Preclinical Models of Nociception

pain

an unpleasant subjective sensory and emotional experience associated with actual or potential tissue damage

analgesia

a selective reduction in pain without affecting other sensory modalities

anesthesia

non-selective reduction in pain and all other sensory modalities

noxious stimulus

a stimulus capable of causing tissue damage

nociception

the neural process of encoding a noxious stimulus, resulting in a stimulus-induced change in physiology or behavior

antinociception

a decrease in nociception induced by a drug/manipulation

allodynia

a pain-like response to a stimulus that would normally be innocuous

hyperalgesia

an exaggerated pain-like response to a normally noxious stimulus

hypersensitivity

increased sensitivity to stimuli in general, including allodynia and hyperalgesia

assay sensitivity

treatments that produce analgesia in humans also produce antinociception in animal models

assay selectivity

treatment that fails to produce analgesia in humans also fails to produce antinociception in animal models

4 types of pain stimuli

-acute noxious stimuli

-inflammatory stimuli

-neuropathic stimuli

-disease state stimuli

acute noxious stimuli

types of pain stimuli that are able to produce tissue damage; models surgical pain and acute injuries

examples of acute noxious stimuli

-thermal (heat → Hargreaves)

-mechanical (pressure → von Frey)

-chemical (acid injection)

inflammatory stimuli

type of chronic pain stimulus that activates or mimics local or systemic inflammatory processes; models arthritis and inflammatory pain

ex: injection of Complete Freund's Adjuvant, Carrageenan, or lipopolysaccharides (all foreign substances)

neuropathic stimulus

type of chronic pain stimulus that damages peripheral sensory or central neurons; models sciatica and chemotherapy-induced neuropathic pain

ex: nerve ligation/constriction or chemotherapy

disease state stimulus

type of chronic pain stimulus involving specific treatments that model a specific disease and the pain associated with that disease

ex: diabetes, bone cancer, and migraines can be modeled via injection with a specific molecule

evocative acute stimulus

a pain stimulus that can be added to chronic pain models at certain time points to determine how chronic pain effects sensitivity to an acute pain stimulus

pain-stimulated unconditioned behavior (PS→UR)

ex: IP acid injection (PS) stimulates stretching behavior in mice (UR); drugs can be evaluated for effectiveness to reduce IP acid-induced stretching

assays are sensitive to but NOT selective for analgesics because other drugs can produce general motor impairment that appears like an antinociceptive effect (false positive)

pain-depressed unconditioned behavior (PS→[US→UR])

ex: IP acid injection (PS) depresses nesting behavior (UR) when nestlet is presented (US); drugs can be evaluated for effectiveness to attenuate IP acid-induced depression of nesting

assays are sensitive to and selective for analgesics because drugs that produce motor impairment will not bring behavior back up to baseline and may decrease behavior even more than PS alone

pain stimulus discrimination (PS→R→SC)

animal is trained to respond for food on one lever following pain stimulus treatment and on another lever following control treatment and then tested with pain stimulus + drug to see which lever it responds on; effective analgesic would produce responding on control lever because animal is not experiencing subjective effects of pain stimulus

decrease general behavior

pain stimulus discrimination has never been done successfully because pain stimuli usually _____ to the point that the animal will not respond

pain stimulus punishment (SD→R→PS)

animal is trained to drink milk with face in between two bars that can have temperature manipulated; at room temperature, animal will freely drink milk, but when bars are heated the animal must experience pain stimulus in order to drink milk, so behavior decreases, which can be further exacerbated by pretreatment with an evocative acute pain stimulus (ex: Carrageenan), resulting in a hypersensitivity to the thermal stimulus; drugs can be evaluated for their ability to attenuate punishment of drinking behavior

pain-depressed operant behavior (PS→[SD→R→SC])

pain stimulus will depress ICSS and induce rightward shift in DEC; drugs can be evaluated for their ability to attenuate PS-induced depression of ICSS back to baseline levels

assay is sensitive to and selective for analgesics because drugs that produce motor impairment will not bring behavior back up to baseline and may decrease behavior even more than PS alone