Painful peripheral neuropathy is the most common neurological complication associated with human ... more Painful peripheral neuropathy is the most common neurological complication associated with human immune deficiency virus (HIV) infection. Currently available treatments fail to provide adequate symptom relief, indicating the need for novel treatment strategies. To address this gap in knowledge, we characterized the impact of cannabinoid CB2 agonists, which lack psychoactivity associated with central CB1 activation, on antiretroviral-induced neuropathic nociception and identified cell types expressing CB2 that mediate the antinociceptive efficacy of CB2 agonists. Two structurally distinct CB2 agonists (AM1710 and LY2828360) alleviated antiretroviral-induced neuropathic pain, benefits which were absent in CB2 knockout mice. Conditional deletion of CB2 from peripheral sensory neurons eliminated the antinociceptive efficacy of CB2 agonists. We also asked whether LY2828360 treatment could reverse established morphine tolerance in the ddC-induced neuropathy model and whether CB2 expressio...
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating, and dose-limiting si... more Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating, and dose-limiting side effect of many chemotherapy regimens yet has limited treatments due to incomplete knowledge of its pathophysiology. Research on the pathophysiology of CIPN has focused on peripheral nerves because CIPN symptoms are felt in the hands and feet. However, better understanding the role of the brain in CIPN may accelerate understanding, diagnosing, and treating CIPN. The goals of this review are to (1) investigate the role of the brain in CIPN, and (2) use this knowledge to inform future research and treatment of CIPN. We identified 16 papers using brain interventions in animal models of CIPN and five papers using brain imaging in humans or monkeys with CIPN. These studies suggest that CIPN is partly caused by (1) brain hyperactivity, (2) reduced GABAergic inhibition, (3) neuroinflammation, and (4) overactivation of GPCR/MAPK pathways. These four features were observed in several brain regi...
Proceedings of the National Academy of Sciences, 1999
Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), the major psychoactive ingredient in preparations of Cannab... more Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Δ 9 -THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Δ 9 -THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological...
BackgroundThe phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promot... more BackgroundThe phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense.MethodsDuring the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements.ResultsCBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD...
The Journal of pharmacology and experimental therapeutics, 2017
GW405833, widely accepted as a cannabinoid receptor 2 (CB) agonist, suppresses pathologic pain in... more GW405833, widely accepted as a cannabinoid receptor 2 (CB) agonist, suppresses pathologic pain in preclinical models without the unwanted central side effects of cannabinoid receptor 1 (CB) agonists; however, recent in vitro studies have suggested that GW405833 may also behave as a noncompetitive CB antagonist, suggesting that its pharmacology is more complex than initially appreciated. Here, we further investigated the pharmacologic specificity of in vivo antinociceptive actions of GW405833 in models of neuropathic (i.e., partial sciatic nerve ligation model) and inflammatory (i.e., complete Freund's adjuvant model) pain using CB and CB knockout (KO) mice, their respective wild-type (WT) mice, and both CB and CB antagonists. GW405833 (3, 10, and 30 mg/kg i.p.) dose dependently reversed established mechanical allodynia in both pain models in WT mice; however, the antiallodynic effects of GW405833 were fully preserved in CBKO mice and absent in CBKO mice. Furthermore, the antiall...
Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved ... more Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved health problem. The management of neuropathic pain has two distinct goals-prevention of development and control of established neuropathic pain. We examined the impact of both prophylactic and therapeutic treatments with the tricyclic antidepressant desipramine on the development and maintenance of toxic neuropathic pain induced by the chemotherapeutic agent paclitaxel. We also investigated the involvement of endogenous analgesic (i.e., endogenous opioid and endocannabinoid) systems in the antinociceptive actions of desipramine in these two distinct phases of neuropathic pain. Chronic subcutaneous infusion of desipramine via osmotic pumps suppressed both the development and maintenance of paclitaxel-induced neuropathic pain. However, only prophylactic desipramine treatment blocked the development of neuropathic pain throughout the three month observation interval. The opioid receptor ant...
Cannabinoid 1 receptor (CB1R) allosteric ligands hold far-reaching therapeutic promise. We report... more Cannabinoid 1 receptor (CB1R) allosteric ligands hold far-reaching therapeutic promise. We report application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, arrestin2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.
Painful peripheral neuropathy is the most common neurological complication associated with human ... more Painful peripheral neuropathy is the most common neurological complication associated with human immune deficiency virus (HIV) infection. Currently available treatments fail to provide adequate symptom relief, indicating the need for novel treatment strategies. To address this gap in knowledge, we characterized the impact of cannabinoid CB2 agonists, which lack psychoactivity associated with central CB1 activation, on antiretroviral-induced neuropathic nociception and identified cell types expressing CB2 that mediate the antinociceptive efficacy of CB2 agonists. Two structurally distinct CB2 agonists (AM1710 and LY2828360) alleviated antiretroviral-induced neuropathic pain, benefits which were absent in CB2 knockout mice. Conditional deletion of CB2 from peripheral sensory neurons eliminated the antinociceptive efficacy of CB2 agonists. We also asked whether LY2828360 treatment could reverse established morphine tolerance in the ddC-induced neuropathy model and whether CB2 expressio...
