SARS-CoV-2 sneezing explained.

Viral protein prods nerve cells, may be treatment target.

Innate Receptors Expression by Lung Nociceptors: Impact on COVID-19 and Aging.

The lungs are constantly exposed to non-sterile air which carries harmful threats, such as particles and pathogens. Nonetheless, this organ is equipped with fast and efficient mechanisms to eliminate these threats from the airways as well as prevent pathogen invasion. The respiratory tract is densely innervated by sensory neurons, also known as nociceptors, which are responsible for the detection of external stimuli and initiation of physiological and immunological responses. Furthermore, expression of functional innate receptors by nociceptors have been reported; however, the influence of these receptors to the lung function and local immune response is poorly described. The COVID-19 pandemic has shown the importance of coordinated and competent pulmonary immunity for the prevention of pathogen spread as well as prevention of excessive tissue injury. New findings suggest that lung nociceptors can be a target of SARS-CoV-2 infection; what remains unclear is whether innate receptor trigger sensory neuron activation during SARS-CoV-2 infection and what is the relevance for the outcomes. Moreover, elderly individuals often present with respiratory, neurological and immunological dysfunction. Whether aging in the context of sensory nerve function and innate receptors contributes to the disorders of these systems is currently unknown. Here we discuss the expression of innate receptors by nociceptors, particularly in the lungs, and the possible impact of their activation on pulmonary immunity. We then demonstrate recent evidence that suggests lung sensory neurons as reservoirs for SARS-CoV-2 and possible viral recognition via innate receptors. Lastly, we explore the mechanisms by which lung nociceptors might contribute to disturbance in respiratory and immunological responses during the aging process.

Different roles of nitric oxide synthase-1 and -2 between herpetic and postherpetic allodynia in mice.

We investigated using the mice role of nitric oxide synthase (NOS) in the spinal dorsal horn in herpetic and postherpetic pain, especially allodynia, which was induced by transdermal inoculation of the hind paw with herpes simplex virus type-1 (HSV-1). The virus inoculation induced NOS2 expression in the lumbar dorsal horn of mice with herpetic allodynia, but not postherpetic allodynia. There were no substantial alternations in the expression level of NOS1 at the herpetic and postherpetic stages. Herpetic allodynia was significantly inhibited by i.p. administration of the selective NOS2 inhibitor S-methylisothiourea, but not the selective NOS1 inhibitor 7-nitroindazole. NOS2 expression was observed around HSV-1 antigen-immunoreactive cells. On the other hand, postherpetic allodynia was significantly inhibited by i.p. administration of 7-nitroindazole, but not S-methylisothiourea. The activity of reduced nicotinamide adenine dinucleotide phosphate diaphorase, an index of NOS1 activity, significantly increased in the laminae I and II of the lumbar dorsal horn of mice with postherpetic allodynia, but not mice without postherpetic allodynia. The expression level of NOS1 mRNA in the dorsal root ganglia was similar between mice with and without postherpetic allodynia. The results suggest that herpetic and postherpetic allodynia is mediated by nitric oxide in the dorsal horn and that NOS2 and NOS1 are responsible for herpetic and postherpetic allodynia, respectively. It may be worth testing the effects of NOS2 and NOS1 inhibitors on herpetic pain and postherpetic neuralgia in human subjects, respectively.

Further characterization of a rat model of varicella zoster virus-associated pain: Relationship between mechanical hypersensitivity and anxiety-related behavior, and the influence of analgesic drugs.

