Operant nociception in nonhuman primates

Abstract

The effective management of pain is a longstanding public health concern. Morphine-like opioids have long been front-line analgesics, but produce undesirable side effects that can limit their application. Slow progress in the introduction of novel improved medications for pain management over the last 5 decades has prompted a call for innovative translational research, including new preclinical assays. Most current in vivo procedures (e.g., tail flick, hot plate, warm water tail withdrawal) assay the effects of nociceptive stimuli on simple spinal reflexes or unconditioned behavioral reactions. However, clinical treatment goals may include the restoration of previous behavioral activities, which can be limited by medication-related side-effects that are not measured in such procedures. The present studies describe an apparatus and procedure to study the disruptive effects of nociceptive stimuli on voluntary behavior in nonhuman primates, and the ability of drugs to restore such behavior through their analgesic actions. Squirrel monkeys were trained to pull a cylindrical thermode for access to a highly palatable food. Next, sessions were conducted in which the temperature of the thermode was increased stepwise until responding stopped, permitting the determination of stable nociceptive thresholds. Tests revealed that several opioid analgesics, but not d-amphetamine or Δ9-THC, produced dose-related increases in threshold that were antagonist-sensitive and efficacy-dependent, consistent with their effects using traditional measures of antinociception. Unlike traditional reflex-based measures, however, the results also permitted the concurrent evaluation of response disruption, providing an index with which to characterize the behavioral selectivity of antinociceptive drugs.

Evaluation of different drug classes on transient sciatic nerve injury–depressed marble burying in mice

“…acid-induced depression of feeding or wheel running in mice [48], i.p. acid-induced depression of feeding or positively reinforced operant behavior in rats, intraplantar formalin-induced depression of operant responding in rats, or noxious-heat-induced depression of operant responding squirrel monkeys [31,39,42,48]. The effects of LEI101 are consistent with previous reports showing that CB 2 receptor agonists reverse CCI-induced behaviors [36,71].…”

Effects of stimulation of mu opioid and nociceptin/orphanin FQ peptide (NOP) receptors on alcohol drinking in rhesus monkeys

“…This result may suggest that NOP receptor stimulation alone is sufficient to reduce alcohol drinking, in agreement with rodent studies [26,27,30]. However, the dose of SCH 221510 required to reduce ethanol drinking was higher than the dose needed to produce antinociception in a previous study [80]. Although the discrepancy might be explained by different efficacy requirements between the two assays, the large potency difference could also indicate that the reduction in drinking resulted from activity at other receptors.…”

Core Outcome Measures in Preclinical Assessment of Candidate Analgesics

“…Other types of operant procedures have also been developed to establish thermal or mechanical punishment of operant behavior in rodents (Mauderli et al, 2000; Boada et al, 2016; Harte et al, 2016) and squirrel monkeys (Kangas and Bergman, 2014). These procedures include “place-escape/avoidance” procedures, in which subjects locomote within an environment with different zones, and entry into a subset of zones results in the delivery of a putative noxious stimulus (e.g., contact with a cooled or heated thermal plate or delivery of mechanical stimuli to the paw) (Pedersen and Blackburn-Munro, 2006; Fuchs and McNabb, 2012; Corder et al, 2019).…”