parabrachial nucleus, amygdala, periaqueductal gray, and somatosensory, anterior cingulate, insular, and supplementary motor cortical areas. Following tissue injury, enhanced pain is evoked near the injury (primary hyperalgesia) due to release of inflammatory mediators that sensitize nociceptors. Within a larger surrounding area of secondary hyperalgesia, innocuous mechanical stimuli elicit pain (allodynia) due to central sensitization of pain pathways. Pruriceptors can also become sensitized in pathophysiological conditions, such as dermatitis. Under chronic itch conditions, low-threshold tactile stimulation can elicit itch (alloknesis), presumably due to central sensitization of itch pathways, although this has not been extensively studied. There is considerable overlap in pain- and itch-signaling pathways and it remains unclear how these sensations are discriminated. Specificity theory states that itch and pain are separate sensations with their own distinct pathways (“labeled lines”). Selectivity theory is similar but incorporates the observation that pruriceptive neurons are also excited by algogenic stimuli that inhibit spinal itch transmission. In contrast, intensity theory states that itch is signaled by low firing rates, and pain by high firing rates, in a common sensory pathway. Finally, the spatial contrast theory proposes that itch is elicited by focal activation of a few nociceptors while activation of more nociceptors over a larger area elicits pain. There is evidence supporting each theory, and it remains to be determined how the nervous system distinguishes between pain and itch.

Dextromethorphan Analgesia in a Human Experimental Model of Hyperalgesia

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-d-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans. Methods This randomized, double-blind, placebo-controlled, crossover study explores the antihyperalgesic effect of single and repeated 30-mg dose of oral dextromethorphan in 20 volunteers, using the freeze-injury pain model. This model leads to development of primary and secondary hyperalgesia, which develops away from the site of injury and is associated with central sensitization and activation of N-methyl-d-aspartate receptor in the spinal cord. The primary outcome was antihyperalgesia calculated with the area under the curve of the percentage change in mechanical pain threshold (electronic von Frey) on the area of secondary hyperalgesia. The secondary outcomes were mechanical pain threshold on the area of primary hyperalgesia and cognitive (reaction time) effect. Results Single 30-mg results are reported. Antihyperalgesia (% · min) is significantly higher on the area of secondary hyperalgesia with dextromethorphan than placebo (median [interquartile range]: 3,029 [746; 6,195] vs. 710 [–3,248; 4,439], P = 0.009, Hedge’s g = 0.8, 95% CI [0.1; 1.4]). On primary hyperalgesia area, mechanical pain threshold 2 h after drug intake is significantly higher with dextromethorphan (P = 0.011, Hedge’s g = 0.63, 95% CI [0.01; 1.25]). No difference in antinociception is observed after thermal painful stimuli on healthy skin between groups. Reaction time (ms) is shorter with placebo than with dextromethorphan (median [interquartile range]: 21.6 [–37.4; 0.1] vs. –1.2 [–24.3; 15.4], P = 0.015, Hedge’s g = 0.75, 95% CI [0.12; 1.39]). Nonserious adverse events occurrence (15%, 3 of 20 volunteers) was similar in both groups. Conclusions This study shows that low-dose (30-mg) dextromethorphan is antihyperalgesic in humans on the areas of primary and secondary hyperalgesia and reverses peripheral and central neuronal sensitization. Because dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-d-aspartate receptor may need to be sensitized by pain for dextromethorphan to be effective.

TRPA1 Antagonists for Pain Relief

Here, we review the literature assessing the role of transient receptor potential ankyrin 1 (TRPA1), a calcium-permeable non-selective cation channel, in various types of pain conditions. In the nervous system, TRPA1 is expressed in a subpopulation of nociceptive primary sensory neurons, astroglia, oligodendrocytes and Schwann cells. In peripheral terminals of nociceptive primary sensory neurons, it is involved in the transduction of potentially harmful stimuli and in their central terminals it is involved in amplification of nociceptive transmission. TRPA1 is a final common pathway for a large number of chemically diverse pronociceptive agonists generated in various pathophysiological pain conditions. Thereby, pain therapy using TRPA1 antagonists can be expected to be a superior approach when compared with many other drugs targeting single nociceptive signaling pathways. In experimental animal studies, pharmacological or genetic blocking of TRPA1 has effectively attenuated mechanical and cold pain hypersensitivity in various experimental models of pathophysiological pain, with only minor side effects, if any. TRPA1 antagonists acting peripherally are likely to be optimal for attenuating primary hyperalgesia (such as inflammation-induced sensitization of peripheral nerve terminals), while centrally acting TRPA1 antagonists are expected to be optimal for attenuating pain conditions in which central amplification of transmission plays a role (such as secondary hyperalgesia and tactile allodynia caused by various types of peripheral injuries). In an experimental model of peripheral diabetic neuropathy, prolonged blocking of TRPA1 has delayed the loss of nociceptive nerve endings and their function, thereby promising to provide a disease-modifying treatment.

Validation of a porcine behavioural model of UVB induced inflammatory pain

Background and aim Cutaneous inflammation induced by ultraviolet B-light (UV-B) is considered a valuable translational pain model. Until now, the development of primary hyperalgesia has been assessed predominantly in rodents, whereas porcine skin might be advantageous due to its greater homology with human skin. The aim of the present study was to investigate porcine behavioural responses to nociceptive mechanical and thermal stimulations following UV-B inflammation. Methods One skin area of 4 cm2 in the flank of 16 male pigs of 55 ± 6 kg was irradiated by UV-B using 3xMED (Minimum Erythema Dose). Changes in pain sensitivity were assessed 24 and 48 h following irradiation via delivery of mechanical (Pressure Application Measurement device) and thermal (CO2 laser) stimulations to the inflamed skin area and to an untreated control site. Results All animals showed higher sensitivity in the inflamed skin site 24 and 48 h following irradiation, compared to the control site (P< 0.05). Pressure withdrawal threshold decreased in the inflamed site: 231 g (148–451) against 408g (347–684) after 24 hours and 200 g (106–293) against 656g (405–902) after 48 h. Similarly, latency to respond to the laser stimulus was lower at the inflamed site: 5 s (3–7) against 9 s (4–2) after 24h and 4 s (3–15) against 20 s (8–25) after 48 h. One and two days after irradiation, a tendency was found for an increased cutaneous mechanical pain sensitivity compared to baseline values in the site irradiated with UV-B light (P = 0.092). Thermal sensitivity was increased within the inflamed site 24 h after irradiation with latency changing from 17s (4–25) at baseline to 5 s (3–7) at 24 h (P =0.001). At 48 h, the response latency had not decreased any further (P = 0.414). Conclusions Our study shows that behavioural recordings are a valid tool for the assessment of mechanical and heat sensitization following UV-B inflammation in porcine skin.