Imaging Drugs with and without Clinical Analgesic Efficacy

Abstract

The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with m-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK 1 receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

“…One consequence of this is that pain‐related targets in one species have strikingly different expression patterns or functions from that of the human homolog (Upadhyay et al. 2011; Chen et al. 2013; Hirai and Hama 2014).…”

“…A combination of invasive procedures, such as electrophysiology and in vivo microdialysis, and noninvasive in vivo imaging could provide useful information regarding duloxetine's site of action and mechanism and set the stage for the development of novel analgesics (Upadhyay et al. 2011). …”

Parallel Buprenorphine phMRI Responses in Conscious Rodents and Healthy Human Subjects

“…On the basis of the work of Schwarz et al and Vollm et al, functional changes in the brain driven by an amphetamine challenge elicited correlated responses in reward circuitry in rodents and humans, respectively (Vollm et al, 2004;Schwarz et al, 2007). Furthermore, brain circuitry, such as the defaultmode network, that were initially observed in nonhuman primates and humans (Raichle et al, 2001;Vincent et al, 2007), have recently been measured to a great extent in the rodent brain (Becerra et al, 2011b;Upadhyay et al, 2011;Lu et al, 2012). This is also true for other networks, such as the striatal system (Becerra et al, 2011b;Jonckers et al, 2011;Liang et al, 2011;Majeed et al, 2011).…”

“…The full drug or placebo delivery was performed over four injections to minimize respiratory depression, which is known to occur after opioid administration. This procedure has been implemented in previous phMRI studies in which pharmacodynamic effects of morphine have been investigated (Borras et al, 2004;Becerra et al, 2006;Leppa et al, 2006;Upadhyay et al, 2011).…”

“…Recently, we reported on the central, dose-dependent pharmacodynamic effects of buprenorphine in humans with use of functional imaging methodology, in part, to further understand the neurobiological mechanisms underlying its analgesic properties (Borras et al, 2004;Becerra et al, 2006;Leppa et al, 2006;Upadhyay et al, 2011). Although buprenorphine is an opioid that has potency for multiple opioid receptor types (m-, d-, and k-opioid-like receptor 1/ nociceptin) (Sadee et al, 1982;Rothman et al, 1995;Hawkinson et al, 2000;Huang et al, 2001), the partial agonist action of buprenorphine at supraspinal m-opioid receptor site is thought to be the major driver of its analgesic effect (Lutfy et al, 2003;Ide et al, 2004).…”