Persistent herpes zoster-associated pain is a significant clinical problem and an area of largely unmet therapeutic need. Progress in elucidating the underlying pathophysiology of zoster-associated pain and related co-morbidity behavior, in addition to appropriately targeted drug development has been hindered by the lack of an appropriate animal model. This study further characterizes a recently developed rat model of zoster-associated hypersensitivity and investigates (a) response to different viral strains; (b) relationship between viral inoculum concentration ('dose') and mechanical hypersensitivity ('response'); (c) attenuation of virus-associated mechanical hypersensitivity by clinically useful analgesic drugs; and (d) measurement of pain co-morbidity (anxiety-like behavior) and pharmacological intervention in the open field paradigm (in parallel with models of traumatic peripheral nerve injury). Varicella zoster virus was propagated on fibroblast cells before s.c. injection into the glabrous footpad of the left hind limb of adult male Wistar rats. Control animals received injection of uninfected fibroblast cells. Hind-limb reflex withdrawal thresholds to mechanical, noxious thermal and cooling stimuli were recorded at specified intervals post-infection. Infection with all viral strains was associated with a dose-dependent mechanical hypersensitivity but not a thermal or cool hypersensitivity. Systemic treatment with i.p. morphine (2.5 mg/kg), amitriptyline (10 mg/kg), gabapentin (30 mg/kg), (S)-(+)-ibuprofen (20 mg/kg) and the cannabinoid WIN55,212-2 (2 mg/kg) but not the antiviral, acyclovir (50 mg/kg), was associated with a reversal of mechanical paw withdrawal thresholds. In the open field paradigm, virus-infected and nerve-injured animals demonstrated an anxiety-like pattern of ambulation (reduced entry into the central area of the open arena) which was positively correlated with mechanical hypersensitivity. This may reflect pain-related co-morbidity. Further, anxiety-like behavior was attenuated by acute i.p. administration of gabapentin (30 mg/kg) in nerve-injured, but not virus-infected animals. This model will prove useful in elucidating the pathophysiology of zoster-associated pain and provide a tool for pre-clinical screening of analgesic drugs.

Differential sensitivity of thick and thin fibers to HIV and therapy-induced neuropathy.

The study assessed HIV-related and anti-retroviral therapy-induced neuropathy in myelinated and unmyelinated nerve fibers. One hundred consecutive HIV patients were examined clinically and standard nerve conduction velocities were measured. In addition, electrically induced sympathetic skin response (SSR) was assessed in the palms and soles. The difference in delay of SSR in palms and soles (DeltaSSR) was calculated as an indirect measure of C-fiber conduction velocity. Thick fiber conduction velocities significantly decreased with age and increasing stage of the disease, whereas no effect of stage was found for DeltaSSR (p=0.6). In contrast, medication of at least one of the most known neurotoxic drugs zalcitabine, stavudine, or didanosine did not result in significantly lower conduction velocities in thick fibers (51.29+/-3.4 m/s vs. 50.86+/-3.5 m/s), but was related to an increased DeltaSSR. DeltaSSR allows an indirect measurement of C-fiber conduction velocity. In HIV this measure of unmyelinated sympathetic fibers was most sensitive to anti-viral treatment whereas conduction velocity of myelinated somatic fibers was more sensitive to disease-related neuropathy. The results suggest that HIV neuropathy preferably affects myelinated and anti-retroviral therapy unmyelinated fibers.

Viral Spread to Enteric Neurons Links Genital HSV-1 Infection to Toxic Megacolon and Lethality.

Herpes simplex virus 1 (HSV-1), a leading cause of genital herpes, infects oral or genital mucosal epithelial cells before infecting the peripheral sensory nervous system. The spread of HSV-1 beyond the sensory nervous system and the resulting broader spectrum of disease are not well understood. Using a mouse model of genital herpes, we found that HSV-1-infection-associated lethality correlated with severe fecal and urinary retention. No inflammation or infection of the brain was evident. Instead, HSV-1 spread via the dorsal root ganglia to the autonomic ganglia of the enteric nervous system (ENS) in the colon. ENS infection led to robust viral gene transcription, pathological inflammatory responses, and neutrophil-mediated destruction of enteric neurons, ultimately resulting in permanent loss of peristalsis and the development of toxic megacolon. Laxative treatment rescued mice from lethality following genital HSV-1 infection. These results reveal an unexpected pathogenesis of HSV associated with ENS infection.

The density of remaining nerve endings in human skin with and without postherpetic neuralgia after shingles.

The mechanisms of chronic neuropathic pain are not well understood. Postherpetic neuralgia (PHN), which occurs in some patients after shingles (herpes zoster), was used to investigate the neural determinants of chronic pain. Skin biopsies were obtained from 38 adults with or without PHN at least 3 months after healing of shingles on the torso. Vertical sections were immunolabeled against PGP9.5, a pan-axonal marker, to measure the density of remaining nerve endings in skin previously affected by shingles. All axons that end in the epidermis are nociceptors, neurons that transmit pain messages. The densities ranged between 2 and 3976 neurites/mm2 skin surface, but the overlap between subjects and without PHN was small. Of 19 subjects without PHN, 17 had more than 670 neurites/mm2 skin surface area (mean +/- SEM = 1569 +/- 230), and 18 of 19 subjects with PHN had 640 or fewer neurites/mm2 (mean +/- SEM = 367 +/- 92). PHN may be a 'phantom-skin' pain associated with loss of nociceptors. This threshold of approximately 650 neurites/mm2 skin surface was not detected in previous studies that used summary statistics. It implies that the absence of pain after shingles may require the preservation of a minimum density of primary nociceptive neurons, and that the density of epidermal innervation may provide an objective correlate for the presence or absence of PHN pain.

