Jasenka Borzan

A Role for Polymodal C-Fiber Afferents in Nonhistaminergic Itch

Recent psychophysical and electrophysiological studies in humans suggest the existence of two peripheral pathways for itch, one that is responsive to histamine and a second pathway that can be activated by nonhistaminergic pruritogens (e.g., cowhage spicules). To explore the peripheral neuronal pathway for nonhistaminergic itch, behavioral responses and neuronal activity in unmyelinated afferent fibers were assessed in monkey after topical application of cowhage spicules or intradermal injection of histamine and capsaicin. Cowhage and histamine, but not capsaicin, evoked scratching behavior indicating the presence of itch. In single-fiber recordings, cowhage, histamine and/or capsaicin were applied to the cutaneous receptive field of 43 mechano-heat-sensitive C-fiber (CMH) nociceptors. The majority of CMHs exhibited a prolonged response to cowhage (39 of 43) or histamine (29 of 38), but not to capsaicin (3 of 34). Seven CMHs were activated by cowhage but not histamine. The average response to cowhage was more than twice the response to histamine, and responses were not correlated. The response of the CMHs to a stepped heat stimulus (49°C, 3 s) was either quickly adapting (QC) or slowly adapting (SC). In contrast, the cowhage response was characterized by bursts of two or more action potentials (at ∼1 Hz). The total cowhage response of the QC fibers (97 action potentials/5 min) was twice that of the SC fibers (49 action potentials/5 min). A subset of QC fibers exhibited high-frequency intraburst discharges (∼30 Hz). These results suggest multiple mechanisms by which CMHs may encode itch to cowhage as well as pain to mechanical and heat stimuli.

A Role for Nociceptive, Myelinated Nerve Fibers in Itch Sensation

Despite its clinical importance, the underlying neural mechanisms of itch sensation are poorly understood. In many diseases, pruritus is not effectively treated with antihistamines, indicating the involvement of nonhistaminergic mechanisms. To investigate the role of small myelinated afferents in nonhistaminergic itch, we tested, in psychophysical studies in humans, the effect of a differential nerve block on itch produced by intradermal insertion of spicules from the pods of a cowhage plant (Mucuna pruriens). Electrophysiological experiments in anesthetized monkey were used to investigate the responsiveness of cutaneous, nociceptive, myelinated afferents to different chemical stimuli (cowhage spicules, histamine, capsaicin). Our results provide several lines of evidence for an important role of myelinated fibers in cowhage-induced itch: (1) a selective conduction block in myelinated fibers substantially reduces itch in a subgroup of subjects with A-fiber-dominated itch, (2) the time course of itch sensation differs between subjects with A-fiber- versus C-fiber-dominated itch, (3) cowhage activates a subpopulation of myelinated and unmyelinated afferents in monkey, (4) the time course of the response to cowhage is different in myelinated and unmyelinated fibers, (5) the time of peak itch sensation for subjects with A-fiber-dominated itch matches the time for peak response in myelinated fibers, and (6) the time for peak itch sensation for subjects with C-fiber-dominated itch matches the time for the peak response in unmyelinated fibers. These findings demonstrate that activity in nociceptive, myelinated afferents contributes to cowhage-induced sensations, and that nonhistaminergic itch is mediated through activity in both unmyelinated and myelinated afferents.

Mitochondrial dysfunction in distal axons contributes to human immunodeficiency virus sensory neuropathy

Accumulation of mitochondrial DNA (mtDNA) damage has been associated with aging and abnormal oxidative metabolism. We hypothesized that in human immunodeficiency virus‐associated sensory neuropathy (HIV‐SN), damaged mtDNA accumulates in distal nerve segments, and that a spatial pattern of mitochondrial dysfunction contributes to the distal degeneration of sensory nerve fibers.

