Analgesia and peripheral c-fiber modulation by selective Nav1.8 inhibition in rhesus.

ABSTRACT: Voltage-gated sodium (Nav) channels present untapped therapeutic value for better and safer pain medications. The Nav1.8 channel isoform is of particular interest because of its location on peripheral pain fibers and demonstrated role in rodent preclinical pain and neurophysiological assays. To-date, no inhibitors of this channel have been approved as drugs for treating painful conditions in human, possibly because of challenges in developing a sufficiently selective drug-like molecule with necessary potency not only in human but also across preclinical species critical to the preclinical development path of drug discovery. In addition, the relevance of rodent pain assays to the human condition is under increasing scrutiny as a number of mechanisms (or at the very least molecules) that are active in rodents have not translated to humans, and direct impact on pain fibers has not been confirmed in vivo. In this report, we have leveraged numerous physiological end points in nonhuman primates to evaluate the analgesic and pharmacodynamic activity of a novel, potent, and selective Nav1.8 inhibitor compound, MSD199. These pharmacodynamic biomarkers provide important confirmation of the in vivo impact of Nav1.8 inhibition on peripheral pain fibers in primates and have high translational potential to the clinical setting. These findings may thus greatly improve success of translational drug discovery efforts toward better and safer pain medications, as well as the understanding of primate biology of Nav1.8 inhibition broadly.

Evaluation of a polymer-coated nanoparticle cream formulation of resiniferatoxin for the treatment of painful diabetic peripheral neuropathy.

ABSTRACT: Painful diabetic peripheral neuropathy (PDPN) is one of the major complications of diabetes. Currently, centrally acting drugs and topical analgesics are used for treating PDPN. These drugs have adverse effects; some are ineffective, and treatment with opioids is associated with use dependence and addiction. Recent research indicates that transient receptor potential vanilloid 1 (TRPV1) expressed in the peripheral sensory nerve terminals is an emerging target to treat pain associated with PDPN. Block of TRPV1 ion channel with specific antagonists, although effective as an analgesic, induced hyperthermia in clinical trials. However, TRPV1 agonists are useful to treat pain by virtue of their ability to cause Ca 2+ influx and subsequently leading to nerve terminal desensitization. Here, we report the effectiveness of an ultrapotent TRPV1 agonist, resiniferatoxin (RTX) nanoparticle, in a topical formulation (RTX-cream; RESINIZIN) that alleviates pain associated with DPN in animal models of diabetes. Resiniferatoxin causes nerve terminal depolarization block in the short term, which prevents pain during application and leading to nerve terminal desensitization/depletion in the long term resulting in long-lasting pain relief. Application of RTX cream to the hind limbs suppresses thermal hyperalgesia in streptozotocin-induced diabetic rats and mini pigs without any adverse effects as compared with capsaicin at therapeutic doses, which induces intense pain during application. Resiniferatoxin cream also decreases the expression of TRPV1 in the peripheral nerve endings and suppresses TRPV1-mediated calcitonin gene-related peptide release in the skin samples of diabetic rats and mini pigs. Our preclinical data confirm that RTX topical formulation is an effective treatment option for PDPN.

Paradoxical increases in anterior cingulate cortex activity during nitrous oxide-induced analgesia reveal a signature of pain affect.

The general consensus is that increases in neuronal activity in the anterior cingulate cortex (ACC) contribute to pain's negative affect. Here, using in vivo imaging of neuronal calcium dynamics in mice, we report that nitrous oxide, a general anesthetic that reduces pain affect, paradoxically, increases ACC spontaneous activity. As expected, a noxious stimulus also increased ACC activity. However, as nitrous oxide increases baseline activity, the relative change in activity from pre-stimulus baseline was significantly less than the change in the absence of the general anesthetic. We suggest that this relative change in activity represents a neural signature of the affective pain experience. Furthermore, this signature of pain persists under general anesthesia induced by isoflurane, at concentrations in which the mouse is unresponsive. We suggest that this signature underlies the phenomenon of connected consciousness, in which use of the isolated forelimb technique revealed that pain percepts can persist in anesthetized patients.

Role of Mechanoinsensitive Nociceptors in Painful Diabetic Peripheral Neuropathy.

