Michele Hummel

The persistence of a long-term negative affective state following the induction of either acute or chronic pain.

Abstract Clinically, pain is a complex phenomenon consisting of both sensory and affective aberrations that can persist indefinitely. Pre‐clinically, several animal paradigms have been established that reliably mimic both the acute and chronic aspects of pain pertinent to the human condition; however, the commonly used behavioral models only assess the sensory component of pain elicited by an evoked nociceptive stimulus. Since the affective‐motivational component of pain is an important determinant of the overall pain experience in man, we investigated how this aspect may be modeled long‐term in rats using novel objects and a modified conditioned place aversion (CPA) paradigm. Findings demonstrate that animals subjected to either neuropathic injury or inflammatory insult display a significant conditioned place aversion to a pain‐paired environment that is paralleled by an increased number of hind paw withdrawals and fewer number of novel object interactions during painful conditioning sessions. Moreover, this aversion is maintained for 1 month in the absence of further conditioning. We also determined that a non‐analgesic, non‐rewarding dose of morphine administered prior to pain‐paired conditioning sessions attenuates the pain‐induced aversion and its relative persistence in both pain models. Together, these findings underscore the importance of negative affect accompanying painful conditions and its long‐term persistence even when the injury or insult has resolved. Lastly, these results suggest how both sensory and affective aberrations associated with neuropathic‐ and inflammatory‐like conditions and the memory of such known to impact quality of life in man may be addressed pre‐clinically in rodents.

Pain is a salient “stressor” that is mediated by corticotropin-releasing factor-1 receptors

Corticotropin-releasing factor (CRF) plays a major role in controlling the bodys response to stress. Because painful conditions are inherently stressful, we hypothesize that CRF may act via CRF-1 receptors to contribute to the pain experience. Studies were designed to investigate whether blocking CRF-1 receptors with selective antagonists or reducing their expression with CRF-Saporin, would attenuate ulcer, inflammatory- and neuropathic-like pain. Five experimental designs were undertaken. In experiment 1, ulcer pain was induced in mice following oral administration of indomethacin, while in experiments 2 and 3, inflammatory pain was induced in rats with either carrageenan or FCA, respectively. For these studies, animals were dosed with CP-154,526 (3, 10, 30 mg/kg) and NBI 27914 (1-30 mg/kg) 1 h prior to the assessment of tactile, thermal or mechanical hypersensitivity, respectively. In experiment 4, neuropathic pain was induced. Twenty-one days following spinal nerve ligation (SNL), animals received CRF-Saporin or control. Three weeks later tactile allodynia was assessed. Similarly, in experiment 5, a separate set of rats received CRF-Saporin or control. Twenty-one days later, mechanical hyperalgesia was assessed following intraplantar carrageenan. Results from the antagonist studies showed that CP-154,526 and NBI 27914 either fully or partially reversed the referred ulcer pain with minimal effective doses (MED) equal to 3 and 10 mg/kg, respectively. Similarly, both NBI 27914 and CP-154,526 reversed the thermal and mechanical hypersensitivity elicited by carrageenan and FCA with MEDs </= 5 and 10 mg/kg, respectively. Findings from the two CRF-Saporin studies determined that pre-treatment with this toxin significantly attenuated SNL- and carrageenan-induced tactile hypersensitivity. Together, these findings suggest that CRF-1 receptors mediate pain and implicate CRF in this regard.

CNS penetration of small molecules following local inflammation, widespread systemic inflammation or direct injury to the nervous system.

AIMS We sought to investigate effects of local and systemic inflammation on CNS permeability of small molecules and compare these to effects of direct injury to the nervous system. MAIN METHODS Evans blue was used to determine the integrity of the blood-brain barrier (BBB) following local inflammation, systemic inflammation, injury to the L5 spinal nerve or transient occlusion of the middle cerebral artery. In addition, three compounds having low, medium and high brain permeability (atenolol, morphine and oxycodone, respectively) were used. Following model establishment (4-hr post-carrageenan, 24-hr post-FCA, 2-, 4- and 24-hr post-LPS, 21 days post-nerve injury) compounds were administered and 30 min later the brain, spinal cord and blood removed. The plasma and tissue concentrations of compounds were quantified by LC/MS/MS. KEY FINDINGS Localized inflammation did not affect Evans blue penetration into the CNS but significantly increased morphine penetration into the spinal cord. Systemic inflammation increased the quantity of Evans blue in the CNS but also decreased the penetration of atenolol, morphine and oxycodone into the brain 4-hr post-insult. Nerve injury had no effect on Evans blue or compound penetration, while middle cerebral artery occlusion resulted in a large but short lived increase in Evans blue penetration into both the cortex and striatum. SIGNIFICANCE The presence of inflammation may affect the CNS penetration of some compounds but is unlikely to lead to a large non-selective BBB breakdown. As a result, it is appropriate to test for side-effects, and conduct brain pharmacokinetic determinations, in naïve rats.

A randomized, double-blind, positive-controlled, 3-way cross-over human experimental pain study of a TRPV1 antagonist (V116517) in healthy volunteers and comparison with preclinical profile.

Abstract This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus–response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus–response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.

Pharmacological evaluation of NSAID-induced gastropathy as a "Translatable" model of referred visceral hypersensitivity

AIM To evaluate whether non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastropathy is a clinically predictive model of referred visceral hypersensitivity. METHODS Gastric ulcer pain was induced by the oral administration of indomethacin to male, CD1 mice (n = 10/group) and then assessed by measuring referred abdominal hypersensitivity to tactile application. A diverse range of pharmacological mechanisms contributing to the pain were subsequently investigated. These mechanisms included: transient receptor potential (TRP), sodium and acid-sensing ion channels (ASICs) as well as opioid receptors and guanylate cyclase C (GC-C). RESULTS Results showed that two opioids and a GC-C agonist, morphine, asimadoline and linaclotide, respectively, the TRP antagonists, AMG9810 and HC-030031 and the sodium channel blocker, carbamazepine, elicited a dose- and/or time-dependent attenuation of referred visceral hypersensitivity, while the ASIC blocker, amiloride, was ineffective at all doses tested. CONCLUSION Together, these findings implicate opioid receptors, GC-C, and sodium and TRP channel activation as possible mechanisms associated with visceral hypersensitivity. More importantly, these findings also validate NSAID-induced gastropathy as a sensitive and clinically predictive mouse model suitable for assessing novel molecules with potential pain-attenuating properties.