Windup in Dorsal Horn Neurons Is Modulated by Endogenous Spinal μ-Opioid Mechanisms

The μ-opioid receptor (MOR) plays a critical role in morphine analgesia and nociceptive transmission. However, the physiological roles for endogenous MOR mechanisms in modulating spinal nociceptive transmission, and particularly in the enhanced excitability of spinal nociceptive neurons after repeated noxious inputs, are less well understood. Using a MOR gene knock-out (−/−) approach and an MOR-preferring antagonist, we investigated the roles of endogenous MOR mechanisms in processing of acute noxious input and in neuronal sensitization during windup-inducing stimuli in wide dynamic range (WDR) neurons. Extracellular single-unit activity of WDR neurons was recorded in isoflurane-anesthetized MOR−/− and wild-type C57BL/6 mice. There were no significant differences between the genotypes in the responses of deep WDR cells to acute mechanical stimuli, graded electrical stimuli, and noxious chemical stimuli applied to the receptive field. Intracutaneous electrical stimulation at 1.0 Hz produced similar levels of windup in both genotypes. In contrast, 0.2 Hz stimulation induced significantly higher levels of windup in MOR−/− mice compared with the wild-type group. In wild-type mice, spinal superfusion with naloxone hydrochloride (10 mm, 30 μl) significantly enhanced windup to 0.2 Hz stimulation in both deep and superficial WDR cells. A trend toward facilitation of windup was also observed during 1.0 Hz stimulation after naloxone treatment. These results suggest that endogenous MOR mechanisms are not essential in the processing of acute noxious mechanical and electrical stimuli by WDR neurons. However, MORs may play an important role in endogenous inhibitory mechanisms that regulate the development of spinal neuronal sensitization.

Three functionally distinct classes of C-fibre nociceptors in primates

In primate C-fiber polymodal nociceptors are broadly classified into two groups based on mechanosensitivity. Here we demonstrate that mechanically-sensitive polymodal nociceptors that respond either quickly (QC) or slowly (SC) to a heat stimulus differ in responses to a mild burn, heat sensitization, conductive properties and chemosensitivity. Superficially applied capsaicin and intradermal injection of β-alanine, a MrgprD agonist, excite vigorously all QCs. Only 40% of SCs respond to β-alanine, and their response is only half that of QCs. Mechanically-insensitive C-fibers (C-MIAs) are β-alanine insensitive but vigorously respond to capsaicin and histamine with distinct discharge patterns. Calcium imaging reveals that β-alanine and histamine activate distinct populations of capsaicin responsive neurons in primate DRG. We suggest that histamine itch and capsaicin pain are peripherally encoded in C-MIAs and that primate polymodal nociceptive afferents form three functionally distinct subpopulations with β-alanine responsive QC fibers likely corresponding to murine MrgprD- expressing, non-peptidergic nociceptive afferents.

Food, pain, and drugs: Does it matter what pain patients eat?

In 2003, the World Health Organization published a report on the global change in diet resulting from industrialization, urbanization, and market globalization, and the impact on the development of chronic disease [12]. The adverse dietary changes are characterized by a high-energy density diet with greater intake of saturated fats and sugars, reduced complex carbohydrates, dietary fibre, and reduced fruit and vegetable intakes. Modern dietary patterns are considered to be risk behaviours, and the World Health Organization identifies nutrition as a ‘‘major modifiable determinant of chronic disease.’’ The importance of nutrition in promoting health and preventing disease is well established. The central nervous system has specific nutritional requirements. Essential fatty acids such as eicosapentaenoic, arachidonic acids, and tryptophan (the precursor of serotonin) are not synthesized by mammals, but derived from foodstuffs. Micronutrients are important for central nervous system function; vitamin B12 and folate deficiencies result in painful peripheral neuropathy, while vitamin D deficiency causes musculoskeletal pain. Scurvy, which causes bone pain and myalgia, is still present in developed countries [22,38]. Malnutrition is a growing problem in industrialized countries and appears to be related to the abundance and availability of the wrong kind of food [35]. Other contributing factors are eating disorders, food allergies, and fad diets. Nutritional strategies may be useful for improving pain management. Such strategies include optimizing the diet to ensure adequate intake of vitamins and essential amino acids, increasing intake of foodstuffs that reduce pain, and restricting foodstuffs that may facilitate pain or reduce the effectiveness of oral analgesics.

A Role for Acid-sensing Ion Channel 3, but Not Acid-sensing Ion Channel 2, in Sensing Dynamic Mechanical Stimuli

