Forebrain medial septum region facilitates nociception in a rat formalin model of inflammatory pain

Abstract

The medial septum is anatomically and functionally linked to the hippocampus, a region implicated in nociception. However, the role of medial septum in nociception remains unclear. To investigate the role of the region in nociception in rats, muscimol, a GABA agonist, or zolpidem, a positive allosteric modulator of GABA(A) receptors, was microinjected into medial septum to attenuate the activity of neurons in the region. Electrophysiological studies in anesthetized rats indicated that muscimol evoked a stronger and longer-lasting suppression of medial septal-mediated activation of hippocampal theta field activity than zolpidem. Similarly, microinjection of muscimol (1 or 2 μg/0.5 μl) into the medial septum of awake rats suppressed both licking and flinching behaviors in the formalin test of inflammatory pain, whereas only the latter behavior was affected by zolpidem (8 or 12 μg/0.5 μl) administered into the medial septum. Interestingly, both drugs selectively attenuated nociceptive behaviors in the second phase of the formalin test that are partly driven by central plasticity. Indeed, muscimol reduced the second phase behaviors by 30% to 60%, which was comparable to the reduction seen with systemic administration of a moderate dose of the analgesic morphine. The reduction was accompanied by a decrease in formalin-induced expression of spinal c-Fos protein that serves as an index of spinal nociceptive processing. The drug effects on nociceptive behaviors were without overt sedation and were distinct from the effects observed after septal lateral microinjections. Taken together, these findings suggest that the activation of medial septum is pro-nociceptive and facilitates aspects of central neural processing underlying nociception.

Analgesic Effect of 17β-Estradiol on Nucleus Paragigantocellularis Lateralis of Male Rats Mediated Via GABAA Receptors

“…Also, Kaneko and Hammond indicated that intrathecal injection of bicuculline significantly increased the number of flinches and weighted nociceptive behavior scores in the second phase in rats (Kaneko & Hammond, 1997). Similar to our findings, Lee et al showed that microinjection of muscimol (1 or 2 μg/0.5 μL) into the medial septum of awake rats suppressed both licking and flinching behaviors during the formalin test of inflammatory pain (Lee et al, 2011). Furthermore, intrathecal application of bicuculline, or the glycine receptor antagonist, strychnine, can elicit allodynia (Torsney & Mac-Dermott, 2006).…”

GABAergic neurons of the medial septum play a nodal role in facilitation of nociception-induced affect

“…6b ; t 17 = 2.40, p < 0.05, unpaired t-test). Likewise, intraperitoneal administration of an analgesic dose of morphine 9 (5 mg/kg, n = 7) also abolished F-CPA vs. animals administered with vehicle (n = 7; Fig. 6c ; t 12 = 2.63 p < 0.05, unpaired t-test).…”

“…The present study, juxtaposed with our published data, provides evidence which suggests that the medial septum is a nodal centre in the forebrain that modulates a range of behaviours to noxious-aversive stimuli. In this context, we have previously shown that the MSDB facilitates acute nociceptive behaviours and spinal nociceptive transmission in the formalin model of persistent inflammatory pain 9 . In the present study, we report the novel findings that KA-induced lesion of the MSDB region abolished the expression of formalin-induced affective behaviour, which was assessed using the F-CPA task.…”

“…In this regard, experimental lesion or pharmacological manipulation of the ACC and the basolateral amygdala (BLA) indicate that these regions selectively attenuate aversion, induced on conditioning with the algogen, formalin, without attenuating acute nociception while manipulation of the hippocampus modulates formalin-induced acute nociceptive behaviours 1 2 3 4 . Interestingly, each of the above area is interconnected with the basal forebrain, including the medial septum diagonal band region (MSDB), which is also implicated in affect 5 6 7 8 9 10 11 . Indeed, more recent evidence suggests that the region facilitates acute nociception in the formalin model of persistent inflammatory pain 9 .…”

“…Interestingly, each of the above area is interconnected with the basal forebrain, including the medial septum diagonal band region (MSDB), which is also implicated in affect 5 6 7 8 9 10 11 . Indeed, more recent evidence suggests that the region facilitates acute nociception in the formalin model of persistent inflammatory pain 9 . However, at present it is not known whether the region modulates aversion as well.…”