Pain and U-Shaped Dose Responses: Occurrence, Mechanisms, and Clinical Implications

Abstract

This article assesses pain within the context of the dose response. A substantial number of studies indicate that the dose response for pain-related endpoints is commonly biphasic, being independent of the type of biological model employed, endpoint measured, or agent tested. The quantitative features of the dose response are also remarkably consistent regardless of the receptor pathway that mediates the nociceptive response, indicating a likely downstream message convergence. These findings have important implications for drug discovery, development, and clinical evaluation.

Endogenous Opioid Antagonism in Physiological Experimental Pain Models: A Systematic Review

“…Naloxone, with a rapid onset and short duration of action, is suited for acute management of opioid-induced serious adverse effects [ 24 ] and is administered in IV doses of 0.04 mg to 0.4 mg [ 76 ]. Interestingly, naloxone expresses a dose-dependent, biphasic response with low doses producing analgesia and high doses producing hyperalgesia, both in animal inflammatory models [ 77 ] and in clinical models [ 78 – 80 ].…”

The role of hormesis in the functional performance and protection of neural systems

“…),[ 31 32 33 ] and reducing damage from stroke and traumatic brain injury. [ 34 ] Hormetic effects were also shown to facilitate neurite outgrowth,[ 35 ] modulate pain,[ 36 ] mediate stress responses,[ 37 ] and enhance adaptive responses in astrocytes. [ 38 ] Hormetic responses were extensively observed in studies assessing pharmacological interventions to enhance memory,[ 33 ] decrease anxiety,[ 39 ] prevent seizure onset, and reduce seizure severity.…”

“…Hormetic dose-response effects appear to be involved in the action of pharmacological agents that have been shown to enhance social interactions,[ 39 ] decrease anxiety,[ 39 ] reduce pain,[ 36 ] and enhance memory[ 33 ] [ Figure 1 ]. In this latter regard, it is noteworthy that all drugs currently approved by the United States Food and Drug Administration to relieve symptoms of Alzheimer's disease and to reduce seizures have been shown to display hormetic dose responses during preclinical phases of testing in animal models.…”

Heat shock proteins and hormesis in the diagnosis and treatment of neurodegenerative diseases

“…Of relevance to the present paper is that the hormetic dose response has been extensively reported across the spectrum of neuroscience research, including anxiolytic drugs [ 132 ], anti-seizure agents [ 133 ], pain [ 134 ] memory enhancing drugs [ 135 ], brain traumatic injury [ 136 ] several neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease as well as for neurite outgrowth [ 137 ] and as astrocyte functioning [ 138 ]. Puzzo et al [ 139 ] also reported that β-amyloid 25–35 enhanced LTP within a very detailed dose response study, clearly demonstrating an hormetic dose response.…”