The Antinociceptive Effect of Milnacipran in the Monosodium Iodoacetate Model of Osteoarthritis Pain and Its Relation to Changes in Descending Inhibition

Abstract

Osteoarthritis (OA) is a chronic joint disorder whose principal symptom is chronic pain. Current analgesics are inadequate and the mechanisms contributing to this pain are poorly understood but likely to include both local joint changes and central consequences. These studies used monoamine receptor agents combined with behavioral studies and single-unit dorsal horn recordings to examine whether descending noradrenergic and serotonergic inhibitions are altered in the monosodium iodoacetate model of OA pain, and whether increasing these inhibitions with the serotonin/noradrenaline reuptake inhibitor milnacipran can attenuate the attendant hypersensitivity. Early and late in the course of this model, milnacipran (s.c.) reduced behavioral hypersensitivity, and inhibited evoked responses from sensitized dorsal horn neurons. In naïve animals and the early, but not late, phase of the model, spinal administration of the a 2 -adrenoceptor antagonist atipamezole fully reversed this neuronal inhibition, whereas atipamezole administered alone revealed that endogenous noradrenergic inhibition was reduced in the late phase. Blocking spinal 5-hydroxytryptamine-7 receptors with (2R)-1-[(3-hydroxyphenyl) sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride suggested that the effects of milnacipran in the late phase were partly mediated by these receptors, and that descending serotonergic inhibition was increased in this phase. An opioidergic mechanism behind the effects of milnacipran was indicated by a partial reversal of these effects with naloxone. These studies demonstrate antinociceptive effects for milnacipran in a model of OA pain, whose effects come via descending serotonergic and noradrenergic, as well as opioidergic, pathways. Variations in the activity of these pathways over the course of this model may contribute to the presence of behavioral hypersensitivity and determine through which endogenous systems milnacipran exerts its effects.

Central Sensitization and Neuropathic Features of Ongoing Pain in a Rat Model of Advanced Osteoarthritis

“…These observations are consistent with other studies reporting signs of neuropathic pain during the late phase of MIA-induced osteoarthritis 5, 17, 38 . Several studies demonstrated that MIA-induced late phase hypersensitivity and weight asymmetry are resistant to anti-inflammatory drugs (e.g.…”

“…gabapentin, pregabalin) and reuptake inhibitors (e.g. amitryptaline, and milnacipran) are effective 5, 17, 38 . Notably, the concentration of MIA used in these studies (2 mg/25 μl corresponding to 80 mg/ml MIA) is the same as that used in our studies (4.8 mg/60 μl corresponding to 80 mg/ml).…”

What goes up must come down: insights from studies on descending controls acting on spinal pain processing

“…Indeed, a clinical study using fMRI identified an abnormal descending facilitatory system from the PAG to the spinal cord in patients with hip OA and descriptions of neuropathic pain (Gwilym et al 2009). An adaptive descending system has also been identified in the MIA model (Rahman et al 2009;Burnham and Dickenson 2013). First, a 5-HT 3 receptor antagonist inhibited evoked responses to innocuous stimuli yet did not produce this effect in controls, indicating an alteration in the facilitatory serotonergic system acting at 5-HT 3 receptors in the spinal cord was modulating low threshold neuronal responses akin to that seen after neuropathy (Rahman et al 2009).…”

Calcium channel modulation as a target in chronic pain control

“…As described earlier, rodent models of osteoarthritis can share common features with neuropathy resulting from peripheral nerve damage, for example, concurrent time‐dependent increases in descending facilitatory drive and loss of descending noradrenergic inhibition (Rahman et al, ; Burnham and Dickenson, ). Hence, the effects of TROX‐1 were additionally examined in the rat intra‐articular iodoacetate model of osteoarthritis, where treatment with TROX‐1 reversed behavioural hypersensitivity and weight‐bearing behaviour (Abbadie et al, ).…”