The cutaneous mechanisms that trigger spontaneous neuropathic pain in diabetic peripheral neuropathy (PDPN) are far from clear. Two types of nociceptors are found within the epidermal and dermal skin layers. Small-diameter lightly myelinated Aδ and unmyelinated C cutaneous mechano and heat-sensitive (AMH and CMH) and C mechanoinsensitive (CMi) nociceptors transmit pain from the periphery to central nervous system. AMH and CMH fibers are mainly located in the epidermis, and CMi fibers are distributed in the dermis. In DPN, dying back intra-epidermal AMH and CMH fibers leads to reduced pain sensitivity, and the patients exhibit significantly increased pain thresholds to acute pain when tested using traditional methods. The role of CMi fibers in painful neuropathies has not been fully explored. Microneurography has been the only tool to access CMi fibers and differentiate AMH, CMH, and CMi fiber types. Due to the complexity, its use is impractical in clinical settings. In contrast, a newly developed diode laser fiber selective stimulation (DLss) technique allows to safely and selectively stimulate Aδ and C fibers in the superficial and deep skin layers. DLss data demonstrate that patients with painful DPN have increased Aδ fiber pain thresholds, while C-fiber thresholds are intact because, in these patients, CMi fibers are abnormally spontaneously active. It is also possible to determine the involvement of CMi fibers by measuring the area of DLss-induced neurogenic axon reflex flare. The differences in AMH, CMH, and CMi fibers identify patients with painful and painless neuropathy. In this review, we will discuss the role of CMi fibers in PDPN.

Characterization of Patients With and Without Painful Peripheral Neuropathy After Receiving Neurotoxic Chemotherapy: Traditional Quantitative Sensory Testing vs C-Fiber and Aδ-Fiber Selective Diode Laser Stimulation.

Painful chemotherapy induced peripheral neuropathy (CIPN) is a common complication of chemotherapy with drugs such as taxanes and platinum compounds. Currently, no methods are available for early detection of sensory changes that are associated with painful CIPN, nor are there biomarkers that are specific to painful CIPN. This study aimed to compare Diode Laser fiber type-selective stimulator (DLss), a method to selectively stimulate cutaneous C and Aδ fibers, to traditional quantitative sensory testing (QST) in determining psychophysical differences between patients with painful CIPN and a control group. Sensory testing was performed on the dorsal mid-foot of 20 patients with painful neuropathy after taxane- or platinum-based chemotherapy, and 20 patients who received similar neurotoxic chemotherapy, without painful CIPN. In a multivariable analysis, C-fiber to Aδ fiber detection threshold ratio, measured by DLss, was significantly different between the groups (P <.05). While QST parameters such as warmth detection threshold were different between the groups in univariate analyses, these findings were likely attributable to group differences in patient age and cumulative chemotherapy dose. PERSPECTIVE: In this study, fiber-specific DLss test showed potential in identifying sensory changes that are specific for painful neuropathy, encouraging future testing of this approach as a biomarker for early detection of painful CIPN. TRIAL REGISTRATION: The study was approved by the Washington University Institutional Review Board (#201807162) and registered at ClinicalTrials.gov (NCT03687970).

Selective nociceptor activation in volunteers by infrared diode laser.

BACKGROUND: Two main classes of peripheral sensory neurons contribute to thermal pain sensitivity: the unmyelinated C fibers and thinly myelinated Aδ fibers. These two fiber types may differentially underlie different clinical pain states and distinctions in the efficacy of analgesic treatments. Methods of differentially testing C and Aδ thermal pain are widely used in animal experimentation, but these methods are not optimal for human volunteer and patient use. Thus, this project aimed to provide psychophysical and electrophysiological evidence that whether different protocols of infrared diode laser stimulation, which allows for direct activation of nociceptive terminals deep in the skin, could differentially activate Aδ or C fiber thermonociceptors in volunteers. RESULTS: Short (60 ms), high intensity laser pulses (SP) evoked monomodal "pricking" pain which was not enhanced by topical capsaicin, whereas longer, lower power pulses (LP) evoked monomodal "burning" pain which was enhanced by topical capsaicin. SP also produced cortical evoked EEG potentials consistent with Aδ mediation, the amplitude of which was directly correlated with pain intensity but was not affected by topical capsaicin. LP also produced a distinct evoked potential pattern the amplitude of which was also correlated with pain intensity, which was enhanced by topical capsaicin, and the latency of which could be used to estimate the conduction velocity of the mediating nociceptive fibers. CONCLUSIONS: Psychophysical and electrophysiological data were consistent with the ability of short high intensity infrared laser pulses to selectively produce Aδ mediated pain and of longer pulses to selectively produce C fiber mediated thermal pain. Thus, the use of these or similar protocols may be useful in developing and testing novel therapeutics based on the differential molecular mechanisms underlying activation of the two fiber types (e.g., TRPV1, TRPV2, etc). In addition, these protocol may be useful in determining the fiber mediation of different clinical pain types which may, in turn be useful in treatment choice.