Background:Acid-sensing ion channels 2 and 3 (ASIC2 and ASIC3, respectively) have been implicated as putative mechanotransducers. Because mechanical hyperalgesia is a prominent consequence of nerve injury, we tested whether male and female ASIC2 or ASIC3 knockout mice have altered responses to mechanical and heat stimuli at baseline and during the 5 weeks after spinal nerve ligation. Methods:Age-matched, adult male and female ASIC2 knockout (n = 21) and wild-type (WT; n = 24) mice or ASIC3 knockout (n = 20) and WT (n = 19) mice were tested for sensitivity to natural stimuli before and after spinal nerve ligation surgery. All animals were first tested for baseline sensitivity to mechanical and heat stimuli and in a novel dynamic mechanical stimulation test. The same testing procedures were then repeated weekly after spinal nerve injury. Results:Compared with their respective WT counterparts, ASIC2 and ASIC3 knockout mice had normal baseline sensitivity to standard mechanical and heat stimuli. However, when exposed to a novel stroking stimulus to test sensitivity to dynamic mechanical stimulation, ASIC3 knockout mice were significantly more sensitive than were WT mice. After spinal nerve ligation, ASIC2 and ASIC3 knockout mice developed mechanical and heat hyperalgesia comparable with that of their respective WT controls. In addition, in both experiments, female mice were more sensitive than male mice to heat at baseline and after the nerve injury. Conclusions:We conclude that ASIC2 and ASIC3 channels are not directly involved in the development or maintenance of neuropathic pain after spinal nerve ligation. However, the ASIC3 channel significantly modulates the sensing of dynamic mechanical stimuli in physiologic condition.

Conduction Properties Distinguish Unmyelinated Sympathetic Efferent Fibers and Unmyelinated Primary Afferent Fibers in the Monkey

Background Different classes of unmyelinated nerve fibers appear to exhibit distinct conductive properties. We sought a criterion based on conduction properties for distinguishing sympathetic efferents and unmyelinated, primary afferents in peripheral nerves. Methodology/Principal Findings In anesthetized monkey, centrifugal or centripetal recordings were made from single unmyelinated nerve fibers in the peroneal or sural nerve, and electrical stimuli were applied to either the sciatic nerve or the cutaneous nerve endings, respectively. In centrifugal recordings, electrical stimulation at the sympathetic chain and dorsal root was used to determine the fibers origin. In centrifugal recordings, sympathetic fibers exhibited absolute speeding of conduction to a single pair of electrical stimuli separated by 50 ms; the second action potential was conducted faster (0.61 0.16%) than the first unconditioned action potential. This was never observed in primary afferents. Following 2 Hz stimulation (3 min), activity-dependent slowing of conduction in the sympathetics (8.6 0.5%) was greater than in one afferent group (6.7 0.5%) but substantially less than in a second afferent group (29.4 1.9%). In centripetal recordings, most mechanically-insensitive fibers also exhibited absolute speeding to twin pulse stimulation. The subset that did not show this absolute speeding was responsive to chemical stimuli (histamine, capsaicin) and likely consists of mechanically-insensitive afferents. During repetitive twin pulse stimulation, mechanosensitive afferents developed speeding, and speeding in sympathetic fibers increased. Conclusions/Significance The presence of absolute speeding provides a criterion by which sympathetic efferents can be differentiated from primary afferents. The differences in conduction properties between sympathetics and afferents likely reflect differential expression of voltage-sensitive ion channels.

Effects of soy diet on inflammation-induced primary and secondary hyperalgesia in rat⋆

Soy consumption is said to prevent or treat atherosclerosis, cancer, pain, and memory deficits, but experimental and clinical evidence to support these claims are lacking. We used in vivo models of inflammation to determine whether a soy diet reduces primary or secondary hyperalgesia. In all three experiments, rats were fed either a soy‐ or casein‐based diet for at least 2 weeks before induction of inflammation and for the duration of experiments. Mechanical and heat paw withdrawal thresholds and edema were measured before and several times after induction of inflammation. Primary hyperalgesia was assessed in two models: unilateral intraplantar injection with 0.1 ml of 25% complete Freunds adjuvant (CFA) or 0.1 ml of 1% carrageenan. Unilateral injection of the intra‐articular knee space with 25% CFA (0.1 ml) was used to determine the effects of soy in a model of secondary hyperalgesia. Following intraplantar injection of CFA, soy‐fed animals exhibited significantly less paw edema, mechanical allodynia, and heat hyperalgesia compared to casein‐fed animals. In the carrageenan model of paw inflammation, soy‐fed animals were also less allodynic to mechanical stimuli, than were casein‐fed animals, but showed no diet based differences in paw edema or heat hyperalgesia. Soy diet did not affect any of the outcome measures after the intra‐articular injection of CFA. Our results suggest that a soy diet significantly decreases aspects of inflammation‐induced primary, but not secondary, hyperalgesia in rats.