Treatment considerations in painful HIV-related neuropathy.

BACKGROUND: Human immunodeficiency virus (HIV)-related distal sensory polyneuropathy (DSP) is the most common HIV-associated sensory neuropathy. The envelope glycoprotein of HIV-1, gp 120, appears to contribute to this painful neuropathy. Two standard treatments for HIV infection/HIV-related painful DSP (e.g., antiviral therapy [e.g., nucleoside reverse transcriptase inhibitors (NRTI)] opioids) should each be carefully evaluated prior to being utilized to ameliorate the pain of DSP, since they may actually promote nociception. Nucleoside reverse transcriptase inhibitors require activation in the cell via the addition of 3 phosphate groups (by cellular kinases) to their deoxyribose moiety, to form NRTI triphosphates. Subsequently, these deoxynucleotide analogs compete with natural deoxynucleotides for incorporation into the growing viral DNA chain. The incorporation of NRTIs into the viral DNA chain leads to chain termination; since the nucleoside reverse transcriptase inhibitors lack a 3'-hydroxyl group on the deoxyribose moiety (unlike natural deoxynucleotides), so that the next incoming deoxynucleotide cannot form the next 5'-3' phosphodiester bond needed to extend the DNA chain. Unfortunately, many conventional agents utilized as pharmacologic therapy for neuropathic pain are not effective for providing satisfactory analgesia in painful HIV-related distal sensory polyneuropathy. Although there is no robust data, there does seem to be information which would support the notion of opioids having increased risk of being particularly pronociceptive when being used to treat painful HIV-related neuropathy. It thus appears conceivable that the use of at least certain opioids in efforts to achieve analgesia in patients with painful HIV-related neuropathy may be less than ideal since at least certain opioid analgesics themselves may potentially contribute to "fueling the fire" of HIV enhanced pain hypersensitivity; at least in part via upregulation of specific chemokine receptors (e.g., CXCR4) which seem to be vitally important in promoting HIV-related pain facilitation. The risk benefit ratio of treatment with agents such as NRTIs as well as opioids should be reviewed for specific individual patients, prior to clinicians initiating these agents. OBJECTIVES: To raise awareness of the theoretical potential downside that opioids may possess if they are used for the treatment of painful HIV-related neuropathy. METHODS: A narrative review of selected literature. LIMITATIONS: Hypothetical in nature. CONCLUSIONS: Clinicians should consider all aspects of various therapeutic options, carefully weighing the risk/benefit ratios of each potential treatment before initiating opioids for painful HIV-related neuropathy.  

Activation of CNS circuits producing a neurogenic cystitis: evidence for centrally induced peripheral inflammation.

We present a model of neurogenic cystitis induced by viral infection of specific neuronal circuits of the rat CNS. Retrograde infection by pseudorabies virus (PRV) of neuronal populations neighboring those that innervate the bladder consistently led to a localized immune response in the CNS and bladder inflammation. Infection of bladder circuits themselves or of circuits distant from these rarely produced cystitis. Absence of virus in bladder and urine ruled out an infectious cystitis. Total denervation of the bladder, selective C-fiber deafferentation, or bladder sympathectomy prevented cystitis without affecting the CNS disease, indicating a neurogenic component to the inflammation. The integrity of central bladder-related circuits is necessary for the appearance of bladder inflammation, because only CNS lesions affecting bladder circuits, i.e., bilateral dorsolateral or ventrolateral funiculectomy, as well as bilateral lesions of Barrington's nucleus/locus coeruleus area, prevented bladder inflammation. The close proximity in the CNS of noninfected visceral circuits to infected somatic neurons would thus permit a bystander effect, leading to activation of the sensory and autonomic circuits innervating the bladder and resulting in a neurogenic inflammation localized to the bladder. The present study indicates that CNS dysfunction can bring about a peripheral inflammation.