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating, and dose-limiting si... more Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating, and dose-limiting side effect of many chemotherapy regimens yet has limited treatments due to incomplete knowledge of its pathophysiology. Research on the pathophysiology of CIPN has focused on peripheral nerves because CIPN symptoms are felt in the hands and feet. However, better understanding the role of the brain in CIPN may accelerate understanding, diagnosing, and treating CIPN. The goals of this review are to (1) investigate the role of the brain in CIPN, and (2) use this knowledge to inform future research and treatment of CIPN. We identified 16 papers using brain interventions in animal models of CIPN and five papers using brain imaging in humans or monkeys with CIPN. These studies suggest that CIPN is partly caused by (1) brain hyperactivity, (2) reduced GABAergic inhibition, (3) neuroinflammation, and (4) overactivation of GPCR/MAPK pathways. These four features were observed in several brain regi...
Proceedings of the National Academy of Sciences, 1999
Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), the major psychoactive ingredient in preparations of Cannab... more Δ 9 -Tetrahydrocannabinol (Δ 9 -THC), the major psychoactive ingredient in preparations of Cannabis sativa (marijuana, hashish), elicits central nervous system (CNS) responses, including cognitive alterations and euphoria. These responses account for the abuse potential of cannabis, while other effects such as analgesia suggest potential medicinal applications. To study the role of the major known target of cannabinoids in the CNS, the CB1 cannabinoid receptor, we have produced a mouse strain with a disrupted CB1 gene. CB1 knockout mice appeared healthy and fertile, but they had a significantly increased mortality rate. They also displayed reduced locomotor activity, increased ring catalepsy, and hypoalgesia in hotplate and formalin tests. Δ 9 -THC-induced ring-catalepsy, hypomobility, and hypothermia were completely absent in CB1 mutant mice. In contrast, we still found Δ 9 -THC-induced analgesia in the tail-flick test and other behavioral (licking of the abdomen) and physiological...
BackgroundThe phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promot... more BackgroundThe phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense.MethodsDuring the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements.ResultsCBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD...
The Journal of pharmacology and experimental therapeutics, 2017
GW405833, widely accepted as a cannabinoid receptor 2 (CB) agonist, suppresses pathologic pain in... more GW405833, widely accepted as a cannabinoid receptor 2 (CB) agonist, suppresses pathologic pain in preclinical models without the unwanted central side effects of cannabinoid receptor 1 (CB) agonists; however, recent in vitro studies have suggested that GW405833 may also behave as a noncompetitive CB antagonist, suggesting that its pharmacology is more complex than initially appreciated. Here, we further investigated the pharmacologic specificity of in vivo antinociceptive actions of GW405833 in models of neuropathic (i.e., partial sciatic nerve ligation model) and inflammatory (i.e., complete Freund's adjuvant model) pain using CB and CB knockout (KO) mice, their respective wild-type (WT) mice, and both CB and CB antagonists. GW405833 (3, 10, and 30 mg/kg i.p.) dose dependently reversed established mechanical allodynia in both pain models in WT mice; however, the antiallodynic effects of GW405833 were fully preserved in CBKO mice and absent in CBKO mice. Furthermore, the antiall...
Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved ... more Neuropathic pain impacts approximately 3-4.5% of the global population and remains an unresolved health problem. The management of neuropathic pain has two distinct goals-prevention of development and control of established neuropathic pain. We examined the impact of both prophylactic and therapeutic treatments with the tricyclic antidepressant desipramine on the development and maintenance of toxic neuropathic pain induced by the chemotherapeutic agent paclitaxel. We also investigated the involvement of endogenous analgesic (i.e., endogenous opioid and endocannabinoid) systems in the antinociceptive actions of desipramine in these two distinct phases of neuropathic pain. Chronic subcutaneous infusion of desipramine via osmotic pumps suppressed both the development and maintenance of paclitaxel-induced neuropathic pain. However, only prophylactic desipramine treatment blocked the development of neuropathic pain throughout the three month observation interval. The opioid receptor ant...
Cannabinoid 1 receptor (CB1R) allosteric ligands hold far-reaching therapeutic promise. We report... more Cannabinoid 1 receptor (CB1R) allosteric ligands hold far-reaching therapeutic promise. We report application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, arrestin2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.
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Papers by Andrea Hohmann